FDA label 6aec4d10-3bac-4afb-bb7f-6a0e23556143

AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION TO OTHERS AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY. MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS.

WARNINGS Serious Cardiovascular Events Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug (see CONTRAINDICATIONS ). Adults Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs (see CONTRAINDICATIONS ). Hypertension and other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm) [see ADVERSE EVENTS ], and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS ). Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g. electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD patients with comorbid bipolar disorder because of concern for possible induction of mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 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 children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (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 Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules in adolescents, mean weight change from baseline within the initial 4 weeks of therapy was –1.1 lbs. and –2.8 lbs., respectively, for patients receiving 10 mg and 20 mg Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they will likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in the absence of seizures, and very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

ADVERSE EVENTS Hypertension [See WARNINGS section] In a controlled 4-week outpatient clinical study of adolescents with ADHD, isolated systolic blood pressure elevations ≥15 mmHg were observed in 7/64 (11%) placebo-treated patients and 7/100 (7%) patients receiving Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules 10 or 20 mg. Isolated elevations in diastolic blood pressure ≥ 8 mmHg were observed in 16/64 (25%) placebo-treated patients and 22/100 (22%) Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules -treated patients. Similar results were observed at higher doses. In a single-dose pharmacokinetic study in 23 adolescents, isolated increases in systolic blood pressure (above the upper 95% CI for age, gender, and stature) were observed in 2/17 (12%) and 8/23 (35%), subjects administered 10 mg and 20 mg Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules, respectively. Higher single doses were associated with a greater increase in systolic blood pressure. All increases were transient, appeared maximal at 2 to 4 hours post dose and not associated with symptoms. The premarketing development program for Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules included exposures in a total of 1315 participants in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients, and 82 healthy adult subjects). Of these, 635 patients (ages 6 to 12) were evaluated in two controlled clinical studies, one open-label clinical study, and two single-dose clinical pharmacology studies (N= 40). Safety data on all patients are included in the discussion that follows. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs. Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and listings that follow, COSTART terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. Adverse events associated with discontinuation of treatment In two placebo-controlled studies of up to 5 weeks duration among children with ADHD, 2.4% (10/425) of Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules treated patients discontinued due to adverse events (including 3 patients with loss of appetite, one of whom also reported insomnia) compared to 2.7% (7/259) receiving placebo. The most frequent adverse events associated with discontinuation of Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules in controlled and uncontrolled, multiple-dose clinical trials of pediatric patients (N=595) are presented below. Over half of these patients were exposed to Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules for 12 months or more. Adverse event % of pediatric patients discontinuing (n=595) Anorexia (loss of appetite) 2.9 Insomnia 1.5 Weight loss 1.2 Emotional lability 1.0 Depression 0.7 In a separate placebo-controlled 4-week study in adolescents with ADHD, eight patients (3.4%) discontinued treatment due to adverse events among Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules -treated patients (N=233). Three patients discontinued due to insomnia and one patient each for depression, motor tics, headaches, light-headedness, and anxiety. In one placebo-controlled 4-week study among adults with ADHD, patients who discontinued treatment due to adverse events among Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules -treated patients (N=191) were 3.1% (n=6) for nervousness including anxiety and irritability, 2.6% (n=5) for insomnia, 1% (n=2) each for headache, palpitation, and somnolence; and, 0.5% (n=1) each for ALT increase, agitation, chest pain, cocaine craving, elevated blood pressure, and weight loss. Adverse events occurring in a controlled trial Adverse events reported in a 3-week clinical trial of pediatric patients and a 4-week clinical trial in adolescents and adults, respectively, treated with Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules or placebo are presented in the tables below. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. Table 1 Adverse Events Reported by More Than 1% of Pediatric Patients Receiving Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release (MAS-ER) Capsules with Higher Incidence Than on Placebo in a 584 Patient Clinical Study Body System Preferred Term MAS-ER (n=374) Placebo (n=210) General Abdominal Pain (stomachache) 14% 10% Accidental Injury 3% 2% Asthenia (fatigue) 2% 0% Fever 5% 2% Infection 4% 2% Viral Infection 2% 0% Digestive System Loss of Appetite Diarrhea Dyspepsia Nausea Vomiting 22% 2% 2% 5% 7% 2% 1% 1% 3% 4% Nervous System Dizziness Emotional Lability Insomnia Nervousness 2% 9% 17% 6% 0% 2% 2% 2% Metabolic/Nutritional Weight Loss 4% 0% Table 2 Adverse Events Reported by More Than 5% or more of Adolescents Weight less than or equal to 75 kg/165 lbs Receiving Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release (MAS-ER) Capsules with Higher Incidence Than Placebo Clinical Forced Weekly-Dose Titration Study* Body System Preferred Term MAS-ER (n=233) Placebo (n=54) General Abdominal Pain (stomachache) 11% 2% Digestive System Loss of Appetite † 36% 2% Nervous System Insomnia † Nervousness 12% 6% 4% 6% ‡ Metabolic/Nutritional Weight Loss † 9% 0% Note: The following events did not meet the criterion for inclusion in Table 2 but were reported by 2% to 4% of adolescent patients receiving Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting. * Included doses up to 40 mg † Dose-related adverse events ‡ Appears the same due to rounding Table 3 Adverse Events Reported by 5% or More of Adults Receiving Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release (MAS-ER) Capsules with Higher Incidence Than on Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study* Body System Preferred Term MAS-ER (n=191) Placebo (n=64) General Asthenia Headache 6% 26% 5% 13% Digestive System Loss of Appetite Diarrhea Dry Mouth Nausea 33% 6% 35% 8% 3% 0% 5% 3% Nervous System Agitation Anxiety Dizziness Insomnia 8% 8% 7% 27% 5% 5% 0% 13% Cardiovascular System Tachycardia 6% 3% Metabolic/Nutritional Weight Loss 11% 0% Urogenital System Urinary Tract Infection 5% 0% Note: The following events did not meet the criterion for inclusion in Table 3 but were reported by 2% to 4% of adult patients receiving Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release Capsules with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder, emotional lability, libido decreased, somnolence, speech disorder, palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence. * Included doses up to 60 mg. The following adverse reactions have been associated with the use of amphetamine, Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release (MAS-ER) Capsules, or ADDERALL ® : Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System: Psychotic episodes at recommended doses, overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, depression, tremor, headache, exacerbation of motor and phonic tics and Tourette's syndrome, seizures, stroke. Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects. Allergic: Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported. Endocrine: Impotence, changes in libido.

