NDC 54092-383 Adderall XR

Dextroamphetamine Sulfate, Dextroamphetamine Saccharate, Amphetamine Sulfate And Amphetamine Aspartate

NDC Product Code 54092-383

NDC CODE: 54092-383

Proprietary Name: Adderall XR What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Dextroamphetamine Sulfate, Dextroamphetamine Saccharate, Amphetamine Sulfate And Amphetamine Aspartate What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This combination medication is used to treat attention deficit hyperactivity disorder - ADHD. It works by changing the amounts of certain natural substances in the brain. Amphetamine/dextroamphetamine belongs to a class of drugs known as stimulants. It can help increase your ability to pay attention, stay focused on an activity, and control behavior problems. It may also help you to organize your tasks and improve listening skills. This drug is also used to treat a certain sleeping disorder (narcolepsy) to help you stay awake during the day. It should not be used to treat tiredness or to hold off sleep in people who do not have a sleep disorder.

Product Characteristics

Color(s):
BLUE (C48333 - BLUE)
Shape: CAPSULE (C48336)
Size(s):
16 MM
Imprint(s):
ADDERALL;XR;5;MG
ADDERALL;XR;10;MG
Score: 1

NDC Code Structure

  • 54092 - Takeda Pharmaceuticals America, Inc.

NDC 54092-383-01

Package Description: 100 CAPSULE, EXTENDED RELEASE in 1 BOTTLE

Price per Unit: $6.82921 per EA

NDC Product Information

Adderall XR with NDC 54092-383 is a a human prescription drug product labeled by Takeda Pharmaceuticals America, Inc.. The generic name of Adderall XR is dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate. The product's dosage form is capsule, extended release and is administered via oral form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 861221, 861222, 861223, 861224, 861225, 861226, 861227, 861228, 861232, 861233, 861237 and 861238.

Dosage Form: Capsule, Extended Release - A solid dosage form in which the drug is enclosed within either a hard or soft soluble container made from a suitable form of gelatin, and which releases a drug (or drugs) in such a manner to allow a reduction in dosing frequency as compared to that drug (or drugs) presented as a conventional dosage form.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

DEA Schedule: Schedule II (CII) Substances What is the Drug Enforcement Administration (DEA) CII Schedule?
The controlled substances in the CII schedule have a high abuse potential with severe psychological or physical dependence liability, but have accepted medical use in the United States. Schedule CII controlled substances include certain narcotic, stimulant, and depressant drugs.

Adderall XR Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) (UNII: 74G4R6TH13)
  • SUCROSE (UNII: C151H8M554)
  • TALC (UNII: 7SEV7J4R1U)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) (UNII: 74G4R6TH13)
  • SUCROSE (UNII: C151H8M554)
  • TALC (UNII: 7SEV7J4R1U)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Central Nervous System Stimulant - [EPC] (Established Pharmacologic Class)
  • Central Nervous System Stimulation - [PE] (Physiologic Effect)
  • Central Nervous System Stimulant - [EPC] (Established Pharmacologic Class)
  • Central Nervous System Stimulation - [PE] (Physiologic Effect)
  • Central Nervous System Stimulant - [EPC] (Established Pharmacologic Class)
  • Central Nervous System Stimulation - [PE] (Physiologic Effect)
  • Central Nervous System Stimulant - [EPC] (Established Pharmacologic Class)
  • Central Nervous System Stimulation - [PE] (Physiologic Effect)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Takeda Pharmaceuticals America, Inc.
Labeler Code: 54092
FDA Application Number: NDA021303 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-11-2001 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Dextroamphetamine and Amphetamine

Dextroamphetamine and Amphetamine is pronounced as (dex troe am fet' a meen) (am fet' a meen)

Why is dextroamphetamine and amphetamine medication prescribed?
The combination of dextroamphetamine and amphetamine is used as part of a treatment program to control symptoms of attention deficit hyperactivity disorder (ADHD; more di...
[Read More]

* Please review the disclaimer below.

Adderall XR Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Potential For Abuse

Amphetamines have a high potential for abuse. Administration of amphetamines for prolonged periods of time may lead to drug dependence. Pay particular attention to the possibility of subjects obtaining amphetamines for non-therapeutic use or distribution to others and the drugs should be prescribed or dispensed sparingly [see DRUG ABUSE AND DEPENDENCE (9)].Misuse of amphetamine may cause sudden death and serious cardiovascular adverse reactions.

