http://www.adderallxr.com/pdf/prescribing_information.pdf

Everything, except the pharmacokinetics applies to regular adderall.


EDITED BECAUSE TOO LONG FOR FORUM.. SEE PDF for DEtails.
ADDERALL XR® CAPSULES CII Rx Only
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 mg

Dextroamphetamine 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 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.

CLINICAL PHARMACOLOGY

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 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 (8 am) and ADDERALL® (immediate-release) 10 mg bid (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 bid administered 4 hours apart.

The mean elimination half-lives for d-amphetamine and l-amphetamine in adults are 10 hours and 13 hours,

respectively. In children aged 6 to 12 years, the mean elimination half-life is 1 hour shorter for d-amphetamine

(9 hours) and 2 hours shorter for l-amphetamine (11 hours). 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.

ADDERALL XR® demonstrates linear pharmacokinetics over the dose range of 20 to 60 mg in adults 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.

Special Populations

Pediatric Patients

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.

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.

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.

Adults

A double-blind, randomized, placebo-controlled, parallel-group study was conducted in adults (N=255) who met

DSM-IV-TR 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.

INDICATIONS

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, 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 hyperactiveimpulsive

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 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.

CONTRAINDICATIONS

Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension,

hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma.

Agitated states.

Patients with a history of drug abuse.

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

result).

WARNINGS

Psychosis: Clinical experience suggests that, in psychotic patients, administration of amphetamine may

exacerbate symptoms of behavior disturbance and thought disorder.

Long-Term Suppression of Growth: Data are inadequate to determine whether chronic use of stimulants in

children, including amphetamine, may be causally associated with suppression of growth. Therefore, growth

should be monitored during treatment, and patients who are not growing or gaining weight as expected should

have their treatment interrupted.

Sudden Death and Pre-existing Structural Cardiac Abnormalities: Sudden death has been reported in

association with amphetamine treatment at usual doses in children with structural cardiac abnormalities.

Adderall XR® generally should not be used in children or adults with structural cardiac abnormalities.

PRECAUTIONS

General: The least amount of amphetamine feasible should be prescribed or dispensed at one time in order to

minimize the possibility of overdosage.

Hypertension: Caution is to be exercised in prescribing amphetamines for patients with even mild hypertension

(see CONTRAINDICATIONS). Blood pressure and pulse should be monitored at appropriate intervals in patients

taking ADDERALL XR®, especially patients with hypertension.

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.

Drug Interactions: Acidifying agents—Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid

HCI, 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.

AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR

PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE. PARTICULAR ATTENTION SHOULD BE

PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR

DISTRIBUTION TO OTHERS AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY.

MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE

EVENTS.

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*included doses up to 60 mg.

The following adverse reactions have been associated with amphetamine use:

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.

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 many times that

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.

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

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.

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

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.

Manufactured for: Shire US Inc., Newport, KY 41071

Made in USA

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

ADDERALL® and ADDERALL XR® are registered in the US Patent and Trademark Office

Copyright ©2004 Shire US Inc.

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381 0107 004 Rev. 9/04