ADDERALL XR® is a once daily extended-release, single-entity amphetamine product. ADDERALL XR® combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate. The ADDERALL XR® capsule contains two types of drug-containing beads designed to give a double-pulsed delivery of amphetamines, which prolongs the release of amphetamine from ADDERALL XR® compared to the conventional ADDERALL® (immediate-release) tablet formulation.

Inactive Ingredients and Colors: The inactive ingredients in ADDERALL XR® capsules include: gelatin capsules, hydroxypropyl methylcellulose, methacrylic acid copolymer, opadry beige, sugar spheres, talc, and triethyl citrate. Gelatin capsules contain edible inks, kosher gelatin, and titanium dioxide. The 5 mg, 10 mg, and 15 mg capsules also contain FD&C Blue #2. The 20 mg, 25 mg, and 30 mg capsules also contain red iron oxide and yellow iron oxide.

ADDERALL XR® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

The efficacy of ADDERALL XR® in the treatment of ADHD was established on the basis of two controlled trials in children aged 6 to 12, one controlled trial in adolescents aged 13 to 17, and one controlled trial in adults who met DSM-IV® criteria for ADHD (see CLINICAL PHARMACOLOGY), along with extrapolation from the known efficacy of ADDERALL®, the immediate-release formulation of this substance.

A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV®) implies the presence of 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 two 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 six 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 six 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 not only of medical but of 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 child and not solely on the presence of the required number of DSM-IV® characteristics.

Need for Comprehensive Treatment Program:

ADDERALL XR® is 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 children with this syndrome. Stimulants are not intended for use in the child who exhibits 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 child's symptoms.

Long-Term Use:

The effectiveness of ADDERALL XR® for long-term use, i.e., for more than 3 weeks in children and 4 weeks in adolescents and adults, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use ADDERALL XR® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Dosage should be individualized according to the therapeutic needs and response of the patient. ADDERALL XR® should be administered at the lowest effective dosage.

Children

In children with ADHD who are 6 years of age and older and are either starting treatment for the first time or switching from another medication, start with 10 mg once daily in the morning; daily dosage may be adjusted in increments of 5 mg or 10 mg at weekly intervals. When in the judgment of the clinician a lower initial dose is appropriate, patients may begin treatment with 5 mg once daily in the morning. The maximum recommended dose for children is 30 mg/day; doses greater than 30 mg/day of ADDERALL XR® have not been studied in children. Amphetamines are not recommended for children under 3 years of age. ADDERALL XR® has not been studied in children under 6 years of age.

Adolescents

The recommended starting dose for adolescents who are 13-17 years of age with ADHD is 10 mg/day. The dose may be increased to 20 mg/day after one week if ADHD symptoms are not adequately controlled.

Adults

In adults with ADHD who are either starting treatment for the first time or switching from another medication, the recommended dose is 20 mg/day.

Patients Currently Using ADDERALL®- Based on bioequivalence data, patients taking divided doses of immediate-release ADDERALL®, for example twice a day, may be switched to ADDERALL XR® at the same total daily dose taken once daily. Titrate at weekly intervals to appropriate efficacy and tolerability as indicated.

ADDERALL XR® capsules may be taken whole, or the capsule may be opened and the entire contents sprinkled on applesauce. If the patient is using the sprinkle administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day.

ADDERALL XR® may be taken with or without food.

ADDERALL XR® should be given upon awakening. Afternoon doses should be avoided because of the potential for insomnia.

Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.

HOW SUPPLIED

ADDERALL XR® 5 mg Capsules: Clear/blue (imprinted ADDERALL XR 5 mg), bottles of 100, NDC 54092-381-01
ADDERALL XR® 10 mg Capsules: Blue/blue (imprinted ADDERALL XR 10 mg), bottles of 100, NDC 54092-383-01
ADDERALL XR® 15 mg Capsules: Blue/white (imprinted ADDERALL XR 15 mg), bottles of 100, NDC 54092-385-01
ADDERALL XR® 20 mg Capsules: Orange/orange (imprinted ADDERALL XR 20 mg), bottles of 100, NDC 54092-387-01
ADDERALL XR® 25 mg Capsules: Orange/white (imprinted ADDERALL XR 25 mg), bottles of 100, NDC 54092-389-01
ADDERALL XR® 30 mg Capsules: Natural/orange (imprinted ADDERALL XR 30 mg), bottles of 100, NDC 54092-391-01

Dispense in a tight, light-resistant container as defined in the USP.