1.1 Attention Deficit Hyperactivity Disorder

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 STUDIES (14)].A diagnosis of 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 ConsiderationsSpecific 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 patient and not solely on the presence of the required number of DSM-IV® characteristics. Need for Comprehensive Treatment ProgramADDERALL 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 patients with this syndrome. Stimulants are not intended for use in the patient 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 UseThe 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.

2.1 Dosing Considerations For All Patients

Individualize the dosage according to the therapeutic needs and response of the patient. Administer ADDERALL XR at the lowest effective dosage.Based on bioequivalence data, patients taking divided doses of immediate-release ADDERALL, (for example, twice daily), 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, ADDERALL XR therapy should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.

2.2 Children

In children with ADHD who are 6-12 years of age 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. ADDERALL XR has not been studied in children under 6 years of age.

2.3 Adolescents

The recommended starting dose for adolescents with ADHD who are 13-17 years of age and are either starting treatment for the first time or switching from another medication is 10 mg/day. The dose may be increased to 20 mg/day after one week if ADHD symptoms are not adequately controlled.

2.4 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.

3 Dosage Forms And Strengths

ADDERALL XR 5 mg capsules: Clear/blue (imprinted ADDERALL XR 5 mg)ADDERALL XR 10 mg capsules: Blue/blue (imprinted ADDERALL XR 10 mg) ADDERALL XR 15 mg capsules: Blue/white (imprinted ADDERALL XR 15 mg)ADDERALL XR 20 mg capsules: Orange/orange (imprinted ADDERALL XR 20 mg) ADDERALL XR 25 mg capsules: Orange/white (imprinted ADDERALL XR 25 mg) ADDERALL XR 30 mg capsules: Natural/orange (imprinted ADDERALL XR 30 mg)

4 Contraindications

  • ADDERALL XR administration is contraindicated in patients with the following conditions:Advanced arteriosclerosisSymptomatic cardiovascular diseaseModerate to severe hypertensionHyperthyroidismIn patients known to be hypersensitive to amphetamine, or other components of ADDERALL XR. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [see ADVERSE REACTIONS (6.2)]GlaucomaAgitated statesHistory of drug abusePatients 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 PRECAUTIONS (5.6) and DRUG INTERACTIONS (7.1)]

5.1 Serious Cardiovascular Events

Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart ProblemsChildren and AdolescentsSudden 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 (4)].AdultsSudden 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 (4)].Hypertension and Other Cardiovascular ConditionsStimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), 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 (4) and ADVERSE REACTIONS (6)].Assessing Cardiovascular Status in Patients being Treated with Stimulant MedicationsChildren, 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.

5.2 Psychiatric Adverse Events

Pre-Existing PsychosisAdministration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychotic disorder.Bipolar IllnessParticular 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 SymptomsTreatment-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.AggressionAggressive 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.

5.3 Long-Term Suppression Of Growth

Monitor growth in children during treatment with stimulants. Patients who are not growing or gaining weight as expected may need to have their treatment interrupted. 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. Chronic use of amphetamines can be expected to cause a similar suppression of growth.

5.4 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, ADDERALL XR should be discontinued.

5.5 Peripheral Vasculopathy, Including Raynaud's Phenomenon

Stimulants, including ADDERALL XR, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon.  Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown.  Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment.  Signs and symptoms generally improve after reduction in dose or discontinuation of drug.  Careful observation for digital changes is necessary during treatment with ADHD stimulants.  Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

5.6 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 MAOIs, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort [see DRUG INTERACTIONS (7.1)]. Amphetamines and amphetamine derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor inhibition of CYP2D6 metabolism [see CLINICAL PHARMACOLOGY (12.3)]. The potential for a pharmacokinetic interaction exists with the co-administration of CYP2D6 inhibitors which may increase the risk with increased exposure to ADDERALL XR. In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see DRUG INTERACTIONS (7.1)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).Concomitant use of ADDERALL XR with MAOI drugs is contraindicated [see CONTRAINDICATIONS (4)]. Discontinue treatment with ADDERALL XR and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. Concomitant use of ADDERALL XR with other serotonergic drugs or CYP2D6 inhibitors should be used only if the potential benefit justifies the potential risk. If clinically warranted, consider initiating ADDERALL XR with lower doses, monitoring patients for the emergence of serotonin syndrome during drug initiation or titration, and informing patients of the increased risk for serotonin syndrome.

