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PRODUCT MONOGRAPH
INCLUDING PATIENT MEDICATION INFORMATION
ADDERALL XR®
mixed salts amphetamine
extended-release capsule
5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg
Oral
Central Nervous System Stimulant
Takeda Canada Inc.
22 Adelaide Street West, Suite 3800
Toronto, Ontario
M5H 4E3
Date of Initial Authorization:
JAN 23, 2004
Date of Revision:
MAR 09, 2023
Submission Control Number: 269618
ADDERALL XR
®
and ADDERALL
®
are registered trademarks of Takeda Pharmaceuticals U.S.A., Inc.
TAKEDA® and the TAKEDA Logo
®
are registered trademarks of Takeda Pharmaceutical Company Limited,
used under license.
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RECENT MAJOR LABEL CHANGES
No major label changes during the past 24 months.
TABLE OF CONTENTS
Sections or subsections that are not applicable at the time of authorization are not listed.
RECENT MAJOR LABEL CHANGES ........................................................................................... 2
TABLE OF CONTENTS ............................................................................................................. 2
PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4
1 INDICATIONS .............................................................................................................. 4
1.1 Pediatrics ................................................................................................................... 5
1.2 Geriatrics ................................................................................................................... 5
2 CONTRAINDICATIONS ................................................................................................. 5
3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 5
4 DOSAGE AND ADMINISTRATION ................................................................................. 5
4.1 Dosing Considerations .............................................................................................. 5
4.2 Recommended Dose and Dosage Adjustment ......................................................... 6
4.4 Administration .......................................................................................................... 6
4.5 Missed Dose .............................................................................................................. 7
5 OVERDOSAGE ............................................................................................................. 7
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 8
7 WARNINGS AND PRECAUTIONS .................................................................................. 9
7.1 Special Populations ................................................................................................. 14
7.1.1 Pregnant Women .............................................................................................. 14
7.1.2 Breast-feeding ................................................................................................... 14
7.1.3 Pediatrics ........................................................................................................... 14
7.1.4 Geriatrics ........................................................................................................... 14
8 ADVERSE REACTIONS................................................................................................ 14
8.1 Adverse Reaction Overview .................................................................................... 14
8.2 Clinical Trial Adverse Reactions .............................................................................. 15
8.2.1 Clinical Trial Adverse Reactions – Pediatrics..................................................... 18
8.5 Post-Market Adverse Reactions .............................................................................. 20
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9 DRUG INTERACTIONS ............................................................................................... 20
9.2 Drug Interactions Overview .................................................................................... 20
9.4 Drug-Drug Interactions ........................................................................................... 21
9.5 Drug-Food Interactions ........................................................................................... 22
9.6 Drug-Herb Interactions ........................................................................................... 22
9.7 Drug-Laboratory Test Interactions.......................................................................... 22
10 CLINICAL PHARMACOLOGY ....................................................................................... 22
10.1 Mechanism of Action ........................................................................................ 22
10.2 Pharmacodynamics ........................................................................................... 22
10.3 Pharmacokinetics .............................................................................................. 23
11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 27
PART II: SCIENTIFIC INFORMATION ...................................................................................... 28
13 PHARMACEUTICAL INFORMATION ........................................................................... 28
14 CLINICAL TRIALS ....................................................................................................... 29
14.1 Clinical Trials by Indication ............................................................................... 29
14.2 Comparative Bioavailability Studies ................................................................. 31
16 NON-CLINICAL TOXICOLOGY ..................................................................................... 33
PATIENT MEDICATION INFORMATION ................................................................................. 35
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PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
ADDERALL XR (mixed salts amphetamine extended-release capsules) is indicated for the treatment of
Attention Deficit Hyperactivity Disorder (ADHD) in:
• Children (6 – 12 years of age)
• Adolescents (13 – 17 years of age)
• Adults (18 years of age or older)
A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive and/or inattentive
symptoms that caused impairment and that were present before age 7 years. The symptoms must be
persistent, must be more severe than is typically observed in individuals at a comparable level of
development, must cause clinically significant impairment (e.g., in social, academic, or occupational
functioning), and must 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.
For a Combined Type diagnosis, both inattentive and hyperactive impulsive criteria must be met.
Special Diagnostic Considerations
The specific etiology of ADHD 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 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 patients with this syndrome. Drug treatment is 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 in patients with this
diagnosis and psychosocial intervention is often helpful. When remedial measures alone are insufficient,
the decision to prescribe drug treatment will depend upon the physician's assessment of the chronicity
and severity of the patient’s symptoms.
Long-Term Use
The effectiveness of ADDERALL XR for long-term use, i.e., for more than 3 weeks in children aged 6 to 12
years and 4 weeks in adolescents aged 13 to 17 years, 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 (see 4 DOSAGE
AND ADMINISTRATION).
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1.1 Pediatrics
Pediatrics (<6 years old): ADDERALL XR should not be used in children under six years, since safety and
efficacy in this age group have not been studied.
1.2 Geriatrics
ADDERALL XR has not been studied in the geriatric population, therefore, Health Canada has not
authorized an indication for geriatric use.
2 CONTRAINDICATIONS
ADDERALL XR (mixed salts amphetamine extended-release capsules) is contraindicated in patients who
are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal
ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS,
COMPOSITION AND PACKAGING.
ADDERALL XR is contraindicated in patients with the following conditions:
• Advanced arteriosclerosis
• Symptomatic cardiovascular disease
• Moderate to severe hypertension
• Hyperthyroidism
• Known hypersensitivity or idiosyncrasy to the sympathomimetic amines
• Glaucoma
• Agitated states
• History of drug abuse
• During or within 14 days following the administration of monoamine oxidase inhibitors
(hypertensive crises may result; see 7 WARNINGS AND PRECAUTIONS; 9.4 Drug-Drug Interactions)
• Allergy to amphetamines
3 SERIOUS WARNINGS AND PRECAUTIONS BOX
Serious Warnings and Precautions
Misuse and Serious Cardiovascular Adverse Events
Amphetamines have a potential for abuse, misuse, dependence, or diversion for non-therapeutic uses
that physicians should consider when prescribing this product (see 7 WARNINGS AND PRECAUTIONS,
Dependence/Tolerance).
The misuse of amphetamines may cause serious cardiovascular adverse events and sudden death.
4 DOSAGE AND ADMINISTRATION
4.1 Dosing Considerations
• ADDERALL XR is a once-a-day capsule administered orally in the morning. ADDERALL XR dosage
should be individualized according to the needs and response of the patient.
• ADDERALL XR should be administered starting at the lowest possible dose. Dosage should then be
individually and slowly adjusted, to the lowest effective dosage, since individual patient response to
ADDERALL XR varies widely.
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• In patients with severe renal insufficiency (GFR 15 to <30 mL/min/1.73 m
2
), the maximum dose
should not exceed 20 mg/day. Further dosage reduction should be considered in patients
undergoing dialysis (see 10.3 Pharmacokinetics, Special Populations and Conditions; 7 WARNINGS
AND PRECAUTIONS, Renal).
• Prior to the initiation of treatment with sympathomimetic medications, a personal and family
history (including assessment for a family history of sudden death or ventricular arrhythmia) and
physical exam should be obtained to assess for the presence of cardiac disease. In patients with
relevant risk factors and based on the clinician’s judgment, further cardiovascular evaluation may be
considered (e.g., electrocardiogram and echocardiogram) (see 7 WARNINGS AND PRECAUTIONS,
Cardiovascular). Patients who develop symptoms such as exertional chest pain, unexplained
syncope, or other symptoms suggestive of cardiac disease during ADHD treatment should undergo a
prompt cardiac evaluation.
• Patients who are considered to need extended treatment with ADDERALL XR should undergo
periodic evaluation of their cardiovascular status (see 7 WARNINGS AND PRECAUTIONS,
Cardiovascular).
4.2 Recommended Dose and Dosage Adjustment
Children (6 to 12 years of age)
Amphetamines are not recommended for children under 6 years of age. When in the judgment of the
clinician a lower dose is appropriate, patients may begin treatment with 5 mg once daily in the morning.
The usual starting dose is 10 mg daily. The daily dosage may be adjusted in increments of 5 mg to 10 mg
at weekly intervals, as determined by clinical response and tolerability up to the maximum
recommended dose of 30 mg per day.
Adolescents (13 to 17 years of age) and Adults (over 18 years of age)
In adolescents and adults with ADHD who are either starting treatment for the first time or switching
from another stimulant medication, start with 10 mg once daily in the morning; daily dosage may be
adjusted in increments of 5 to 10 mg at weekly intervals up to a usual maximum of 20 mg. In some
cases, higher doses not to exceed 30 mg/day may be required, as determined by clinical response and
tolerability.