Store at 25º C (77º F). Excursions permitted to 15-30º C (59-86º F) [see USP Controlled Room Temperature]

For more information call 1-800-828-2088 or visit www.adderallxr.com

Pharmacist: Medication Guide to be dispensed to patients

ADDERALL XR® is registered in the US Patent ® is a registered trademark of Shire LLC, under license to Duramed Pharmaceuticals, Inc.
Manufactured for Shire US Inc., Wayne, PA 19087.
ADDERALL XR® is registered in the US Patent and Trademark Office
©2007 Shire US Inc.
Rev. 3/07
FDA rev date: 5/22/2007

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 ADDERALL XR® 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%) ADDERALL XR®-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 ADDERALL XR®, 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 ADDERALL XR® 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 ADDERALL XR® 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 ADDERALL XR® in controlled and uncontrolled, multiple-dose clinical trials of pediatric patients (N=595) are presented below. Over half of these patients were exposed to ADDERALL XR® for 12 months or more.                 

In a separate placebo-controlled 4-week study in adolescents with ADHD, eight patients (3.4%) discontinued treatment due to adverse events among ADDERALL XR®-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 ADDERALL XR®-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 ADDERALL XR® 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 ADDERALL XR® with Higher Incidence Than on Placebo in a 584 Patient Clinical Study

Table 2 Adverse Events Reported by 5% or more of Adolescents Weighing ≤ 75 kg/165 lbs Receiving ADDERALL XR® with Higher Incidence Than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study*

Table 3 Adverse Events Reported by 5% or More of Adults Receiving ADDERALL XR® with Higher Incidence Than on Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study*

The following adverse reactions have been associated with the use of amphetamine, ADDERALL XR®, 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.

DRUG ABUSE AND DEPENDENCE

ADDERALL XR® is a Schedule II controlled substance.

Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have increased the dosage to levels many times higher than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines may include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.

Acidifying agents -Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, etc.) lower absorption of amphetamines.

Urinary acidifying agents -These 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. Co-administration of ADDERALL XR® and gastrointestinal alkalinizing agents, such as antacids, should be avoided. 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 antidepressants 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.

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 toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results.

Antihistamines -Amphetamines may counteract the sedative effect of antihistamines.

Antihypertensives -Amphetamines may antagonize the hypotensive effects of antihypertensives.

Chlorpromazine -Chlorpromazine blocks dopamine and norepinephrine receptors, 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 receptors, thus inhibiting the central stimulant effects of amphetamines.

Lithium carbonate -The anorectic and 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.

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 ADDERALL XR® 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 ADDERALL XR®. 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 seizure, in patients with prior EEG abnormalities in 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.

General:

The least amount of amphetamine feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. ADDERALL XR® should be used with caution in patients who use other sympathomimetic drugs.

Tics:

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.

Information for Patients:

Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with amphetamine and should counsel them in its appropriate use. A patient Medication Guide is available for ADDERALL XR®. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Carcinogenesis/Mutagenesis and Impairment of Fertility:

No evidence of carcinogenicity was found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 2.4, 1.5, and 0.8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m ² body surface area basis.

Amphetamine, in the enantiomer ratio present in ADDERALL® (immediate-release)(d- to l- ratio of 3:1), was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d,l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays.

Amphetamine, in the enantiomer ratio present in ADDERALL® (immediate-release)(d- to l- ratio of 3:1), did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day (approximately 5 times the maximum recommended human dose of 30 mg/day on a mg/m² body surface area basis).

Pregnancy:

Pregnancy Category C. Amphetamine, in the enantiomer ratio present in ADDERALL® (d- to l- ratio of 3:1), had no apparent effects on embryofetal morphological development or survival when orally administered to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately 1.5 and 8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m² body surface area basis. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 6 times that of a human dose of 30 mg/day [child] on a mg/m2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity.

A number of studies 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.

There are no adequate and well-controlled studies in pregnant women. There has been one report of severe congenital bony deformity, tracheo-esophageal 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. Amphetamines 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.