<table width="80%" ID="ieb56efcd-faf7-47a5-879c-7644c8ad358a"> <col align="left" valign="top" width="35%"/> <col align="center" valign="top" width="65%"/> <thead> <tr> <th>Adverse event</th> <th>% of pediatric patients discontinuing (n=595)</th> </tr> </thead> <tbody> <tr> <td>Anorexia (loss of appetite)</td> <td>2.9</td> </tr> <tr> <td>Insomnia</td> <td>1.5</td> </tr> <tr> <td>Weight loss</td> <td>1.2</td> </tr> <tr> <td>Emotional lability</td> <td>1.0</td> </tr> <tr> <td>Depression</td> <td>0.7</td> </tr> </tbody> </table>

<table width="90%" ID="i147ff0e6-473c-41e5-8b37-27c6e1ddb121"> <caption>Table 1 Adverse Events Reported by More Than 1% of Pediatric Patients Receiving Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release (MAS-ER) Capsules with Higher Incidence Than on Placebo in a 584 Patient Clinical Study</caption> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <thead> <tr> <th>Body System</th> <th>Preferred Term</th> <th>MAS-ER (n=374)</th> <th>Placebo (n=210)</th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">General</content> </td> <td>Abdominal Pain (stomachache)</td> <td>14%</td> <td>10%</td> </tr> <tr> <td> </td> <td>Accidental Injury</td> <td>3%</td> <td>2%</td> </tr> <tr> <td> </td> <td>Asthenia (fatigue)</td> <td>2%</td> <td>0%</td> </tr> <tr> <td> </td> <td>Fever</td> <td>5%</td> <td>2%</td> </tr> <tr> <td> </td> <td>Infection</td> <td>4%</td> <td>2%</td> </tr> <tr> <td> </td> <td>Viral Infection</td> <td>2%</td> <td>0%</td> </tr> <tr> <td> <content styleCode="bold">Digestive System</content> </td> <td>Loss of Appetite Diarrhea Dyspepsia Nausea Vomiting</td> <td>22% 2% 2% 5% 7%</td> <td>2% 1% 1% 3% 4%</td> </tr> <tr> <td> <content styleCode="bold">Nervous System</content> </td> <td>Dizziness Emotional Lability Insomnia Nervousness</td> <td>2% 9% 17% 6%</td> <td>0% 2% 2% 2%</td> </tr> <tr> <td> <content styleCode="bold">Metabolic/Nutritional</content> </td> <td>Weight Loss</td> <td>4%</td> <td>0%</td> </tr> </tbody> </table>

<table width="90%" ID="i929a8706-3202-4f75-80e5-51a4c29d559d"> <caption>Table 2 Adverse Events Reported by More Than 5% or more of Adolescents Weight less than or equal to 75 kg/165 lbs Receiving Dextroamphetamine Saccharate, Amphetamine Asparate Monohydrate, Dextroamphetamine Sulfate and, Amphetamine Sulfate Extended-Release (MAS-ER) Capsules with Higher Incidence Than Placebo Clinical Forced Weekly-Dose Titration Study*</caption> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <thead> <tr> <th>Body System</th> <th>Preferred Term</th> <th>MAS-ER (n=233)</th> <th>Placebo (n=54)</th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">General</content> </td> <td>Abdominal Pain (stomachache)</td> <td>11%</td> <td>2%</td> </tr> <tr> <td> </td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td> <content styleCode="bold">Digestive System</content> </td> <td>Loss of Appetite <linkHtml href="#footnote-2">&#x2020;</linkHtml> </td> <td>36% </td> <td>2% </td> </tr> <tr> <td> <content styleCode="bold">Nervous System</content> </td> <td>Insomnia <linkHtml href="#footnote-2">&#x2020;</linkHtml> Nervousness</td> <td>12% 6%</td> <td>4% 6%<linkHtml href="#footnote-3">&#x2021;</linkHtml> </td> </tr> <tr> <td> <content styleCode="bold">Metabolic/Nutritional</content> </td> <td>Weight Loss <linkHtml href="#footnote-2">&#x2020;</linkHtml> </td> <td>9%</td> <td>0%</td> </tr> </tbody> </table>