DEXTROAMPHETAMINE: 2,148 Adverse Event Reports & Safety Profile

DESCRIPTION Dextroamphetamine Sulfate, USP is the dextro isomer of the compound d,l -amphetamine sulfate, a sympathomimetic amine of the amphetamine group. Chemically, dextroamphetamine is d -alpha-methylphenethylamine, and is present in all forms of dextroamphetamine sulfate extended-release as the neutral sulfate. Structural formula: Each extended-release capsule is so prepared that an initial dose is released promptly and the remaining medication is released gradually over a prolonged period.

Each

5 mg capsule, with a light brown opaque cap and body, contains 5 mg of dextroamphetamine sulfate, USP.

The

5 mg capsule is printed with and 0303 on both cap and body in black ink.

Each

10 mg capsule, with a light brown opaque cap and light orange transparent body, contains 10 mg of dextroamphetamine sulfate, USP.

The

10 mg capsule is printed with and 0304 on both cap and body in black ink.

Each

15 mg capsule, with a light brown opaque cap and light orange transparent body, contains 15 mg of dextroamphetamine sulfate, USP.

The

15 mg capsule is printed with and 0305 on both cap and body in black ink. Inactive ingredients: ethylcellulose dispersion type B (which contains, ethylcellulose, medium chain triglycerides, oleic acid, ammonium hydroxide and water), hydroxypropyl cellulose, hypromellose 2910, polyethylene glycol 400 & 8000, purified water, sugar spheres (which contain sucrose and corn starch), and talc. The capsule shells of the 5 mg, 10 mg and 15 mg contain carboxymethylcellulose, gelatin, iron oxide black, iron oxide red, iron oxide yellow, silicon dioxide, sodium lauryl sulfate, titanium dioxide. In addition, the 10 mg and 15 mg capsule shell contains D&C yellow # 10, FD&C red # 40. The capsule shells are imprinted with black ink which contains: ammonium hydroxide, black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution. 1 2 3 4

INDICATIONS AND USAGE Dextroamphetamine sulfate extended-release capsules are indicated in: Narcolepsy Attention Deficit Disorder with Hyperactivity As an integral part of a total treatment program that typically includes other measures (psychological, educational, social) for patients (ages 6 years to 16 years) with this syndrome. A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of the hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go”; excessive talking; blurting answers; can’t wait turn; intrusive.

The Combined

Type requires both inattentive and hyperactive-impulsive criteria to be met.

Special Diagnostic Considerations

Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use of medical and special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presences of the required number of DSM-IV characteristics. Need for Comprehensive Treatment Program Dextroamphetamine sulfate extended-release capsules are indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Stimulants are not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms. Limitations of Use The use of dextroamphetamine sulfate extended-release capsules 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 PRECAUTIONS, Pediatric Use ).

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) <span class="opacity-50 text-xs">[see WARNINGS AND PRECAUTIONS (5.2) ]</span> . the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating XELSTRYM <span class="opacity-50 text-xs">[see WARNINGS AND PRECAUTIONS (5.11) ]</span> .

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 <span class="opacity-50 text-xs">[see WARNINGS AND PRECAUTIONS (5.9) ]</span> . 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 <span class="opacity-50 text-xs">[see WARNINGS AND PRECAUTIONS (5.10) ]</span> . When heat is applied to XELSTRYM after application, both the rate and the extent of absorption are increased <span class="opacity-50 text-xs">[see CLINICAL PHARMACOLOGY (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see DOSAGE AND ADMINISTRATION (2.2) ]</span> . Do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine base compositions and differing pharmacokinetic profiles <span class="opacity-50 text-xs">[see CLINICAL PHARMACOLOGY (12.3) ]</span> .

2.5 Dosage in Patients with Renal Impairment In patients with severe renal impairment (GFR 15 to &lt; 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 &lt; 15 mL/min/1.73 m 2 ) patients is 9 mg/9 hours <span class="opacity-50 text-xs">[see USE IN SPECIFIC POPULATIONS (8.6) ]</span>.

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 <span class="opacity-50 text-xs">[see DRUG INTERACTIONS (7.1) ]</span>.

CONTRAINDICATIONS Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma. Agitated states. Patients with a history of drug abuse. Known hypersensitivity or idiosyncrasy to amphetamine. In patients known to be hypersensitive to amphetamine, or other components of dextroamphetamine sulfate. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [see Adverse Reactions ]. Patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Drug Interactions ].