Usage in Nursing Mothers:

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

Pediatric Use:

ADDERALL XR® is indicated for use in children 6 years of age and older.

Use in Children Under Six Years of Age:

Effects of ADDERALL XR® in 3-5 year olds have not been studied. Long-term effects of amphetamines in children have not been well established. Amphetamines are not recommended for use in children under 3 years of age.

Geriatric Use:

ADDERALL XR® has not been studied in the geriatric population.

Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses.

Symptoms: Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.

Treatment: Consult with a Certified Poison Control Center for up to date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic and sedation. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication.

The prolonged release of mixed amphetamine salts from ADDERALL XR® should be considered when treating patients with overdose.

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.

During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result).

Pharmacodynamics

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Amphetamines are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

Pharmacokinetics

Pharmacokinetic studies of ADDERALL XR® have been conducted in healthy adult and pediatric (6-12 yrs) subjects, and adolescent (13-17 yrs) and pediatric patients with ADHD. Both ADDERALL® (immediate-release) tablets and ADDERALL XR® capsules contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following administration of ADDERALL® (immediate-release), the peak plasma concentrations occurred in about 3 hours for both d-amphetamine and l-amphetamine.

The time to reach maximum plasma concentration (Tmax) for ADDERALL XR® is about 7 hours, which is about 4 hours longer compared to ADDERALL® (immediate-release). This is consistent with the extended-release nature of the product.

Figure 1 Mean d-amphetamine and l-amphetamine plasma concentrations following administration of ADDERALL XR® 20 mg (8am) and ADDERALL® (immediate-release) 10 mg bid (8am and 12 noon) in the fed state.

A single dose of ADDERALL XR® 20 mg capsules provided comparable plasma concentration profiles of both d-amphetamine and l-amphetamine to ADDERALL® (immediate-release) 10 mg bid administered 4 hours apart.

The mean elimination half-life for d-amphetamine is 10 hours in adults; 11 hours in adolescents aged 13-17 years and weighing less than or equal to 75 kg/165 lbs; and 9 hours in children aged 6 to 12 years. For the l-amphetamine, the mean elimination half-life in adults is 13 hours; 13 to 14 hours in adolescents; and 11 hours in children aged 6 to 12 years. On a mg/kg body weight basis children have a higher clearance than adolescents or adults (See Special Populations).

ADDERALL XR® demonstrates linear pharmacokinetics over the dose range of 20 to 60 mg in adults and adolescents weighing greater than 75 kg/165lbs, over the dose range of 10 to 40 mg in adolescents weighing less than or equal to 75 kg/165 lbs, and 5 to 30 mg in children aged 6 to 12 years. There is no unexpected accumulation at steady state in children.

Food does not affect the extent of absorption of d-amphetamine and l-amphetamine, but prolongs Tmax by 2.5 hours (from 5.2 hrs at fasted state to 7.7 hrs after a high-fat meal) for d-amphetamine and 2.1 hours (from 5.6 hrs at fasted state to 7.7 hrs after a high fat meal) for l-amphetamine after administration of ADDERALL XR® 30 mg. Opening the capsule and sprinkling the contents on applesauce results in comparable absorption to the intact capsule taken in the fasted state. Equal doses of ADDERALL XR® strengths are bioequivalent.

Metabolism and Excretion

Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.

Amphetamine is known to inhibit monoamine oxidase, whereas the ability of amphetamine and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. However, due to the probability of auto-inhibition and the lack of information on the concentration of these metabolites relative to in vivo concentrations, no predications regarding the potential for amphetamine or its metabolites to inhibit the metabolism of other drugs by CYP isozymes in vivo can be made.

With normal urine pHs approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30%-40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that effect urinary pH are known to alter the elimination of amphetamine, and any decrease in amphetamine's metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased, (See PRECAUTIONS).

Special Populations

Comparison of the pharmacokinetics of d- and l-amphetamine after oral administration of ADDERALL XR® in pediatric (6-12 years) and adolescent (13-17 years) ADHD patients and healthy adult volunteers indicates that body weight is the primary determinant of apparent differences in the pharmacokinetics of d- and l-amphetamine across the age range. Systemic exposure measured by area under the curve to infinity (AUC_∞) and maximum plasma concentration (Cmax) decreased with increases in body weight, while oral volume of distribution (V_z/F), oral clearance (CL/F), and elimination half-life (t _½) increased with increases in body weight.