5.7 Visual Disturbance

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

5.8 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 patients and their families should precede use of stimulant medications.

5.9 Prescribing And Dispensing

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.

6 Adverse Reactions

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.

6.1 Clinical Studies Experience

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 reactions, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.Adverse reactions 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 reactions without first grouping similar types of reactions into a smaller number of standardized event categories. In the tables and listings that follow, COSTART terminology has been used to classify reported adverse reactions.The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed.Adverse Reactions Leading to Discontinuation of TreatmentIn 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 reactions (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 reactions leading to discontinuation of ADDERALL XR in controlled and uncontrolled, multiple-dose clinical trials of children (N=595) were anorexia (loss of appetite) (2.9%), insomnia (1.5%), weight loss (1.2%), emotional lability (1%), and depression (0.7%). 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, five patients (2.1%) discontinued treatment due to adverse events among ADDERALL XR-treated patients (N=233) compared to none who received placebo (N=54). The most frequent adverse event leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation in at least 1% of ADDERALL XR-treated patients and at a rate at least twice that of placebo) was insomnia (1.3%, n=3).In one placebo-controlled 4-week study among adults with ADHD with doses 20 mg to 60 mg, 23 patients (12.0%) discontinued treatment due to adverse events among ADDERALL XR-treated patients (N=191) compared to one patient (1.6%) who received placebo (N=64). The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation in at least 1% of ADDERALL XR-treated patients and at a rate at least twice that of placebo) were insomnia (5.2%, n=10), anxiety (2.1%, n=4), nervousness (1.6%, n=3), dry mouth (1.6%, n=3), anorexia (1.6%, n=3), tachycardia (1.6%, n=3), headache (1.6%, n=3), and asthenia (1.0%, n=2).Adverse Reactions Occurring in Controlled TrialsAdverse reactions reported in a 3-week clinical trial of children and a 4-week clinical trial in adolescents and adults, respectively, treated with ADDERALL XR or placebo are presented in the tables below.Table 1 Adverse Reactions Reported by 2% or More of Children (6-12 Years Old) Receiving ADDERALL XR with Higher Incidence Than on Placebo in a 584-Patient Clinical Study Body System  Preferred Term ADDERALL XR (n=374) Placebo (n=210) General Abdominal Pain (stomachache) Fever Infection Accidental Injury Asthenia (fatigue) 14% 5% 4% 3% 2% 10% 2% 2% 2% 0% Digestive System Loss of Appetite Vomiting  Nausea Dyspepsia 22% 7% 5% 2% 2% 4% 3% 1% Nervous System Insomnia Emotional Lability Nervousness  Dizziness 17% 9% 6% 2% 2% 2% 2% 0%  Metabolic/Nutritional Weight Loss 4% 0%Table 2 Adverse Reactions Reported by 5% or More of Adolescents (13-17 Years Old) Weighing ≤ 75 kg/165 lbs Receiving ADDERALL XR with Higher Incidence Than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study**Included doses up to 40 mga Appears the same due to rounding b Dose-related adverse reactionsNote: The following reactions did not meet the criterion for inclusion in Table 2 but were reported by 2% to 4% of adolescent patients receiving ADDERALL XR with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting. Body SystemPreferred TermADDERALL XR(n=233)Placebo(n=54) GeneralAbdominal Pain (stomachache) 11% 2%  Digestive SystemLoss of Appetite b36% 2%  Nervous SystemInsomnia bNervousness 12%6% 4%6%a Metabolic/NutritionalWeight Loss b9% 0% Table 3 Adverse Reactions 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**Included doses up to 60 mg.a Appears the same due to roundingNote: The following reactions did not meet the criterion for inclusion in Table 3 but were reported by 2% to 4% of adult patients receiving ADDERALL XR with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder (e.g., teeth clenching, tooth infection), emotional lability, libido decreased, somnolence, speech disorder (e.g., stuttering, excessive speech), palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence. Body SystemPreferred TermADDERALL XR(n=191)Placebo(n=64) GeneralHeadacheAsthenia 26%6% 13%5%  Digestive SystemDry MouthLoss of AppetiteNauseaDiarrhea 35%33%8%6% 5%3%3%0%  Nervous SystemInsomniaAgitationAnxietyDizzinessNervousness27%8%8%7%13%13%5%5%0%13%a Cardiovascular SystemTachycardia 6% 3%  Metabolic/NutritionalWeight Loss 10% 0%  Urogenital SystemUrinary Tract Infection 5% 0% Hypertension [see WARNINGS AND PRECAUTIONS (5.1)]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 with ADHD, 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.