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) <span class="opacity-50 text-xs">[see CLINICAL TRIALS (14) ]</span> .

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.

AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease ( 5.2 )

Increased Blood

Pressure and Heart Rate: Monitor blood pressure and pulse ( 5.3 )

Psychiatric Adverse

Reactions: Prior to initiating XELSTRYM, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing XELSTRYM ( 5.4 ) Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted ( 5.5 )

Peripheral

Vasculopathy, including Raynaud’s phenomenon: Careful observation for digital changes is necessary during XELSTRYM treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy ( 5.6 )

Serotonin

Syndrome: Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue XELSTRYM and initiate supportive treatment ( 5.7 , 10 )

Contact

Sensitization: Use of XELSTRYM may lead to contact sensitization. Discontinue XELSTRYM if contact sensitization is suspected ( 5.8 )

Application Site

Reactions: During wear time or immediately after removal of XELSTRYM, local skin reactions may occur. Select a different application site each day to limit the occurrence of skin reactions ( 5.9 )

External

Heat: Avoid exposing XELSTRYM to external heat sources during wear because both the rate and extent of absorption are increased ( 5.10 ) Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Before initiating XELSTRYM, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate ( 5.11 )

5.1 Abuse, Misuse, and Addiction XELSTRYM has a high potential for abuse and misuse. The use of XELSTRYM exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. XELSTRYM can be diverted for non-medical use into illicit channels or distribution <span class="opacity-50 text-xs">[see Drug Abuse and Dependence (9.2) ]</span> . Misuse and abuse of CNS stimulants, including XELSTRYM, can result in overdose and death <span class="opacity-50 text-xs">[see Overdosage (10) ]</span> , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing XELSTRYM, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store XELSTRYM in a safe place, preferably locked, and instruct patients to not give XELSTRYM to anyone else. Throughout XELSTRYM treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid XELSTRYM use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Monitor all XELSTRYM-treated patients for potential tachycardia and hypertension.

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 manic or mixed episode in patients. Prior to initiating XELSTRYM treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, and depression).

New

Psychotic or Manic Symptoms CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing XELSTRYM.

5.5 Long-Term Suppression of Growth in Pediatric Patients XELSTRYM is not approved for use and is not recommended in pediatric patients below 6 years of age <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span>. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in XELSTRYM-treated pediatric patients treated with CNS stimulants, including XELSTRYM. In a 7-week trial with a dose-optimization phase and a placebo-controlled phase of XELSTRYM in pediatric patients 6 to 17 years old with ADHD, there was a mean decrease in weight while taking XELSTRYM. Additionally, in studies of another CNS stimulant, there was slowing of the increase in height <span class="opacity-50 text-xs">[see ADVERSE REACTIONS (6.1) ]</span> . Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. XELSTRYM is not approved for use in pediatric patients below 6 years of age <span class="opacity-50 text-xs">[see USE IN SPECIFIC POPULATIONS (8.4) ]</span> .

5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including XELSTRYM, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud&apos;s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud&apos;s phenomenon, were observed in post-marketing reports and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during XELSTRYM treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for XELSTRYM-treated patients who develop signs or symptoms of peripheral vasculopathy.

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&apos;s Wort <span class="opacity-50 text-xs">[see DRUG INTERACTIONS (7.1) ]</span> . 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 <span class="opacity-50 text-xs">[see DRUG INTERACTIONS (7.1) ]</span> . 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 <span class="opacity-50 text-xs">[see CONTRAINDICATIONS (4) ]</span> . 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 <span class="opacity-50 text-xs">[see CONTRAINDICATION (4) ]</span> . 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 <span class="opacity-50 text-xs">[see ADVERSE REACTIONS (6.1) ]</span> . 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 (AUC 0-9h ) was about 1.5-times greater than without heating pad application <span class="opacity-50 text-xs">[see CLINICAL PHARMACOLOGY (12.3) ]</span>. 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.

5.11 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including amphetamine, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported <span class="opacity-50 text-xs">[see ADVERSE REACTIONS (6.2) ]</span> . Before initiating XELSTRYM, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor XELSTRYM-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

PRECAUTIONS General The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of dextroamphetamine sulfate extended-release capsules, which can lead to overdose and death, and proper disposal of any unused drug ( see WARNINGS , DRUG ABUSE AND DEPENDENCE , OVERDOSAGE ). Advise patients to store dextroamphetamine sulfate extended-release capsules in a safe place, preferably locked, and instruct patients to not give dextroamphetamine sulfate extended-release capsules to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with dextroamphetamine sulfate extended-release capsules use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease ( see WARNINGS ).