Pediatric Patients

On a mg/kg weight basis, children eliminated amphetamine faster than adults. The elimination half-life (t_½) is approximately 1 hour shorter for d-amphetamine and 2 hours shorter for l-amphetamine in children than in adults. However, children had higher systemic exposure to amphetamine (Cmax and AUC) than adults for a given dose of ADDERALL XR®, which was attributed to the higher dose administered to children on a mg/kg body weight basis compared to adults. Upon dose normalization on a mg/kg basis, children showed 30% less systemic exposure compared to adults.

Gender

Systemic exposure to amphetamine was 20-30% higher in women (N=20) than in men (N=20) due to the higher dose administered to women on a mg/kg body weight basis. When the exposure parameters (Cmax and AUC) were normalized by dose (mg/kg), these differences diminished. Age and gender had no direct effect on the pharmacokinetics of d- and l-amphetamine.

Race

Formal pharmacokinetic studies for race have not been conducted. However, amphetamine pharmacokinetics appeared to be comparable among Caucasians (N=33), Blacks (N=8) and Hispanics (N=10).

Clinical Trials

Children

A double-blind, randomized, placebo-controlled, parallel-group study was conducted in children aged 6-12 (N=584) who met DSM-IV® criteria for ADHD (either the combined type or the hyperactive-impulsive type). Patients were randomized to fixed dose treatment groups receiving final doses of 10, 20, or 30 mg of ADDERALL XR® or placebo once daily in the morning for three weeks. Significant improvements in patient behavior, based upon teacher ratings of attention and hyperactivity, were observed for all ADDERALL XR® doses compared to patients who received placebo, for all three weeks, including the first week of treatment, when all ADDERALL XR® subjects were receiving a dose of 10 mg/day. Patients who received ADDERALL XR® showed behavioral improvements in both morning and afternoon assessments compared to patients on placebo.

In a classroom analogue study, patients (N=51) receiving fixed doses of 10 mg, 20 mg or 30 mg ADDERALL XR® demonstrated statistically significant improvements in teacher-rated behavior and performance measures, compared to patients treated with placebo.

Adolescents

A double-blind, randomized, multi-center, parallel-group, placebo-controlled study was conducted in adolescents aged 13-17 (N=327) who met DSM-IV® criteria for ADHD. The primary cohort of patients (n=287, weighing ≤ 75kg/165lbs) was randomized to fixed dose treatment groups and received four weeks of treatment. Patients were randomized to receive final doses of 10 mg, 20 mg, 30 mg, and 40 mg ADDERALL XR® or placebo once daily in the morning; patients randomized to doses greater than 10 mg were titrated to their final doses by 10 mg each week. The secondary cohort consisted of 40 subjects weighing > 75kg/165lbs who were randomized to fixed dose treatment groups receiving final doses of 50 mg and 60 mg ADDERALL XR® or placebo once daily in the morning for 4 weeks. The primary efficacy variable was the ADHD-RS-IV total scores for the primary cohort. Improvements in the primary cohort were statistically significantly greater in all four primary cohort active treatment groups (ADDERALL XR® 10 mg, 20 mg, 30 mg, and 40 mg) compared with the placebo group. There was not adequate evidence that doses greater than 20 mg/day conferred additional benefit.

Adults

A double-blind, randomized, placebo-controlled, parallel-group study was conducted in adults (N=255) who met DSM-IV® criteria for ADHD. Patients were randomized to fixed dose treatment groups receiving final doses of 20, 40, or 60 mg of ADDERALL XR® or placebo once daily in the morning for four weeks. Significant improvements, measured with the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS), an 18-item scale that measures the core symptoms of ADHD, were observed at endpoint for all ADDERALL XR® doses compared to patients who received placebo for all four weeks. There was not adequate evidence that doses greater than 20 mg/day conferred additional benefit.

ANIMAL TOXICOLOGY

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

MEDICATION GUIDE
ADDERALL XR®
(ADD-ur-all X-R) CII

Read the Medication Guide that comes with ADDERALL XR® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about you or your child's treatment with ADDERALL XR®.

What Is ADDERALL XR®?