4.4 Administration
ADDERALL XR is a once-a-day capsule for the treatment of ADHD containing immediate-release and
delayed-release pellets. Capsules may be taken whole with water in the morning, or the capsule may be
opened and the entire contents sprinkled on applesauce. If using the sprinkle administration method,
the sprinkled applesauce should be consumed immediately and not stored. Patients should eat the
applesauce with sprinkled beads in its entirety and refrain from chewing.
The dose of a single capsule should not be divided - the contents of the entire capsule should be taken.
Afternoon doses should be avoided because of the long-acting nature of the drug, including 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.
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4.5 Missed Dose
If a dose is missed in the morning, wait until the next morning and carry on with the next dose at the
usual time. Do not double dose.
5 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: Treatment of overdosage consists of appropriate supportive measures. Consult with a
Certified Poison Control Center for up to date guidance and advice. Management of acute
amphetamine intoxication is largely symptomatic and includes administration of activated charcoal,
administration of a cathartic and sedation. Experience with hemodialysis or peritoneal dialysis is
inadequate to permit its recommendation in this regard. D-amphetamine is not dialyzable. 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 salts amphetamine from ADDERALL XR (mixed salts amphetamine
extended-release capsules) should be considered when treating patients with overdose.
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.
For management of a suspected drug overdose, contact your regional poison control centre.
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6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
a
5 mg, 10 mg and 15 mg capsules only
b
20 mg, 25 mg, 30 mg capsules only
ADDERALL XR is a long-acting, modified-release, single-entity amphetamine product designed for once-
daily administration combining the neutral sulfate salts of d-amphetamine and amphetamine, with the
d-isomer of amphetamine saccharate and d,l amphetamine aspartate. The ADDERALL XR capsule
contains two types of drug-containing beads designed to give a double-pulsed delivery of
amphetamines, which provides for its prolonged duration of action.
Table 1– Dosage Forms, Strengths, Composition and Packaging.
Route of
Administration
Dosage Form /
Strength/Composition
Non-medicinal Ingredients
Oral
Capsule 5 mg, 10 mg, 15
mg, 20 mg, 25 mg, 30 mg
- FD&C Blue #2
a
- gelatin capsules (containing: edible inks,
kosher gelatin, and titanium dioxide)
- hydroxypropyl methylcellulose
- methacrylic acid copolymer
- opadry beige
- red iron oxide
b
- starch
- sugar spheres
- talc
- triethyl citrate
- yellow iron oxide
b
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Table 2 – Amphetamine Quantities in ADDERALL XR Capsules
5 mg
10 mg
15 mg
20 mg
25 mg
30 mg
d-amphetamine Saccharate (mg)
1.25
2.5
3.75
5.0
6.25
7.5
Amphetamine Aspartate
Monohydrate (mg)
1.25
2.5
3.75
5.0
6.25
7.5
d-amphetamine Sulfate USP (mg)
1.25
2.5
3.75
5.0
6.25
7.5
Amphetamine Sulfate USP (mg)
1.25
2.5
3.75
5.0
6.25
7.5
Total racemic amphetamine base
equivalence (mg)
1.5
3.0
4.5
6.0
7.5
9.0
Total non-racemic
d-amphetamine base
equivalence (mg)
1.6
3.3
4.9
6.5
8.1
9.8
ADDERALL XR 5 mg Capsules: Clear/blue, imprinted "ADDERALL XR" on one end and "5mg" on the other.
Bottles of 100.
ADDERALL XR 10 mg Capsules: Blue/blue, imprinted "ADDERALL XR" on one end and "10mg" on the
other. Bottles of 100.
ADDERALL XR 15 mg Capsules: Blue/white, imprinted "ADDERALL XR" on one end and "15mg" on the
other. Bottles of 100.
ADDERALL XR 20 mg Capsules: Orange/orange, imprinted "ADDERALL XR" on one end and "20mg" on
the other. Bottles of 100.
ADDERALL XR 25 mg Capsules: Orange/white, imprinted "ADDERALL XR" on one end and "25mg" on the
other. Bottles of 100.
ADDERALL XR 30 mg Capsules: Clear/orange, imprinted "ADDERALL XR" on one end and "30mg" on the
other. Bottles of 100.
7 WARNINGS AND PRECAUTIONS
Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.
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 (mixed salts amphetamine extended-release
capsules) should be used with caution in patients who use other sympathomimetic drugs.
Carcinogenesis and Mutagenesis
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
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2.4, 1.5, and 0.8 times, respectively, the maximum recommended human dose of 30 mg/day on a mg/m
2
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.
Cardiovascular
Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems and Sudden Death
Children/Adolescents: Sudden death has been reported with sympathomimetic drugs used for ADHD
treatment at therapeutic doses in children/adolescents with structural cardiac abnormalities or other
serious heart problems. Although some serious heart problems alone carry an increased risk of sudden
death, ADDERALL XR (mixed salts amphetamine extended-release capsules) generally should not be
used in children/adolescents with known serious structural cardiac abnormalities or other serious heart
problems (e.g., cardiomyopathy, serious heart rhythm abnormalities) that may place them at increased
vulnerability to the sympathomimetic effects of ADHD drugs (see 2 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
2 CONTRAINDICATIONS).
Children: Theoretically there exists a pharmacological potential for all ADHD drugs to increase the risk of
sudden/cardiac death. Although confirmation of an incremental risk for adverse cardiac events arising
from treatment with ADHD medications is lacking, prescribers should consider this potential risk.
Hypertension and other Cardiovascular Conditions
Sympathomimetic medications can cause a modest increase in average blood pressure and average
heart rate 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 2
CONTRAINDICATIONS). Blood pressure and pulse should be monitored at appropriate intervals in
patients taking ADDERALL XR, especially patients with hypertension.
All drugs with sympathomimetic effects prescribed in the management of ADHD should be used with
caution in patients who: a) are involved in strenuous exercise or activities b) use other sympathomimetic
drugs or c) have a family history of sudden/cardiac death. Prior to the initiation of treatment with
sympathomimetic medications, a personal and family history (including assessment for a family history
of sudden death or ventricular arrhythmia) and physical exam should be obtained to assess for the
presence of cardiac disease. In patients with relevant risk factors and based on the clinician’s judgment,
further cardiovascular evaluation may be considered (e.g., electrocardiogram and echocardiogram).
Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms
suggestive of cardiac disease during ADHD treatment should undergo a prompt cardiac evaluation.
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Dependence/Tolerance
Amphetamines have been extensively abused (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX).
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. The
smallest possible amount of the drug should be prescribed or dispensed at one time. The possibility of
tolerance and psychological dependence, particularly with excessive use, should be kept in mind.
Therefore, care should be taken in the selection of patients for ADDERALL therapy, in particular if
patients have a previous history of drug or alcohol abuse/dependence. Abrupt cessation following
prolonged high dosage administration results in extreme fatigue and mental depression; changes are
also noted on the sleep EEG. Careful supervision is therefore recommended during drug withdrawal.
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.
Endocrine and Metabolism
Long-Term Suppression of Growth
In a controlled trial of ADDERALL XR in adolescents aged 13 to 17 years, 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 for other stimulants report that in children aged 7-10 years, there is a temporary slowing
in growth rate without evidence of growth rebound on treatment. Data are inadequate to determine
whether the chronic use of amphetamines, in children 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 may need to have their treatment interrupted.
Neurologic
Tics
Amphetamines have been reported to exacerbate motor and phonic tics in Tourette’s syndrome.
Therefore, careful clinical evaluation for tics in Tourette’s syndrome in children and their families should
precede use of stimulant medications. ADDERALL XR has been associated with new onset of tics (not
necessarily associated with Tourette’s syndrome).
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 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.
Serotonin toxicity/Serotonin syndrome
Serotonin toxicity also known as serotonin syndrome is a potentially life-threatening condition and has
been reported with amphetamines, including ADDERALL XR, particularly during combined use with other
serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine
reuptake inhibitors (SNRIs). Other common serotonergic drugs include: tricyclic antidepressants (TCAs),
monoamine oxidase inhibitors (MAOIs), serotonin 5-HT
1
receptor agonists (triptans), and 5-HT
3
receptor
antagonist antiemetics (See 9.4 Drug-Drug Interactions).
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Serotonin toxicity is characterised by neuromuscular excitation, autonomic stimulation (e.g. tachycardia,
flushing) and altered mental state (e.g. anxiety, agitation, hypomania). In accordance with the Hunter
Criteria, serotonin toxicity diagnosis is likely when, in the presence of at least one serotonergic agent,
one of the following is observed:
• Spontaneous clonus
• Inducible clonus or ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia and body temperature >38°C and ocular clonus or inducible clonus.
If concomitant treatment with ADDERALL XR and other serotonergic agents is clinically warranted,
careful observation of the patient is advised, particularly during treatment initiation and dose increases
(see 9.4 Drug-Drug Interactions). If serotonin toxicity is suspected, discontinuation of the serotonergic
agents should be considered.