Increased Blood

Pressure and Heart Rate Instruct patients that dextroamphetamine sulfate extended-release capsules can elevate blood pressure and heart rate ( see WARNINGS ).

Psychiatric Adverse Reactions

Advise patients that dextroamphetamine sulfate extended-release capsules, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania ( see WARNINGS ). Long-Term Suppression of Growth in Pediatric Patients Advise patients that dextroamphetamine sulfate extended-release capsules may cause slowing of growth and weight loss in pediatric patients ( see WARNINGS ). Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon] Instruct patients beginning treatment with dextroamphetamine sulfate extended-release capsules about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking dextroamphetamine sulfate extended-release capsules. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients ( see WARNINGS ). Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s syndrome may occur during treatment with dextroamphetamine sulfate extended-release capsules. Instruct the patients to notify their healthcare provider if emergence or worsening of tics or Tourette’s syndrome occurs ( see WARNINGS ).

Drug Interactions Acidifying Agents

Lower blood levels and efficacy of amphetamines. Increase dose based on clinical response. Examples of acidifying agents include gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) and urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).

Adrenergic Blockers

Adrenergic blockers are inhibited by amphetamines.

Alkalinizing Agents

Increase blood levels and potentiate the action of amphetamine. Co-administration of dextroamphetamine sulfate extended-release capsules and gastrointestinal alkalinizing agents should be avoided. Examples of alkalinizing agents include gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) and urinary alkalinizing agents (e.g., acetazolamide, some thiazides).

Tricyclic Antidepressants

May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. Monitor frequently and adjust or use alternative therapy based on clinical response. Examples of tricyclic antidepressants include desipramine, Protriptyline. CYP2D6 Inhibitors The concomitant use of dextroamphetamine sulfate extended-release capsules and CYP2D6 inhibitors may increase the exposure of dextroamphetamine sulfate extended-release capsules compared to the use of the drug alone and increase the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during dextroamphetamine sulfate extended-release capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine sulfate extended-release capsules and the CYP2D6 inhibitor ( see WARNINGS , OVERDOSAGE ). Examples of CYP2D6 Inhibitors include paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir.

Serotonergic Drugs

The concomitant use of dextroamphetamine sulfate extended-release capsules and serotonergic drugs increases the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during dextroamphetamine sulfate extended-release capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine sulfate extended-release capsules and the concomitant serotonergic drug(s) ( see WARNINGS and PRECAUTIONS ). Examples of serotonergic drugs include selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort.

Mao

Inhibitors Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. Do not administer dextroamphetamine sulfate extended-release capsules concomitantly or within 14 days after discontinuing MAOI ( see CONTRAINDICATIONS and WARNINGS ). Examples of MAOIs include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue.

Proton Pump Inhibitors

Time to maximum concentration (T max ) of amphetamine is decreased compared to when administered alone. Monitor patients for changes in clinical effect and adjust therapy based on clinical response. An example of a proton pump inhibitor is omeprazole.

Antihistamines

Amphetamines may counteract the sedative effect of antihistamines.

Antihypertensives

Amphetamines may antagonize the hypotensive effects of antihypertensives.

Chlorpromazine

Chlorpromazine blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.

Ethosuximide

Amphetamines may delay intestinal absorption of ethosuximide.

Haloperidol

Haloperidol blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines.

Lithium Carbonate

The stimulatory effects of amphetamines may be inhibited by lithium carbonate.

Meperidine

Amphetamines potentiate the analgesic effect of meperidine.

Methenamine Therapy

Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy.

Norepinephrine

Amphetamines enhance the adrenergic effect of norepinephrine.

Phenobarbital

Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action.

Phenytoin

Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.

Veratrum Alkaloids

Amphetamines inhibit the hypotensive effect of veratrum alkaloids.

Drug/Laboratory

Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.

Carcinogenesis/Mutagenesis

Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of dextroamphetamine sulfate extended-release capsules have not been performed.

Pregnancy Teratogenic Effects

Dextroamphetamine sulfate extended-release capsules have been shown to have embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses approximately 41 times the maximum human dose. Embryotoxic effects were not seen in New Zealand white rabbits given the drug in doses 7 times the human dose nor in rats given 12.5 times the maximum human dose. While there are no adequate and well-controlled studies in pregnant women, there has been one report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. Dextroamphetamine sulfate extended-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude.