ADDERALL XR® is a once daily central nervous system stimulant prescription medicine. It is used for the treatment of Attention Deficit Hyperactivity Disorder(ADHD).

ADDERALL XR® may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.

ADDERALL XR® should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.

Who should not take ADDERALL XR®?

ADDERALL XR® should not be taken if you or your child:

• have heart disease or hardening of the arteries
• have moderate to severe high blood pressure
• have hyperthyroidism
• have an eye problem called glaucoma
• are very anxious, tense, or agitated
• have a history of drug abuse
• are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI
• is sensitive to, allergic to, or had a reaction to other stimulant medicines

ADDERALL XR® has not been studied in children less than 6 years old.

ADDERALL XR® is not recommended for use in children less than 3 years old.

ADDERALL XR® may not be right for you or your child. Before starting ADDERALL XR® tell your or your child's doctor about all health conditions (or a family history of) including:

•  heart problems, heart defects, high blood pressure
• mental problems including psychosis, mania, bipolar illness, or depression
• tics or Tourette's syndrome
• liver or kidney problems
• thyroid problems
• seizures or have had an abnormal brain wave test (EEG)

Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding.

Can ADDERALL XR® be taken with other medicines?

Tell your doctor about all of the medicines that you or your child takes including prescription and non-prescription medicines, vitamins, and herbal supplements. ADDERALL XR® and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking ADDERALL XR®.

Your doctor will decide whether ADDERALL XR® can be taken with other medicines.

Especially tell your doctor if you or your child takes:

• anti-depression medicines including MAOIs
• anti-psychotic medicines
• lithium
• narcotic pain medicines
• seizure medicines
• blood thinner medicines
• blood pressure medicines
• stomach acid medicines
• cold or allergy medicines that contain decongestants

Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist.

Do not start any new medicine while taking ADDERALL XR® without talking to your doctor first.

How should ADDERALL XR® be taken?

• Take ADDERALL XR® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.
• Take ADDERALL XR® once a day in the morning when you first wake up. ADDERALL XR® is an extended release capsule. It releases medicine into your body throughout the day.
• Swallow ADDERALL XR® capsules whole with water or other liquids. If you or your child cannot swallow the capsule, open it and sprinkle the medicine over a spoonful of applesauce. Swallow all of the applesauce and medicine mixture without chewing immediately. Follow with a drink of water or other liquid. Never chew or crush the capsule or the medicine inside the capsule.
• ADDERALL XR® can be taken with or without food.
• From time to time, your doctor may stop ADDERALL XR® treatment for a while to check ADHD symptoms.
• Your doctor may do regular checks of the blood, heart, and blood pressure while taking ADDERALL XR®. Children should have their height and weight checked often while taking ADDERALL XR®. ADDERALL XR® treatment may be stopped if a problem is found during these check-ups.
• If you or your child takes too much ADDERALL XR® or overdoses, call your doctor or poison control center right away, or get emergency treatment.

What are possible side effects of ADDERALL XR®?

See "What is the most important information I should know about ADDERALL XR®?" for information on reported heart and mental problems.

Other serious side effects include:

• slowing of growth (height and weight) in children
• seizures, mainly in patients with a history of seizures
• eyesight changes or blurred vision

Common side effects include:

ADDERALL XR® may affect you or your child's ability to drive or do other dangerous activities.

Talk to your doctor if you or your child has side effects that are bothersome or do not go away.

This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information

How should I store ADDERALL XR®?

• Store ADDERALL XR® in a safe place at room temperature, 59 to 86° F (15 to 30° C).
• Keep ADDERALL XR® and all medicines out of the reach of children.

General information about ADDERALL XR®

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ADDERALL XR® for a condition for which it was not prescribed. Do not give ADDERALL XR® to other people, even if they have the same condition. It may harm them and it is against the law.

This Medication Guide summarizes the most important information about ADDERALL XR®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ADDERALL XR® that was written for healthcare professionals. For more information, you may also contact Shire Pharmaceuticals (the maker of ADDERALL XR®) at 1-800-828-2088 or visit the website at http://www.adderallxr.com.

What are the ingredients in ADDERALL XR®?