Ophthalmologic
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment
(see 2 CONTRAINDICATIONS).
Psychiatric
Pre-existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in
patients with a pre-existing psychotic disorder.
Screening Patients for Bipolar Disorder
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar
disorder because of concern for possible induction of a 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 / adolescents without a 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.
Suicidal Behavior and Ideation
There have been post-marketing reports of suicide-related events in patients treated with ADHD drugs,
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including cases of ideation, attempts, and very rarely, completed suicide. The mechanism of this risk is
not known. ADHD and its related co-morbidities may be associated with increased risk of suicidal
ideation and/or behavior. Therefore, it is recommended for patients treated with ADHD drugs that
caregivers and physicians monitor for signs of suicide-related behavior, including at dose
initiation/optimization and drug discontinuation. Patients should be encouraged to report any
distressing thoughts or feelings at any time to their healthcare professional. Patients with emergent
suicidal ideation and behavior should be evaluated immediately. The physician should initiate
appropriate treatment of the underlying psychiatric condition and consider a possible change in the
ADHD treatment regimen.
Renal
Due to reduced clearance of d-amphetamine in patients with severe renal insufficiency (GFR 15 to <30
mL/min/1.73 m
2
), observed in a study with lisdexamfetamine, the maximum dose of ADDERALL XR
should not exceed 20 mg/day. Further dosage reduction should be considered in patients undergoing
dialysis, as d-amphetamine is not dialyzable. (see 10.3 Pharmacokinetics, Special Populations and
Conditions; 6 DOSAGE AND ADMINISTRATION).
Reproductive Health: Female and Male Potential
• Fertility
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 5 times the maximum recommended human dose of 30 mg/day on a mg/m
2
body
surface area basis).
• Teratogenic Risk
Amphetamine, in the enantiomer ratio present in ADDERALL XR (d- to l- ratio of 3:1), had no
apparent effect on embryofetal morphological development or survival when orally administered to
pregnant rats and rabbits throughout the period of organogenesis at doses up to 6 and
16 mg/kg/day, respectively. These doses are approximately 1.5 and 8 times the maximum
recommended human dose of 30 mg/day on a mg/m
2
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 the maximum recommended human dose of 30 mg/day on
a mg/m
2
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 in children, 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.
Please see 7.1.1 Pregnant Women.
Vascular
Peripheral Vasculopathy, Including Raynaud’s Phenomenon
Stimulants, such as ADDERALL XR, 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. Although rare, a number of instances of a
condition resembling Raynaud's phenomenon have been reported in clinical trials. Effects of peripheral
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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 stimulants. Further clinical evaluation (e.g.,
rheumatology referral) may be appropriate for certain patients. Caution should therefore be observed if
patients with Raynaud's disease or thromboangiitis obliterans (Buerger’s disease) are to be treated with
ADDERALL XR.
7.1 Special Populations
7.1.1 Pregnant Women
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.
Amphetamines should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
There are no adequate and well-controlled studies with ADDERALL XR in pregnant women. There has
been one report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia
(VATER association) in a baby born to a woman who took d-amphetamine sulfate with lovastatin during
the first trimester of pregnancy.
7.1.2 Breast-feeding
Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain
from nursing.
7.1.3 Pediatrics
Pediatrics (6 to 17 years old): ADDERALL XR is indicated for use in children 6 years of age and older. The
long-term effects of amphetamines in children have not been well established. Amphetamines are not
recommended for use in children with ADHD under 6 years of age.
7.1.4 Geriatrics
ADDERALL XR has not been studied in the geriatric population.
8 ADVERSE REACTIONS
8.1 Adverse Reaction Overview
The pre-marketing development program for ADDERALL XR (mixed salts amphetamine extended-release
capsules) included exposures in a total of 1315 participants in clinical trials (635 pediatric patients aged
6 to 12 years, 350 adolescent patients aged 13-17 years, 248 adult patients, 82 healthy adult subjects).
The 635 pediatric patients were evaluated in two controlled clinical studies, one open-label clinical
study, and two single-dose clinical pharmacology studies (n=40). The 248 adult patients were evaluated
in one controlled clinical study and one open-label clinical study. The 350 adolescent patients were
evaluated in one controlled clinical study and one pharmacokinetic study. Safety data on all patients are
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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.
In a single-dose pharmacokinetic study in 23 adolescents aged 13 to 17 years, 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.
8.2 Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the
clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to
the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be
useful in identifying and approximating rates of adverse drug reactions in real-world use.
Adverse Events Occurring in a Controlled Trial
Adverse events reported in a controlled fixed dose clinical study of adult patients treated with
ADDERALL XR at doses up to 60 mg/day, or placebo, for up to 4 weeks are presented in the following
table.
Table 3 - Adverse Events Reported by ≥1% or More of Adults Receiving Fixed Doses of
ADDERALL XR (up to final doses of 20, 40 or 60 mg/day) with an Incidence Greater than Placebo in
a Controlled Clinical Trial
ADDERALL XR
(n=191)
(%)
Placebo
(n=64)
(%)
General
Headache
Asthenia
Pain
Infection
Photosensitivity Reaction
Chills
Fungal Infection
Neck Pain
26
6
5
4
3
2
2
2
13
5
5
a
2
0
0
0
0
Digestive System
Dry Mouth
Loss of Appetite
Nausea
Diarrhea
Constipation
Tooth Disorder
Gastroenteritis
Thirst
Vomiting
35
33
8
6
4
3
1
1
1
5
3
3
0
0
2
0
0
0
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Table 3 - Adverse Events Reported by ≥1% or More of Adults Receiving Fixed Doses of
ADDERALL XR (up to final doses of 20, 40 or 60 mg/day) with an Incidence Greater than Placebo in
a Controlled Clinical Trial
ADDERALL XR
(n=191)
(%)
Placebo
(n=64)
(%)
Nervous System
Insomnia
Nervousness
Agitation
Anxiety
Dizziness
Hyperkinesia
Libido Decreased
Emotional Lability
Somnolence
Speech Disorder
Amnesia
Depersonalization
Libido Increased
27
13
8
8
7
4
4
3
3
2
1
1
1
13
13
a
5
5
0
3
0
2
2
0
0
0
0
Cardiovascular System
Tachycardia
Palpitation
Hypertension
Vasodilation
6
4
2
1
3
0
0
0
Metabolic/Nutritional
Weight Loss
Bilirubinemia
SGOT Increased
SGPT Increased
10
1
1
1
0
0
0
0
Musculoskeletal
Twitching
Myalgia
Arthralgia
3
2
1
0
2
a
0
Respiratory
Dyspnea
Cough Increased
Sinusitis
3
1
1
0
0
0
Skin and Appendages
Sweating
Rash
3
2
0
0
Special Senses
Taste Perversion
2
0
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Table 3 - Adverse Events Reported by ≥1% or More of Adults Receiving Fixed Doses of
ADDERALL XR (up to final doses of 20, 40 or 60 mg/day) with an Incidence Greater than Placebo in
a Controlled Clinical Trial
ADDERALL XR
(n=191)
(%)
Placebo
(n=64)
(%)
Urogenital System
Urinary Tract Infection
Dysmenorrhea
Impotence
Oliguria
Urinary Tract Disorder
Urination Impaired
5
2
2
1
1
1
0
0
0
0
0
0
a
Appears the same due to rounding
The following adverse reactions have also been associated with the use of amphetamine, or mixed salts
amphetamine:
Cardiovascular System: elevation of blood pressure, sudden death, myocardial infarction, stroke,
palpitations, tachycardia; there have been isolated reports of cardiomyopathy associated with chronic
amphetamine use
Digestive System: anorexia, constipation, diarrhea, dryness of the mouth, unpleasant taste, other
gastrointestinal disturbances
Eye Disorders: mydriasis, vision blurred
Metabolic and Nutritional: weight loss
Nervous System: aggressive behavior, anger, bruxism, depression, dermatillomania, dizziness,
dyskinesia, dysphoria, euphoria, headache, hostility, insomnia, irritability, change in libido, logorrhea,
overstimulation, psychotic and manic episodes at recommended doses (e.g., hallucinations, delusional
thinking, and mania), paresthesia (including formication), restlessness, tremor, new onset of tics or
exacerbation of phonic and motor tics and Tourette’s syndrome, seizures
Skin and Appendages: alopecia, hypersensitivity reactions including angioedema and anaphylaxis,
urticaria, rash. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis
have been reported.
Urogenital System: impotence
Vascular Disorders: Raynaud’s phenomenon, peripheral coldness
Adverse Events Associated with Discontinuation of Treatment
In one placebo-controlled, 4-week study in adults with ADHD, the most frequent adverse events
resulting in discontinuation (>0.5%) in ADDERALL XR treated patients (n=191) were for nervousness
including anxiety and irritability (3.1%); for insomnia (2.6%); and for headache, palpitation, and
somnolence (1% each). In an open-label extension of the trial (n=223), at 12 months, the only adverse
event leading to discontinuation that was reported by at least 2% of patients was depression (4.9%).