6.2 Adverse Reactions Associated With The Use Of Amphetamine, Adderall Xr, Or Adderall

The following adverse reactions have been associated with the use of amphetamine, ADDERALL XR, or ADDERALL:CardiovascularPalpitations. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.Central Nervous SystemPsychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression, anger, logorrhea, dermatillomania, paresthesia (including formication), and bruxism.Eye DisordersVision blurred, mydriasis.GastrointestinalUnpleasant taste, constipation, other gastrointestinal disturbances.AllergicUrticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported.EndocrineImpotence, changes in libido, frequent or prolonged erections.SkinAlopecia.Vascular DisordersRaynaud's phenomenon.Musculoskeletal and Connective Tissue DisordersRhabdomyolysis

7.1 Clinically Important Interactions With Amphetamines

Table 4: Drugs Having Clinically Important Interactions with AmphetaminesMonoamine Oxidase Inhibitors (MAOIs)Clinical ImpactConcomitant 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.InterventionDo not administer ADDERALL XR concomitantly or within 14 days after discontinuing MAOI [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.6)].Examplesselegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blueSerotonergic DrugsClinical ImpactThe concomitant use of ADDERALL XR and serotonergic drugs increases the risk of serotonin syndrome.InterventionInitiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during ADDERALL XR initiation or dosage increase. If serotonin syndrome occurs, discontinue ADDERALL XR and the concomitant serotonergic drug(s) [see WARNINGS AND PRECAUTIONS (5.6)].Examplesselective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's WortCYP2D6 InhibitorsClinical ImpactThe concomitant use of ADDERALL XR and CYP2D6 inhibitors may increase the exposure of ADDERALL XR compared to the use of the drug alone and increase the risk of serotonin syndrome.InterventionInitiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during ADDERALL XR initiation and after a dosage increase. If serotonin syndrome occurs, discontinue ADDERALL XR and the CYP2D6 inhibitor [see WARNINGS AND PRECAUTIONS (5.6) and OVERDOSAGE (10)].Examplesparoxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavirAlkalinizing AgentsClinical ImpactIncrease blood levels and potentiate the action of amphetamine.InterventionCo-administration of ADDERALL XR and gastrointestinal or urinary alkalinizing agents should be avoided.ExamplesGastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides).Acidifying AgentsClinical ImpactLower blood levels and efficacy of amphetamines.InterventionIncrease dose based on clinical response.ExamplesGastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid).Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).Tricyclic AntidepressantsClinical ImpactMay 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.InterventionMonitor frequently and adjust or use alternative therapy based on clinical response.Examplesdesipramine, protriptylineProton Pump InhibitorsClinical ImpactTime to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone.InterventionMonitor patients for changes in clinical effect and adjust therapy based on clinical response.Examplesomeprazole

8.1 Pregnancy

Teratogenic EffectsPregnancy Category C. Amphetamine, in the enantiomer ratio present in ADDERALL XR (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 2 and 12 times, respectively, the maximum recommended human dose (MRHD) for adolescents of 20 mg/day, 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 10 times the MRHD for adolescents on a mg/m2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity.A study was conducted in which pregnant rats received daily oral doses of amphetamine (d- to l- enantiomer ratio of 3:1, the same as in ADDERALL XR) of 2, 6, and 10 mg/kg from gestation day 6 to lactation day 20. These doses are approximately 0.8, 2, and 4 times the MRHD for adolescents of 20 mg/day, on a mg/m2 basis. All doses caused hyperactivity and decreased weight gain in the dams. A decrease in pup survival was seen at all doses. A decrease in pup bodyweight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks. Increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at 5 weeks postweaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg.A number of studies 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 EffectsInfants 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.