Active Ingredients: dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, USP, amphetamine sulfate USP

Inactive Ingredients: gelatin capsules, hydroxypropyl methylcellulose, methacrylic acid copolymer, opadry beige, sugar spheres, talc, and triethyl citrate. Gelatin capsules contain edible inks, kosher gelatin, and titanium dioxide. The 5 mg, 10 mg, and 15 mg capsules also contain FD&C Blue #2. The 20 mg, 25 mg, and 30 mg capsules also contain red iron oxide and yellow iron oxide

This Medication Guide has been approved by the U.S. Food and Drug Administration.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

AMPHETAMINE/DEXTROAMPHETAMINE EXTENDED-RELEASE - ORAL

(am-FET-a-meen/DEX-troe-am-FET-a-meen)

COMMON BRAND NAME(S): Adderall XR

WARNING: Misuse or abuse of amphetamine may result in serious (possibly fatal) heart and blood pressure problems. Amphetamine-type medications can be habit-forming. Use only as directed. With prolonged use, drug dependence may occur, and withdrawal symptoms may occur after stopping the drug. Consult your doctor or pharmacist for more details.

USES: This combination medication is used as part of a total treatment program to control attention deficit hyperactivity disorder (ADHD). It may help to increase the ability to pay attention, stay focused, and control behavior problems.

This product is a combination of stimulants (amphetamine and dextroamphetamine). It is thought to work by restoring the balance of certain natural substances (neurotransmitters) in the brain.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to treat certain sleeping disorders (narcolepsy). It should not be used to treat tiredness or to hold off sleep in people who do not have a sleep disorder.

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using amphetamine/ dextroamphetamine and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth with or without food, usually once daily in the morning or as directed by your doctor. Taking this medication after noon may cause trouble sleeping.

Swallow the capsules whole. Do not crush or chew the capsules. Doing so can destroy the long action of the drug and increase side effects. If you have difficulty swallowing this medication whole, you may sprinkle the entire contents of a capsule on a small amount of cool soft food (e.g., applesauce or yogurt) just before taking. Swallow the mixture immediately. Do not chew the mixture, and do not save it for future use. Drink a glass of liquid after each dose.

The dosage is based on your medical condition and response to therapy. Your doctor may adjust your dose to find the dose that is best for you. Follow your doctor's instructions carefully.

Use this medication regularly and exactly as prescribed in order to get the most benefit from it. To help you remember, use it at the same time each day.

This medication may cause dependence, especially if it has been used regularly for a long period of time (more than a few weeks) or if it has been used in high doses. In such cases, if you suddenly stop this drug, withdrawal reactions may occur. Such reactions can include severe tiredness, mood changes including depression, and sleep problems. Report any such reactions to your doctor immediately. When stopping long-term, regular treatment with this drug, gradually reducing the dosage as directed will help prevent withdrawal reactions. Consult your doctor or pharmacist for more details.

Though it is unlikely to occur, this medication can also result in abnormal drug-seeking behavior (addiction/habit-forming). Do not increase your dose, take it more frequently or use it for a longer period of time than prescribed. Properly stop the medication when so directed. This will lessen the chances of becoming addicted.

When used for a long period, this medication may not work as well and may require different dosing. Talk with your doctor if this medication stops working well.

If you are taking this drug for ADHD, your doctor may recommend "drug holidays" when the medication is stopped for a short time to observe any changes in behavior. Inform your doctor if your condition does not improve or if it worsens.

SIDE EFFECTS: Loss of appetite, weight loss, dry mouth, stomach upset/pain, nausea/vomiting, dizziness, headache, diarrhea, fever, nervousness, and trouble sleeping may occur. If any of these effects persist or worsen, notify your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood/behavior changes (e.g., agitation, aggression, mood swings, depression, abnormal thoughts), uncontrolled movements, continuous chewing movements/teeth grinding, outbursts of words/sounds, change in sexual ability/desire.