Adverse events leading to discontinuations for ADDERALL XR
trials in adults were consistent with those
reported in ADDERALL XR trials in children (see 8.2.1 Clinical Trial Adverse Reactions – Pediatrics) and
were also consistent with the known side effects for amphetamines.
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8.2.1 Clinical Trial Adverse Reactions – Pediatrics
Adverse Events Occurring in a Controlled Trial
Adverse events reported in a controlled fixed-dose clinical study of pediatric patients treated with
ADDERALL XR at doses up to 30 mg/day, or placebo, for up to 3 weeks are presented in the following
table.
Table 4 - Adverse Events Reported by More than 1% of Children aged 6 to 12 years Receiving Fixed
Doses of ADDERALL XR (up to final doses of 10, 20 or 30 mg/day) with an Incidence Greater than
Placebo in a Controlled Clinical Study
ADDERALL XR
(n=374)
(%)
Placebo
(n=210)
(%)
General
Abdominal pain (stomach ache)
Fever
Infection
Accidental Injury
Asthenia (fatigue)
Viral Infection
14
5
4
3
2
2
10
2
2
2
0
0
Digestive System
Loss of Appetite
Vomiting
Nausea
Diarrhea
Dyspepsia
22
7
5
2
2
2
4
3
1
1
Nervous System
Insomnia
Emotional Lability
Nervousness
Dizziness
17
9
6
2
2
2
2
0
Metabolic/Nutritional
Weight Loss
4
0
Adverse events reported in a 4-week clinical trial in adolescents aged 13 to 17 years treated with
ADDERALL XR at doses up to 40 mg/day in adolescents weighing 75 kg/165 lbs, or placebo are
presented in the following table.
Table 5 - Adverse Events Reported by ≥1%
a
or more of Adolescents Weighing 75 kg/165 lbs
Receiving ADDERALL XR with Higher Incidence than Placebo in a Forced Weekly-Dose Titration
Study
a
ADDERALL XR
(n=233)
(%)
Placebo
(n=54)
(%)
General
Abdominal pain (stomach ache)
Asthenia
11
3
2
0
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Table 5 - Adverse Events Reported by ≥1%
a
or more of Adolescents Weighing 75 kg/165 lbs
Receiving ADDERALL XR with Higher Incidence than Placebo in a Forced Weekly-Dose Titration
Study
a
ADDERALL XR
(n=233)
(%)
Placebo
(n=54)
(%)
Cardiovascular
Tachycardia
1
0
Digestive
Loss of Appetite
b
Dry Mouth
Dyspepsia
Nausea
Vomiting
Diarrhea
36
4
3
3
3
2
2
0
0
0
0
0
Nervous
Insomnia
b
Nervousness
Somnolence
Emotional Lability
Depression
Twitching
12
6
5
3
1
1
4
6
c
4
0
0
0
Metabolic/Nutritional
Weight Loss
b
9
0
Skin and Appendages
Herpes Simplex
1
0
Urogenital
Albuminuria
Dysmenorrhea
2
1
0
0
a
Included doses up to 40 mg
b
Dose-related adverse events
c
Appears the same due to rounding
Adverse Events Associated with Discontinuation of Treatment
In two placebo-controlled studies of up to 5 weeks duration in children aged 6 to 12 years 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.
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Table 6 - Most Frequent Adverse Events Resulting in Discontinuation (>0.5%)
Adverse Event
% of Pediatric Patients Discontinuing (n=595)
Anorexia (loss of appetite)
2.9
Insomnia
1.5
Weight Loss
1.2
Emotional Lability
1.0
Depression
0.7
In a separate placebo-controlled 4-week study in adolescents aged 13 to 17 years 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.
8.5 Post-Market Adverse Reactions
The following adverse reactions have been identified during post approval use of ADDERALL XR. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal Disorders: intestinal ischemia
Vascular Disorders: epistaxis, contusion
Suicidal Behavior and Ideation: There have been post-marketing reports of suicide-related events,
including completed suicide, suicide attempt, and suicidal ideation in patients treated with ADHD drugs.
In some of these reports, comorbid conditions may have contributed to the event (see 7 WARNINGS
AND PRECAUTIONS, Psychiatric, Suicidal Behavior and Ideation).
9 DRUG INTERACTIONS
9.1 Serious Drug Interactions
Serious Drug Interactions
• Co-Administration of Monoamine Oxidase Inhibitors (MAOIs); see 2 CONTRAINDICATIONS, 9.4
Drug-Drug Interactions, Monoamine Oxidase Inhibitors
9.2 Drug Interactions Overview
Serotonergic Drugs
On rare occasions, serotonin syndrome has occurred in association with the use of amphetamines, such
as ADDERALL XR, when given in conjunction with serotonergic drugs, including selective serotonin
reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) (see 7
WARNINGS AND PRECAUTIONS, Serotonin toxicity/Serotonin Syndrome). It has also been reported in
association with overdose of amphetamines, including ADDERALL XR (see 5 OVERDOSAGE).
As these syndromes may result in potentially life-threatening conditions (characterized by clusters of
symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation
progressing to delirium and coma), treatment with serotonergic drugs should be discontinued if such
events occur and supportive symptomatic treatment should be initiated. ADDERALL XR should be used
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with caution in combination with serotonergic and/or neuroleptic drugs (e.g. triptans, certain tricyclic
antidepressants and opiate analgesics, lithium, St. John’s Wort, MAOI) due to the risk of serotonergic
syndrome (see 7 WARNINGS AND PRECAUTIONS, Serotonin toxicity/Serotonin Syndrome).
9.4 Drug-Drug Interactions
The drugs listed below are based on either drug interaction case reports or studies, or potential
interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as
contraindicated).
Acidifying agents: Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl,
ascorbic acid, etc.) may lower absorption of amphetamines.
Urinary acidifying agents: (ammonium chloride, sodium acid phosphate, etc.) increase the concentration
of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups
of agents lower blood levels and efficacy of amphetamines.
Adrenergic blockers: As expected by their pharmacologic action, adrenergic blockers are inhibited by
amphetamines.
Alkalinizing agents: Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.), may 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.
Proton Pump Inhibitors: Proton Pump Inhibitors act on proton pumps by blocking acid production
thereby reducing gastric acidity. In the presence of a proton pump inhibitor, the median T
max
of
ADDERALL XR was shortened from 5 hours to 2.75 hours. Therefore, co-administration of ADDERALL XR
and proton pump inhibitors should be avoided.
Antidepressants, tricyclic: Amphetamines may enhance the activity of tricyclic antidepressant 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: Monoamine oxidase inhibitor antidepressants, as well as a metabolite of furazolidone,
slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the
release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause
headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant
hyperpyrexia can occur, sometimes with fatal results.
Antihistamines: Amphetamines may counteract the sedative effect of some 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
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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.
9.5 Drug-Food Interactions
Food does not affect the extent of absorption of ADDERALL XR capsules, but prolongs T
max
by 2.5 hours.
Opening the capsule and sprinkling the contents on applesauce results in comparable absorption to the
intact capsule taken in the fasted states.
9.6 Drug-Herb Interactions
Interactions with herbal products have not been established.
9.7 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.
10 CLINICAL PHARMACOLOGY
10.1 Mechanism of Action
ADDERALL XR (mixed salts amphetamine extended-release capsules) is a once a day product containing
immediate-release and delayed-release pellets that has been shown to provide a double-pulsed delivery
of amphetamine in patients with ADHD.
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.
10.2 Pharmacodynamics
The behavioral manifestations of ADHD are believed to involve an interactive imbalance between
dopaminergic and other neurotransmitter systems. However, a fundamental dopaminergic dysfunction
appears to have special significance. Amphetamine increases the availability of synaptic dopamine at
key sites in the brain by stimulating its release from newly synthesized (cytoplasmic) dopamine pools.
Thus, unlike methylphenidate, which increases dopamine availability primarily by blocking reuptake,
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amphetamine’s effect does not appear to be highly dependent on impulse-released dopamine.
This primary mechanism of action of amphetamine is supported by experiments with reserpine and α
methyltyrosine. Pretreatment with reserpine, which is believed to reduce stored vesicular (but not
cytoplasmic) dopamine, was ineffective in attenuating responses to amphetamine challenge. In
contrast, the depletion of newly synthesized cytoplasmic dopamine through the inhibition of tyrosine
hydroxylase (the rate limiting anabolic enzyme) using α-methyltyrosine, did reduce responses following
amphetamine challenge.
Systemically administered amphetamine produced stimulation of dopamine release from the nucleus
accumbens and dorsal caudate. Administration of a low acute dose of amphetamine produced a region-
specific decrease in dopamine from the “shell” in comparison to the “core” regions of the nucleus
accumbens. Higher acute doses increased extracellular dopamine to the same extent in both regions.