Nursing Mothers

Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing.

Pediatric Use

The safety and effectiveness of dextroamphetamine sulfate extended-release capsules have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release amphetamine products, patients 4 to <6 years of age had higher systemic amphetamine exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. Clinical experience suggests that in psychotic children, administration of amphetamines may exacerbate symptoms of behavior disturbance and thought disorder. Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications. Data are inadequate to determine whether chronic administration of amphetamines may be associated with growth inhibition; therefore, growth should be monitored during treatment. Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe amphetamines should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his or her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with amphetamines is usually not indicated.

Drug Interactions MAO Inhibitors - MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results.

Serotonergic

Drugs - The concomitant use of dextroamphetamine sulfate oral solution and serotonergic drugs increases the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during dextroamphetamine sulfate oral solution initiation or dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine sulfate oral solution and the concomitant serotonergic drug(s) (see WARNINGS , PRECAUTIONS ) . Examples of serotonergic drugs include selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort. CYP2D6 Inhibitors - The concomitant use of dextroamphetamine sulfate oral solution and CYP2D6 inhibitors may increase the exposure of dextroamphetamine sulfate oral solution compared to the use of the drug alone and increase the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during dextroamphetamine sulfate oral solution initiation and after a dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine sulfate oral solution and the CYP2D6 inhibitor (see WARNINGS , OVERDOSAGE ) . Examples of CYP2D6 Inhibitors include paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir.

Acidifying

Agents – Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines. Urinary acidifying agents (ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines.

Adrenergic

Blockers – Adrenergic blockers are inhibited by amphetamines.

Alkalinizing

Agents – Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines. Antidepressants, Tricyclic – Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. Antihistamines – Amphetamines may counteract the sedative effect of antihistamines. Antihypertensives – Amphetamines may antagonize the hypotensive effects of antihypertensives. Chlorpromazine – Chlorpromazine blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning. Ethosuximide – Amphetamines may delay intestinal absorption of ethosuximide. Haloperidol – Haloperidol blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines.

Lithium

Carbonate – The stimulatory effects of amphetamines may be inhibited by lithium carbonate. Meperidine – Amphetamines potentiate the analgesic effect of meperidine.

Methenamine

Therapy – Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy. Norepinephrine – Amphetamines enhance the adrenergic effect of norepinephrine. Phenobarbital – Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action. Phenytoin – Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene – In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.

Veratrum

Alkaloids – Amphetamines inhibit the hypotensive effect of veratrum alkaloids.

Drug/Laboratory

Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.

Carcinogenesis/Mutagenesis

Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of dextroamphetamine sulfate have not been performed.

Pregnancy Teratogenic Effects Pregnancy

Category C Dextroamphetamine sulfate has been shown to have embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses approximately 41 times the maximum human dose. Embryotoxic effects were not seen in New Zealand white rabbits given the drug in doses 7 times the human dose nor in rats given 12.5 times the maximum human dose. While there are no adequate and well-controlled studies in pregnant women, there has been one report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. Dextroamphetamine sulfate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude.

Nursing Mothers

Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing.

Pediatric Use

Long-term effects of amphetamines in pediatric patients have not been well established. Amphetamines are not recommended for use in pediatric patients under 3 years of age with Attention Deficit Disorder with Hyperactivity described under INDICATIONS AND USAGE . Clinical experience suggests that in psychotic children, administration of amphetamines may exacerbate symptoms of behavior disturbance and thought disorder. Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications. Data are inadequate to determine whether chronic administration of amphetamines may be associated with growth inhibition; therefore, growth should be monitored during treatment. Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe amphetamines should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his or her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with amphetamines is usually not indicated.

INACTIVE INGREDIENTS Each tablet, for oral administration, contains dextroamphetamine sulfate, USP in either 5 mg, 10 mg, 15 mg, 20 mg or 30 mg. Each tablet also contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, microcrystalline cellulose and stearic acid.

The

5 mg tablets also contain D&C Red #27 and FD&C Yellow #6.

The

10 mg tablets also contain FD&C Red #40, FD&C Yellow #6 and FD&C Blue #2.

The

15 mg tablets also contain FD&C Blue #1, FD&C Blue #2, and FD&C Red #40.

The

20 mg tablets also contain FD&C Blue #1 and D&C Red #27.

The

30 mg tablets also contain D&C Yellow #10.