Seek immediate medical attention if any of these rare but very serious side effects occur: shortness of breath, chest pain, fainting, severe headache, fast/pounding/irregular heartbeat, jaw/left arm pain, seizures, weakness on one side of the body, slurred speech, confusion, swelling of the ankles/feet, extreme tiredness, blurred vision.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking this medication, tell your doctor or pharmacist if you are allergic to it; or to sympathomimetic drugs (e.g., epinephrine, pseudoephedrine); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: certain mental/mood conditions (e.g., agitation, psychosis), heart/blood vessel disease (e.g., irregular heartbeat, coronary artery disease, angina, heart failure, cardiomyopathy), problems with heart structure (e.g., valve problems), history of heart attack or stroke, moderate or severe high blood pressure (hypertension), over-active thyroid (hyperthyroidism), a certain eye problem (glaucoma), personal or family history of regular use/abuse of drugs/alcohol.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: personal or family history of uncontrolled movements or outbursts of words/sounds (e.g., due to Tourette's syndrome), family history of sudden death/irregular heartbeat/rhythm, mild high blood pressure (hypertension), kidney disease, liver disease, family/personal history of mental/mood disorders (e.g., bipolar disorder, depression, psychotic disorder, suicidal thoughts), seizures.

This drug may make you dizzy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist that you are taking this medication.

Caution is advised when using this drug in children because it may affect weight, growth rate, and final height. The doctor may recommend temporarily stopping the medication from time to time to reduce this risk. Monitor your child's weight and height and consult your doctor or pharmacist for more details. This drug is not recommended for use in children under 3.

This medication should be used only when clearly needed during pregnancy. Infants born to mothers dependent on this medication may have birth defects, be born too soon (premature delivery) and have low birth weight. They may also have withdrawal symptoms. Tell your doctor immediately if you notice possible mood changes, agitation, or unusual tiredness in your newborn. Discuss the risks and benefits with your doctor.

This medication passes into breast milk and may have undesirable effects on a nursing infant. Breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: MAO inhibitors.

Avoid taking MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine) within 2 weeks before, during, and after treatment with this medication. In some cases, a serious, possibly fatal drug interaction may occur.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting this medication.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: alpha blockers (e.g., prazosin), certain antidepressants (e.g., tricyclic antidepressants such as nortriptyline and imipramine, SSRIs such as fluoxetine and paroxetine, and SSNRIs such as venlafaxine), certain antihistamines (e.g., diphenhydramine), beta blockers (e.g., atenolol, metoprolol), drugs for high blood pressure (e.g., clonidine, guanabenz, methyldopa), certain drugs for mental/mood conditions (e.g., antipsychotics such as chlorpromazine/haloperidol, lithium), certain pain medicines (e.g., meperidine, propoxyphene), certain anti-seizure drugs (e.g., ethosuximide, phenytoin, phenobarbital), stimulants (e.g., norepinephrine, phenylephrine), veratrum alkaloids (e.g., cevadine, veratridine).

Certain foods and drugs can affect the amount of acid in your stomach/intestines or urine. This can affect how well your body absorbs and uses this medication. Tell your doctor if you take any of these products: ammonium chloride, antacids, anti-ulcer medicine (e.g., H2 blockers such as famotidine and ranitidine, proton pump inhibitors such as omeprazole and lansoprazole), ascorbic acid (vitamin C), aspirin, carbonic anhydrase inhibitors (e.g., acetazolamide), fruit juices, glutamic acid, guanethidine, methenamine, reserpine, sodium acid phosphate, sodium bicarbonate, certain "water pills" (diuretics, including some thiazides).

Also report the use of drugs which might increase seizure risk (decrease seizure threshold) when combined with this medication such as bupropion, isoniazid (INH), phenothiazines (e.g., thioridazine), theophylline, tramadol, or tricyclic antidepressants (e.g., amitriptyline), among others. Consult your doctor or pharmacist for details.

Check the labels on all your medicines (e.g., cough-and-cold products, diet aids) because they may contain ingredients that could increase your heart rate or blood pressure. Ask your pharmacist about the safe use of these products.

Avoid drinking large amounts of beverages containing caffeine (e.g., coffee, tea, colas) or eating large amounts of chocolate. Caffeine can increase the side effects of this medication.

This medication may affect the results of certain lab tests (blood and urine steroid levels). Tell your doctor or laboratory personnel if you are taking this medication.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: severe mental/mood changes, seizures, severe or persistent headache, severe restlessness, fast breathing.

NOTES: Do not share this medication with others. It is against the law.

Laboratory and/or medical tests (e.g., blood pressure, heart rate, growth monitoring in children) may be performed to check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember in the morning hours. If it is after noon, or if it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) in a tightly closed container. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Protect from light and moisture. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.