In addition to a dopaminergic mechanism of action, there is experimental evidence to suggest
involvement of other neurotransmitter systems in the regulation of behavioral effects (e.g., motor
activity). These include interactions between dopaminergic, GABAergic and glutamatergic pathways and
possible involvement of cholinergic pathways.
Amphetamine-induced effects are primarily mediated by D
1
and D
2
receptors. In addition, 5-HT
2A
and 5-
HT
3
receptors, and NMDA receptors are suggested to play a role in amphetamine-induced release of
dopamine, and in the regulation of the firing rate and pattern of midbrain dopamine neurons,
respectively.
Prenatal exposure to amphetamine was associated with a variety of responses in offspring that included
increases in conditioned avoidance, exploratory behavior, and sexual behavior, and decreases in 5-HT
content in the medial hypothalamus.
Repeated administration of high concentrations of amphetamine produced striatal, neostriatum, and
frontal cortex dopamine nerve fiber degeneration.
Amphetamine interacted with a variety of compounds that included caffeine, cocaine, morphine,
diazepam, phencyclidine, clonidine, fluoxetine, lithium, pentobarbital, ethanol, and THC. The
mechanism of many of these interactions is currently not known.
10.3 Pharmacokinetics
Pharmacokinetic Results in Healthy Adult and Pediatric Subjects
Following oral administration of a single dose of ADDERALL XR (mixed salts amphetamine extended-
release capsules) in healthy adult subjects, peak plasma concentrations (C
max
) of 28.1 ng/mL and
8.7 ng/mL occurred in about 7 hours for d-amphetamine and 8 hours for l-amphetamine, respectively.
The AUC
0-inf
for d-amphetamine and l-amphetamine were 567 ng•hr/mL and 203 ng•hr/mL, respectively
(see table 7).
The mean elimination half-life is 1 hour shorter for d-amphetamine and 2 hours shorter for
l-amphetamine in children aged 6 to 12 years compared to that in adults (t
1/2
is 10 hours for
d-amphetamine and 13 hours for l-amphetamine in adults, and 9 hours and 11 hours, respectively, for
children). Children had higher systemic exposure to amphetamine (C
max
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.
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Table 7 - Pharmacokinetic Parameters for Single 20 mg Dose of ADDERALL XR
Treatment
d-amphetamine
l-amphetamine
AUC
0-inf
(ng•hr/mL)
T
max
(hours)
C
max
(ng/mL)
AUC
0-inf
(ng•hr/mL)
T
max
(hours)
C
max
(ng/mL)
ADDERALL XR
(20 mg, qd)
567
7.0
28.1
203
8.2
8.7
Figure 1 - Mean d-amphetamine and l-amphetamine Plasma Concentrations following a single 20 mg
morning Administration of ADDERALL XR in the Fed State.
Food Effect Study in Healthy Adult Subjects
A single-dose study compared the relative bioavailability of d-amphetamine and l-amphetamine
following administration of a single 30 mg dose of ADDERALL XR fasted, fed (high-fat meal) and sprinkled
on food (otherwise fasted) in 21 healthy adult subjects. Food does not affect the extent of absorption of
ADDERALL XR capsules, but prolongs T
max
by 2.5 hours (from 5.2 hours at fasted state to 7.7 hours after a
high-fat meal). Opening the capsule and sprinkling the contents on applesauce results in comparable
absorption to the intact capsule taken in the fasted states.
Absorption
Pharmacokinetic studies of ADDERALL XR have been conducted in healthy adult and pediatric (aged 6 to
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12 years) subjects, and adolescent (aged 13 to 17 years) and pediatric patients with ADHD. ADDERALL
XR capsules contain dextroamphetamine (d-amphetamine) and levoamphetamine (l-amphetamine) salts
in the ratio of 3:1.
ADDERALL XR demonstrates linear pharmacokinetics over the dose range of 20 to 60 mg in adults and
adolescents aged 13 to 17 years 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 was no unexpected accumulation at steady state.
Comparison of the pharmacokinetics of d- and l-amphetamine after oral administration of ADDERALL XR
in pediatric (aged 6 to 12 years) and adolescent (aged 13 to 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 (C
max
) decreased with increases
in body weight, while oral volume of distribution (V
z
/F), oral clearance (CL/F), and elimination half-life
(t
1/2
) increased with increases in body weight.
Distribution
Literature studies indicated a stereospecific distribution of the individual dextro (d-) and levo (l-)
enantiomers of amphetamine in the brain and heart of mice. Distribution kinetics in the rat indicated
that similar amounts of both enantiomers were excreted in the urine as parent drug and as the hydroxy
metabolite.
Radiolabelled
3
H-d-amphetamine was distributed in many tissues of pregnant and non-pregnant female
and male mice. Amphetamine crossed the placenta and was present in the placenta, whole fetus, and in
fetal brain and liver. Fetal tissue concentrations were generally much lower than maternal tissue
concentrations.
Metabolism
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.
Metabolism of amphetamine was affected by induction of the CYP450 system with phenobarbital. The
direct benzene ring hydroxylation of parent drug was mediated by CYP2D1 in the rat and by the human
homologue, CYP2D6, in human microsomes. The deamination of amphetamine was shown to be
mediated by the CYP isoform 2C3 from the rabbit, but not the 2C11 and 2C13 isoforms from the rat. N-
oxygenation of amphetamine to the hydroxylamine and oxime metabolites was demonstrated in vitro
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with flavin containing monooxygenase Form 3 from humans.
Elimination
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 affect 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 7
WARNINGS AND PRECAUTIONS, Renal; 9.4 Drug-Drug Interactions).
In rats, the urinary excretion of amphetamine and its major rat metabolite, 4-hydroxyamphetamine, was
influenced by strain of rat, significant differences occurring between poor metabolizer versus extensive
metabolizer strains.
Special Populations and Conditions
• Pediatrics
Pharmacokinetic Results in Children and Adolescents with ADHD
In a 20 mg single-dose study in 51 children (aged 6 to 12 years) with ADHD, the mean T
max
for d-
amphetamine was 6.8 hours and the mean C
max
was 48.8 ng/mL. The corresponding mean T
max
and C
max
values for l-amphetamine were 6.9 hours and 14.8ng/mL, respectively. The mean
elimination half-life for d-amphetamine and l-amphetamine was 9.5 and 10.9 hours,
respectively. Following dosing of children with ADHD to steady state with ADDERALL XR 10, 20
and 30 mg, the mean d-amphetamine C
max
(ng/mL) in plasma for ADDERALL XR was 28.8
(10 mg), 54.6 (20 mg) and 89.0 (30 mg). For l-amphetamine, the mean C
max
values for the three
ADDERALL XR doses were 8.8, 17.2 and 28.1ng/mL, respectively.
In adolescents aged 13-17 years and weighing less than or equal to 75 kg/165 lbs, the mean
elimination half-life for d-amphetamine is 11 hours, and 13-14 hours for l-amphetamine.
Table 8 - ADDERALL XR Pharmacokinetic Parameters at Steady State in Children with ADHD
Treatment
d-amphetamine
l-amphetamine
AUC
0-24
(ng•hr/mL)
T
max
(hours)
C
max
(ng/mL)
AUC
0-24
(ng•hr/mL)
T
max
(hours)
C
max
(ng/mL)
ADDERALL XR
(10 mg)
432
6.4
28.8
138
6.4
8.8
ADDERALL XR
(20 mg)
777
5.8
54.6
262
5.7
17.2
ADDERALL XR
(30 mg)
1364
5.5
89.0
444
5.5
28.1
• Renal Insufficiency
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In a pharmacokinetic study of lisdexamfetamine in subjects with normal and impaired renal
function, d-amphetamine clearance was reduced from 0.7 L/hr/kg in normal subjects to
0.4 L/hr/kg in subjects with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m
2
).
D-amphetamine is not dialyzable. (see 7 WARNINGS AND PRECAUTIONS, Renal; 4 DOSAGE AND
ADMINISTRATION).
11 STORAGE, STABILITY AND DISPOSAL
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).
Any unused medicinal product should be disposed of in accordance with local requirements.
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PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
Proper name:
1. d-amphetamine Saccharate
2. Amphetamine Aspartate Monohydrate
3. d-amphetamine Sulfate USP
4. Amphetamine Sulfate USP
Chemical name:
1. (+)-α-Methylphenethylamine saccharate (2:1)
2. (±)-α-Methylphenethylamine aspartate monohydrate
3. (+)-α-Methylphenethylamine sulfate (2:1)
4. (±)-α-Methylphenethylamine sulfate (2:1)
Structural formula, Molecular formula and molecular weights:
1) d-amphetamine Saccharate
(C
9
H
13
N)
2
• C
6
H
10
O
8
480.56
2) Amphetamine Aspartate Monohydrate
C
9
H
13
N •C
4
H
7
NO
4
• H
2
O 286.33
3) d-amphetamine Sulfate
(C
9
H
13
N)
2
• H
2
SO
4
368.50
4) Amphetamine Sulfate
(C
9
H
13
N)
2
• H
2
SO
4
368.50
Physicochemical properties: The four amphetamine salts are white to off-white, crystalline powder.