8.2 Labor And Delivery

The effects of ADDERALL XR on labor and delivery in humans is unknown.

8.3 Nursing Mothers

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

8.4 Pediatric Use

ADDERALL XR is indicated for use in children 6 years of age and older.The safety and efficacy of ADDERALL XR in children under 6 years of age have not been studied. Long-term effects of amphetamines in children have not been well established.In a juvenile developmental study, rats received daily oral doses of amphetamine (d to l enantiomer ratio of 3:1, the same as in ADDERALL XR) of 2, 6, or 20 mg/kg on days 7-13 of age; from day 14 to approximately day 60 of age these doses were given b.i.d. for total daily doses of 4, 12, or 40 mg/kg. The latter doses are approximately 0.6, 2, and 6 times the maximum recommended human dose for children of 30 mg/day, on a mg/m2 basis. Post dosing hyperactivity was seen at all doses; motor activity measured prior to the daily dose was decreased during the dosing period but the decreased motor activity was largely absent after an 18 day drug-free recovery period. Performance in the Morris water maze test for learning and memory was impaired at the 40 mg/kg dose, and sporadically at the lower doses, when measured prior to the daily dose during the treatment period; no recovery was seen after a 19 day drug-free period. A delay in the developmental milestones of vaginal opening and preputial separation was seen at 40 mg/kg but there was no effect on fertility.

8.5 Geriatric Use

ADDERALL XR has not been studied in the geriatric population.

9.1 Controlled Substance

ADDERALL XR is a Schedule II controlled substance.

9.2 Abuse And Dependence

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.

10 Overdosage

Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Serotonin syndrome has been reported with amphetamine use, including ADDERALL XR. 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.TreatmentConsult with a Certified Poison Control Center for up to date guidance and advice.The prolonged release of mixed amphetamine salts from ADDERALL XR should be considered when treating patients with overdose.

11 Description

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.Each capsule contains:  5 mg  10 mg  15 mg  20 mg  25 mg  30 mgDextroamphetamine Saccharate   1.25 mg   2.5 mg   3.75 mg   5.0 mg   6.25 mg   7.5 mg Amphetamine Aspartate Monohydrate   1.25 mg   2.5 mg   3.75 mg   5.0 mg   6.25 mg   7.5 mg Dextroamphetamine Sulfate USP   1.25 mg   2.5 mg   3.75 mg   5.0 mg   6.25 mg   7.5 mg Amphetamine Sulfate USP   1.25 mg   2.5 mg   3.75 mg   5.0 mg   6.25 mg   7.5 mg Total amphetamine base equivalence   3.1 mg   6.3 mg   9.4 mg   12.5 mg   15.6 mg   18.8 mg Inactive Ingredients and ColorsThe 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.

12.1 Mechanism Of Action

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in 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.

12.3 Pharmacokinetics

Pharmacokinetic studies of ADDERALL XR have been conducted in healthy adult and pediatric (children aged 6-12 yrs) subjects, and adolescent (13-17 yrs) and children 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 (8 am) and ADDERALL (immediate-release) 10 mg Twice Daily (8 am 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 twice daily 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 below).ADDERALL XR demonstrates linear pharmacokinetics over the dose range of 20 to 60 mg in adults and adolescents weighing greater than 75 kg/165 lbs, 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 2.7 hours (from 5.6 hrs at fasted state to 8.3 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 ExcretionAmphetamine 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 DRUG INTERACTIONS (7)].Special PopulationsComparison of the pharmacokinetics of d- and l-amphetamine after oral administration of ADDERALL XR in children (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 (VZ/F), oral clearance (CL/F), and elimination half-life (t1/2) increased with increases in body weight.Pediatric PatientsOn a mg/kg weight basis, children eliminated amphetamine faster than adults. The elimination half-life (t1/2) 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.GenderSystemic 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.RaceFormal 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).

13.1 Carcinogenesis, Mutagenesis, 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 for children of 30 mg/day, on a mg/m2 body surface area basis.Amphetamine, in the enantiomer ratio present in ADDERALL XR (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 XR (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 8 times the maximum recommended human dose for adolescents of 20 mg/day, on a mg/m2 body surface area basis).