The amphetamine sulfate is freely soluble in water while d-amphetamine sulfate, amphetamine
aspartate and d-amphetamine saccharate are soluble in water. Also, the amphetamine salts are known
to be stable molecules.
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14 CLINICAL TRIALS
14.1 Clinical Trials by Indication
Treatment of ADHD in Children (6 – 12 years of age)
Table 9 - Summary of patient demographics for clinical trials in children (6 – 12 years of age)
Study #
Study design
Dosage, route of
administration and duration
Study
subjects
(n)
Mean
age
(Range)
Sex
SLI381.
301
double-blind,
randomized,
placebo-controlled,
parallel-group study
ADDERALL XR 10, 20, or 30 mg
or placebo
Oral, QD for three weeks
584
8.6
(6 to 12)
years
Male (77%)
and Female
(23%)
SLI381.
201
double-blind,
randomized,
placebo- and
active-controlled
crossover study
ADDERALL XR 10, 20, or 30 mg
or placebo
or ADDERALL 10 mg
Oral, QD for one week*
51
9.5
(6 to 12)
years
Male (86%)
and Female
(14%)
*Each subject was randomized to sequentially taking each of the 5 treatments for one week, for a total of 5 weeks
A double-blind, randomized, placebo-controlled, parallel-group study of 584 children aged 6 to 12 years
who met DSM-IV
®
criteria for ADHD (either combined type or hyperactive-impulsive type) was
conducted in a naturalistic setting. Patients were randomized to fixed dose treatment groups receiving
final doses of 10, 20, or 30 mg/day of ADDERALL XR or placebo. ADDERALL XR or placebo was taken
once daily in the morning for three weeks. Significant improvements in patient behavior, based upon
teacher and parent 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 titration dose of 10 mg/day. Patients who received
ADDERALL XR showed behavioral improvements within the first week of treatment (p<0.001) and in
both morning (p<0.001) and afternoon (p<0.001) compared to patients on placebo.
A double-blind, randomized, placebo- and active-controlled crossover study of 51 children aged 6 to 12
years with ADHD was conducted in a classroom laboratory setting. In comparison to placebo, ADDERALL
XR 10, 20, and 30 mg/day showed rapid improvement and continued significant efficacy (p<0.05) up to
12 hours post-dose for all cognitive and behavioral measures.
In these two clinical trials conducted in different settings, ADDERALL XR taken once in the morning
demonstrated efficacy in the treatment of ADHD (either combined type or hyperactive-impulsive type)
for at least 12 hours.
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Treatment of ADHD in Adolescents (13 - 17 years of age)
Table 10 - Summary of patient demographics for clinical trials in adolescents (13 – 17 years of age)
Study #
Study design
Dosage, route of
administration and
duration
Study
subjects
(n)
Mean age
(Range)
Sex
SLI381.
314a
double-blind,
randomized,
multi-center,
parallel-group,
placebo-
controlled study
ADDERALL XR 10, 20, 30, 40,
50, or 60 mg
or placebo
Oral, QD for four weeks
327
14.2
(13 to 17)
years
Male (65%)
and Female
(35%)
A double-blind, randomized, multi-center, parallel-group, placebo-controlled study was conducted in
adolescents aged 13-17 years (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/165 lbs 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. ADDERALL XR at
doses of 10-40 mg is effective in the treatment of ADHD in adolescents weighing ≤75 kg/165 lbs. There
was not adequate evidence that doses greater than 20 mg/day conferred additional benefit.
Treatment of ADHD in Adults (18 years of age or older)
Table 11 - Summary of patient demographics for clinical trials in adults (18 years of age or older)
Study #
Study design
Dosage, route of
administration and duration
Study
subjects
(n)
Mean age
(Range)
Sex
SLI381.
303
double-blind,
randomized,
placebo-controlled,
parallel-group study
ADDERALL XR 20, 40, or 60 mg
or placebo
Oral, QD for four weeks
255
39.2
(18 to 76)
years
Male
(60%)
and
Female
(40%)
SLI381.
304
Long-term, multi-
center, open-label
extension study
ADDERALL XR 20, 40, or 60 mg
or placebo
Oral, QD for twelve months
223
39.8
(18 to 76)
years
Male
(59%)
and
Female
(41%)
A double-blind, randomized, placebo-controlled, parallel-group study of 255 adults who met DSM-IV
criteria for ADHD was conducted. Patients were randomized to fixed dose treatment groups receiving
final doses of 20, 40 or 60 mg/day of ADDERALL XR or placebo. ADDERALL XR or placebo was taken once
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daily in the morning for four weeks. Significant improvements in patient symptoms of inattention and
impulsivity/hyperactivity, based upon the 18-item total ADHD symptom score, were observed at
endpoint for all ADDERALL XR doses compared to patients who received placebo for all four weeks
(p<0.001). There was not adequate evidence that doses greater than 20 mg/day conferred additional
benefit.
A long-term, open-label extension of the above-mentioned clinical study was conducted in 223 adult
patients. At 12 months, all patients showed continuing symptomatic improvement as measured by the
18 item total ADHD symptom score.
14.2 Comparative Bioavailability Studies
Bioequivalence of 1 x 20 mg Capsule to 4 x 5 mg Capsules (Children with ADHD)
In a single dose study in 20 children (aged 6 to 12 years) with ADHD, a single administration of four 5 mg
capsules of ADDERALL XR was shown to be bioequivalent to a single 20 mg capsule for both d- and
l-amphetamine under fasting conditions.
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Table 12 - Pharmacokinetic Parameters for ADDERALL XR
Summary Table of the Comparative Bioavailability Data
ADDERALL XR 4 x 5 mg Capsules vs 1 x 20 mg Capsule - Under Fasting Conditions From
Measured Data
Parameter
Geometric Mean
Arithmetic Mean (CV%)
% Ratio
of Geo-
metric
Means
Confidence
Interval
(90% CI)
ADDERALL XR
4 x 5 mg capsules
ADDERALL XR
1 x 20 mg capsules
d-amphetamine
AUC
T
(ng•h/mL)
823.5
843.5 (22.2%)
775.7
794.8 (22.6%)
106.2
101.0 -111.6
AUC
I
(ng•h/mL)
845.8
863.9 (21.1%)
797.8
815.3 (21.4%)
106.0
101.5 - 110.7
C
max
(ng/mL)
50.4
51.9 (24.5%)
49.9
51.9 (28.9%)
101.0
92.4 -110.3
T
max
a
(h)
4.65 (50.0%)
4.50 (37.8%)
T
1/2
a
(h)
8.10 (14.5%)
7.98 (17.0%)
l-amphetamine
AUC
T
(ng•h/mL)
276.8
286.2 (26.4%)
238.5
247.0 (27.1%)
116.0
108.6 -124.0
AUC
I
(ng•h/mL)
297.1
304.0 (22.3%)
263.7
269.6 (21.7%)
112.7
107.6 -118.0
C
max
(ng/mL)
16.2
16.7 (24.1%)
15.2
15.8 (28.6%)
106.6
98.5 -115.3
T
max
a
(h)
4.95 (50.1%)
4.85 (39.7%)
T
1/2
a
(h)
9.16 (14.5%)
9.13 (18.5%)
a
Arithmetic mean (CV%)
For both d- and l- amphetamine, statistically significant differences were noted between the two
treatment groups for AUC, with the 4 x 5 mg group showing higher AUC, but not for C
max
and T
max
.
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16 NON-CLINICAL TOXICOLOGY
Acute Toxicity Studies
The acute LD
50
amphetamine is as follows:
Table 13 – Acute LD
50
for amphetamine
Species
LD
50
(mg/kg)
Mice (i.v.)
52
Mice (oral)
353
Rat (i.p.)
70
Dog (i.v.)
8.5
Monkey (i.v., oral)
5
Acute toxicity studies conducted in mice, rats, dogs and monkeys showed similar dose-dependent
responses. The order for comparative toxicity ranking, based upon the LD
50
values, was
monkey>dog>mouse.
Acute toxicity to dextro (d-), and levo (l-) amphetamine was age-dependent. Young mice (3-30 days old)
tolerated higher doses (up to 180 mg/kg i.p.) than adults. Toxicity increased from 18-days of age
onward. Mortality response curves were biphasic for developing mice and polyphasic for adult mice.
Acute toxicity signs noted in mice (25-75 mg/kg i.v.), rats (45-178 mg/kg i.p.), dogs (5-9 mg/kg i.v.) and
monkeys (1-6 mg/kg i.v.) included marked to severe hyperactivity, stereotypic behavior, mild to marked
clonic and/or tonic convulsions, and (in monkeys) marked increase in respiratory rate, body temperature
and pupil size. Death was associated with convulsions and, in dogs, massive endocardial hemorrhages in
both ventricles.
Subacute and Subchronic Toxicity Studies
Subacute and subchronic toxicity signs noted in mice (0-2000 ppm of d,l-amphetamine in feed) and rats
(0-750 ppm of d,l-amphetamine in feed) from 14-day and 13-week dietary studies included
hyperactivity, decreased body weight and food consumption. Deaths in the order of 15 to 65% were
reported in mice administered 500-2000 ppm of d,l-amphetamine in feed. No treatment-related deaths
occurred in the rat study.
Genotoxicity Studies
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.
Carcinogenicity Studies
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 on a mg/m
2
body surface area basis.
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Reproduction and Teratology Studies
Amphetamine, in the enantiomer ratio present in ADDERALL XR (mixed salts amphetamine extended
release capsules) (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/m
2
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 the maximum recommended human dose of 30 mg/day 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.
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PATIENT MEDICATION INFORMATION
READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE
ADDERALL XR
®
mixed salts amphetamine extended-release capsules
Read this carefully before you start taking ADDERALL XR and each time you get a refill. This leaflet is a
summary and will not tell you everything about this drug. Talk to your healthcare professional about
your medical condition and treatment and ask if there is any new information about ADDERALL XR.
What is ADDERALL XR used for?
ADDERALL XR is used to treat Attention Deficit Hyperactivity Disorder (ADHD)
• It is used in children (6 to 12 years), adolescents (13 to 17 years) and adults.
• It may be a part of your or your child’s overall treatment for ADHD. The doctor may also recommend
that you or your child have counseling or other therapy.
How does ADDERALL XR work?
It is believed that ADDERALL XR acts on certain parts of the brain to help increase your or your child’s
attention and concentration. This includes the ability to follow directions, finish tasks, and reduce rash
and uncontrolled behaviour. The ADDERALL XR capsule contains the medicinal ingredient,
amphetamine, which is released immediately after taking the drug and later during the day to keep
improving the symptoms of ADHD throughout the day.
What are the ingredients in ADDERALL XR?
Medicinal ingredients: Amphetamine Aspartate Monohydrate, Amphetamine Sulfate, d-amphetamine
Saccharate, and d-amphetamine Sulfate
Non-medicinal ingredients: Edible inks, FD&C Blue #2 (5 mg, 10 mg and 15 mg capsules), hydroxypropyl
methylcellulose, kosher gelatin, methacrylic acid copolymer, opadry beige, red iron oxide (20 mg, 25 mg
and 30 mg capsules), starch, sugar spheres, talc, titanium dioxide, triethyl citrate, yellow iron oxide
(20 mg, 25 mg and 30 mg capsules).
ADDERALL XR comes in the following dosage forms:
Extended-release capsules: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg and 30 mg
Do not use ADDERALL XR if you/your child:
• Are allergic to amphetamines or any of the nonmedicinal ingredients in the formulation or its
container
• Are sensitive to, allergic to or had a reaction to other stimulant medicines
• Have a condition that hardens the arteries
Serious Warnings and Precautions
The use of ADDERALL XR can lead to drug dependence in you or your child. ADDERALL XR may also
lead to the abuse and misuse of the drug.
Misusing ADDERALL XR may cause serious heart problems and even sudden death.
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• Have symptoms of heart disease
• Have moderate to severe high blood pressure
• Have a condition that causes anxious and distressful feelings
• Have glaucoma, an eye disease
• Have hyperthyroidism (a condition that causes the thyroid gland to make too much of a
hormone)
• Have a history of drug abuse
• Are taking or have taken medications from the group called monoamine oxidase inhibitors
(MAOI) within the last 14 days.
• Are breastfeeding or plan to breastfeed. ADDERALL XR passes into breast milk.
To help avoid side effects and ensure proper use, talk to your healthcare professional before you/your
child take ADDERALL XR. Talk about any health conditions or problems you/your child may have,
including if you/your child:
• Are involved in any physical exercises that are tiring on the body
• Take other drugs for the treatment of ADHD
• Have motion tics, verbal tics or Tourette’s syndrome (See Serious side effects and what to do
about them below)
• Have family with motion tics, verbal tics, or Tourette’s syndrome
• Have a history of seizures (convulsions, epilepsy)
• Have had an abnormal brain wave test when using an Electroencephalogram (EEG)
• Have symptoms of:
- Raynaud’s phenomenon (a condition that causes fingers and toes feeling numb, tingling and
changing colour when cold)
- Thromboangitis obliterans (that causes pain in hands and feet)
• Have any kidney related problems as your doctor may reduce the dose.
• Have a history of drug abuse or alcoholism
Other warnings you should know about:
Pregnancy: Tell your doctor if you are pregnant or plan to become pregnant. Taking ADDERALL XR
during pregnancy can cause harm to your unborn baby. If ADDERALL XR is required during pregnancy,
the risk to the unborn baby should be weighed against the benefits for the mother. Your doctor can
discuss these issues with you.
The following have been reported with use of medicines used to treat ADHD such as ADDERALL XR:
Serotonin Syndrome:
ADDERALL XR may cause serotonin syndrome, a rare but potentially life-threatening condition. There is
a potential for serious adverse reactions when ADDERALL XR is taken with other serotonergic drugs.
Careful observation by the doctor is recommended if you or your child are taking ADDERALL XR with the
following medications:
• selective serotonin reuptake inhibitors (SSRIs)
• serotonin-norepinephrine reuptake inhibitors (SNRIs)
• tricyclic antidepressants (TCAs)
• monoamine oxidase inhibitors (MAOIs)
• serotonin 5-HT
1
receptor agonists (triptans)
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• 5-HT
3
receptor antagonist antiemetics
Serotonin syndrome symptoms include:
• fever, sweating, shivering, diarrhea, nausea, vomiting;
• muscle shakes, jerks, twitches or stiffness, overactive reflexes, loss of coordination;
• fast heartbeat, changes in blood pressure;
• confusion, agitation, restlessness, hallucinations, mood changes, unconsciousness, and coma.
Heart-related problems: The following heart related problems have been reported in people taking
medications to treat ADHD, like ADDERALL XR:
• Sudden death in children, adolescents and adults who have heart problems or heart defects
• Stroke and heart attack in adults
• Increased blood pressure and heart rate
Sudden death has been reported in children and adolescents treated with drugs for ADHD. Those
children and adolescents had problems with the structure of their heart or had other serious heart
problems. ADDERALL XR generally should not be used in children, adolescents or adults who have any
serious heart diseases or conditions, such as
• high blood pressure or
• problems with the structure of their heart or
• diseases that impact the muscles of their heart or
• serious problems with their heartbeat
Tell your doctor if you or your child has any heart problems, heart defects, high blood pressure, or a
family history of these problems. Your doctor may wish to check you or your child for
• heart problems before starting ADDERALL XR.
• Irregular blood pressure and heart rate during treatment with ADDERALL XR.
Call your doctor right away if you or your child has any signs of heart problems such as chest pain,
shortness of breath, or fainting while taking ADDERALL XR.
Mental (Psychiatric) problems:
• New or worse thoughts or feelings related to suicide. This can include thinking about or feeling
like killing yourself and suicide attempts. This may happen at any time during treatment,
especially at the start or during dose changes, and also after stopping the treatment of
ADDERALL XR. Should this happen to you or your child, talk to your doctor immediately. Close
observation by a doctor is necessary in this situation
• New symptoms of mania. This can include unusual excited, over-active or unrestrained behavior
• New or worse bipolar illness. This can appear as extreme mood swings (alternating from feelings
of unusual excitement, over-active or un-inhibited to feelings of depression, sadness,
worthlessness or hopelessness)
• New or worse aggressive behavior, anxiety, agitation or hostility
• New symptoms of psychosis. This includes seeing or hearing voices that are not real, believing
things that are not true, or are suspicious
These problems are more likely to occur if you or your child have any known or unknown mental
disorders. Speak to the doctor if you, your child or family have or had:
• Any mental disorders
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®
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• Bipolar illness
• Depression
• A history of suicide
Drug Abuse and Dependence
• ADDERALL XR includes the medicinal ingredient, amphetamine. Amphetamines have the
potential to cause drug abuse and misuse.
• Abuse of amphetamines can lead to dependence, tolerance, social disorders and possibly
serious heart problems and death.
• Long term misuse of amphetamines may cause:
- Skin diseases
- Sleeping problems
- Personality changes
- Anxious and distressful feelings
- Rash, uncontrolled behaviour
- Psychosis
- Schizophrenia
• Doctor supervision is needed when you or your child stop taking ADDERALL XR. Suddenly ending
treatment when taking higher doses of ADDERALL XR for a long period of time can cause:
- extreme fatigue
- depression
- changes in sleep patterns.