13.2 Animal Toxicology And/Or Pharmacology

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

14 Clinical Studies

Pediatric PatientsA 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.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 Attention Deficit Hyperactivity Disorder-Rating Scale IV (ADHD-RS-IV) total score for the primary cohort. The ADHD-RS-IV is an 18-item scale that measures the core symptoms of ADHD. 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.Adult PatientsA 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.

16 How Supplied/Storage And Handling

ADDERALL XR 5 mg capsules: Clear/blue (imprinted ADDERALL XR 5 mg), bottles of 100, NDC 54092-381-01ADDERALL XR 10 mg capsules: Blue/blue (imprinted ADDERALL XR 10 mg), bottles of 100, NDC 54092-383-01ADDERALL XR 15 mg capsules: Blue/white (imprinted ADDERALL XR 15 mg), bottles of 100, NDC 54092-385-01ADDERALL XR 20 mg capsules: Orange/orange (imprinted ADDERALL XR 20 mg), bottles of 100, NDC 54092-387-01ADDERALL XR 25 mg capsules: Orange/white (imprinted ADDERALL XR 25 mg), bottles of 100, NDC 54092-389-01ADDERALL XR 30 mg capsules: Natural/orange (imprinted ADDERALL XR 30 mg), bottles of 100, NDC 54092-391-01Dispense in a tight, light-resistant container as defined in the USP.Store at 25° C (77° F). Excursions permitted to 15-30° C (59-86° F) [see USP Controlled Room Temperature]

17.1 Information On Medication Guide

Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with ADDERALL XR and should counsel them in its appropriate use. A patient Medication Guide is available for ADDERALL XR. Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. Give patients 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.

17.2 Controlled Substance Status/Potential For Abuse, Misuse, And Dependence

Advise patients that ADDERALL XR is a federally controlled substance because it can be abused or lead to dependence. Additionally, emphasize that ADDERALL XR should be stored in a safe place to prevent misuse and/or abuse. Evaluate patient history (including family history) of abuse or dependence on alcohol, prescription medicines, or illicit drugs [see DRUG ABUSE AND DEPENDENCE (9)].

17.3 Serious Cardiovascular Risks

Advise patients of serious cardiovascular risk (including sudden death, myocardial infarction, stroke, and hypertension) with ADDERALL XR. Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during treatment should undergo a prompt cardiac evaluation [see WARNINGS AND PRECAUTIONS (5.1)].

17.4 Psychiatric Risks

Prior to initiating treatment with ADDERALL XR, adequately screen patients with comorbid depressive symptoms 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/or depression. Additionally, ADDERALL XR therapy at usual doses may cause treatment-emergent psychotic or manic symptoms in patients without prior history of psychotic symptoms or mania [see WARNINGS AND PRECAUTIONS (5.2)].

17.5 Circulation Problems In Fingers And Toes [Peripheral Vasculopathy, Including Raynaud's Phenomenon]

Instruct patients beginning treatment with ADDERALL XR about the risk of peripheral vasculopathy, including Raynaud's Phenomenon, and in 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 ADDERALL XR.  Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see WARNINGS AND PRECAUTIONS (5.5)].

17.6 Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with concomitant use of ADDERALL XR and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.6) and DRUG INTERACTIONS (7.1)]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

17.7 Concomitant Medications

Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs because there is a potential for interactions [see DRUG INTERACTIONS (7.1)].

17.8 Growth

Monitor growth in children during treatment with ADDERALL XR, and patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see WARNINGS AND PRECAUTIONS (5.3)].

17.9 Pregnancy

Advise patients to notify their physicians if they become pregnant or intend to become pregnant during treatment [see USE IN SPECIFIC POPULATIONS (8.1)].

17.10 Nursing

Advise patients not to breast feed if they are taking ADDERALL XR [see USE IN SPECIFIC POPULATIONS (8.3)].

17.11 Impairment In Ability To Operate Machinery Or Vehicles

ADDERALL XR 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.Manufactured for Shire US Inc., 300 Shire Way, Lexington, MA 02421, Made in USA.For more information call 1-800-828-2088Pharmacist: Medication Guide to be dispensed to patientsADDERALL XR® is a registered trademark of Shire LLCADDERALL® is a registered trademark of Shire LLC, under license to Duramed Pharmaceuticals, Inc.Copyright© 2017 Shire US Inc.Rev. 01/2017

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