• ADDERALL XR should only be given under close medical supervision to patients whose condition
has been properly diagnosed.
Growth in Children
Stimulants are possibly believed to temporarily slow growth in children. Your child’s doctor will be
monitoring your child’s height and weight while they are taking ADDERALL XR. If your child is not
growing or gaining weight as the doctor expects, the doctor may stop ADDERALL XR treatment.
Tell your healthcare professional about all the medicines you or your child take, including any drugs,
vitamins, minerals, natural supplements or alternative medicines.
Serious Drug Interactions
Do not take ADDERALL XR if you:
• are taking or have recently taken (in the last 14 days) any MAOIs such as phenelzine,
tranylcypromine, or moclobemide as you may have serious side effects.
The following may interact with ADDERALL XR:
• medicines used to treat depression including St. John’s Wort, selective serotonin reuptake
inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs)
• medicines that make urine or digestive contents more acidic (e.g., guanethidine, reserpine,
ascorbic acid, ammonium chloride, sodium acid phosphate)
• medicines that make urine more alkaline (e.g., acetazolamide, thiazides)
• medicines used to reduce or increase blood pressure
• cold and allergy medicines
• antipsychotic medicines (e.g., chlorpromazine, haloperidol)
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• lithium
• methenamine therapy
• narcotic pain medicines (e.g., meperidine)
• seizure medicines (e.g., ethosuximide, phenobarbital, phenytoin)
While on ADDERALL XR, do not start taking a new medicine or herbal remedy before checking with the
doctor.
You or your child should not take the following medications with ADDERALL XR:
• medicines that make digestive contents more alkaline (e.g., sodium bicarbonate, antacids)
• Proton Pump Inhibitors, commonly known as PPI (e.g., omeprazole).
How to take ADDERALL XR:
• Take exactly as the doctor tells you or your child to take it. Do NOT take more of it than
prescribed
• Take it only by mouth, once-a-day early in the morning.
• Avoid taking ADDERALL XR in the afternoon as it can cause to insomnia
• You or your child may take ADDERALL XR by
- Swallowing capsules whole or
- Opening the capsule and sprinkling all the beads on applesauce. Use immediately and do
not store for later use if this method is used.
• Do not crush or chew the capsule or the beads before swallowing.
• Can be taken with or without meals.
• Capsules may be swallowed whole with water
Usual dose:
Children (6 to 12 years of age): The usual starting dose is 10 mg once a day in the morning. In some
cases, the starting dose can be 5 mg once a day. Do not take more than 30 mg once a day.
Adolescents (13 to 17 years of age) and Adults (18 years of age and over): The usual starting dose is
10 mg once a day in the morning. The dose may be adjusted up to the usual maximum dose of 20 mg
once a day. Do not take more than 30 mg once a day.
Your or your child’s doctor may:
• stop your or your child’s treatment of ADDERALL XR to assess the return of symptoms
• change the dose depending on how you respond to ADDERALL XR
Overdose:
If you think you, or a person you are caring for, have taken too much ADDERALL XR, contact a healthcare
professional, hospital emergency department, or regional poison control centre immediately, even if
there are no symptoms.
Missed Dose:
If you/your child forget to take your/his or her dose in the morning, wait until the next morning and
carry on with the next dose at the usual time. Do not double dose.
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What are possible side effects from using ADDERALL XR?
These are not all the possible side effects you may have when taking ADDERALL XR. If you experience
any side effects not listed here, tell your healthcare professional.
• Behavioural changes
- Anxiety
- Irritability
- Mood swings
- Nervousness
• Chills
• Decrease or loss of appetite
• Difficulty falling asleep
• Digestive problems
- Constipation
- Diarrhea
- Indigestion
- Nausea
- Vomiting
• Dizziness
• Drowsiness
• Dry mouth and thirst
• Fever
• Grinding of Teeth
• Headache
• Neck Pain
• Reduced sexual drive
• Sensitive to light
• Stomach ache
• Sweating
• Unpleasant taste
• Weight loss
Serious side effects and what to do about them
Symptom / effect
Talk to your healthcare professional
Stop taking drug and
get immediate
medical help
Only if severe
In all cases
COMMON
Allergic Reaction: rash, hives,
swelling of the face, lips, tongue or
throat, difficulty swallowing or
breathing
✓
Cardiomyopathy (signs of heart
muscle disease): breathlessness or
swelling of the legs
✓
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®
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Serious side effects and what to do about them
Symptom / effect
Talk to your healthcare professional
Stop taking drug and
get immediate
medical help
Only if severe
In all cases
Depression: feeling sad, loss of
interest in usual activities,
hopelessness, insomnia or sleeping
too much
✓
Dysmenorrhea (Menstrual
cramps): Throbbing or cramping
pain in your lower abdomen that
can be intense
✓
Dyspnea: Shortness of breath
✓
Fungal Infection
✓
Heart palpitations or fast heart
beat: skipping beats, beating too
fast, pounding, fluttering rapidly
✓
New Tics: hard to control motion
tics (repeat twitching of any parts
of the body) or verbal tics
(repeating of sounds or words)
✓
Urinary Tract Infection (infection
in urinary system including
kidneys, ureters, bladder and
urethra): Pain or burning sensation
while urinating, frequent urination,
blood in urine, pain in the pelvis,
strong smelling urine, cloudy urine
✓
UNCOMMON
Aggressive Behavior, Anger or
Hostility
✓
High Blood Pressure: headaches,
dizziness, lightheadedness, ringing
in the ears, fainting
✓
Trouble with vision: eyesight
changes or blurred vision
✓
UNKNOWN FREQUENCY
Condition Resembling Raynaud’s
Phenomenon: discoloration of the
hands and feet, pain, sensations of
cold and/or numbness
✓
Epistaxis or contusion:
unexplained nosebleeds or
bruising
✓
Seizures (fits): loss of
consciousness with uncontrollable
shaking
✓
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®
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Serious side effects and what to do about them
Symptom / effect
Talk to your healthcare professional
Stop taking drug and
get immediate
medical help
Only if severe
In all cases
Heart attack: severe, crushing
chest pain that can radiate into the
arm and/or jaw, palpitations,
shortness of breath, nausea,
vomiting, sweating
✓
Intestinal ischemia (blood flow to
your intestines decreases due to a
narrowed or blocked blood vessel):
sudden or worsening abdominal
pain (usually severe), urgent need
to have a bowel movement,
frequent, forceful bowel
movements, nausea, vomiting,
diarrhea, blood in your stool,
confusion in older adults
✓
New Psychotic or Manic
Symptoms: Paranoia, delusions
-Hallucinations: Seeing, feeling or
hearing things that are not real
-Mania: feeling unusually excited,
over-active, or uninhibited, picking
of skin
✓
Serious Skin Conditions (Steven’s
Johnson Syndrome, Toxic
Epidermal Necrolysis): Swelling of
the skin or serious skin rash seen
as severe blisters of the skin and
mucous membranes
✓
Serotonin Syndrome: agitation or
restlessness, loss of muscle control
or muscle twitching, tremor,
diarrhea
✓
Stroke: weakness, trouble
speaking, vision problems,
headache, dizziness
✓
Suicidal Behavior:
Thoughts or actions about hurting
or killing yourself
✓
If you have a troublesome symptom or side effect that is not listed here or becomes bad enough to
interfere with your daily activities, tell your healthcare professional.
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Reporting Side Effects
You can report any suspected side effects associated with the use of health products to Health
Canada by:
• Visiting the Web page on Adverse Reaction Reporting (https://www.canada.ca/en/health-
canada/services/drugs-health-products/medeffect-canada/adverse-reaction-reporting.html)
for information on how to report online, by mail or by fax; or
• Calling toll-free at 1-866-234-2345.
NOTE: Contact your health professional if you need information about how to manage your side
effects. The Canada Vigilance Program does not provide medical advice.
Storage:
Store at room temperature (15-30C) in a tight, light-resistant container.
Keep out of reach and sight of children.
If you want more information about ADDERALL XR:
• Talk to your healthcare professional
• Find the full product monograph that is prepared for healthcare professionals and includes this
Patient Medication Information by visiting the Health Canada website:
(https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-
product-database.html); the manufacturer’s website www.takeda.com/en-ca, or by calling 1-800-
268-2772.
This leaflet was prepared by Takeda Canada Inc.
22 Adelaide Street West, Suite 3800
Toronto, Ontario
M5H 4E3
Last Revised MAR 09, 2023
ADDERALL XR
®
and ADDERALL
®
are registered trademarks of Takeda Pharmaceuticals U.S.A., Inc.
TAKEDA® and the TAKEDA Logo
®
are registered trademarks of Takeda Pharmaceutical Company Limited,
used under license.
