PRODUCT MONOGRAPH

INCLUDING PATIENT MEDICATION INFORMATION

VYVANSE®
lisdexamfetamine dimesylate capsules
Capsules, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg and 70 mg, oral
lisdexamfetamine dimesylate chewable tablets
Chewable Tablets, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg and 60 mg, oral
Central Nervous System Stimulant

Takeda Canada Inc. Date of Initial Authorization:

22 Adelaide Street West, Suite 3800 19 February 2009
Toronto, Ontario Date of Revision:
M5H 4E3 MAR 20, 2024

Submission Control Number: 280611

VYVANSE® and the VYVANSE Logo® 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.

VYVANSE® (lisdexamfetamine dimesylate) Page 1 of 67

RECENT MAJOR LABEL CHANGES

7 WARNINGS AND PRECAUTIONS, Cardiovascular, QTc Prolongation 03/2024

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 ................................................................................................................. 6
2 CONTRAINDICATIONS ................................................................................................... 6
3 SERIOUS WARNINGS AND PRECAUTIONS BOX .............................................................. 6
4 DOSAGE AND ADMINISTRATION .................................................................................. 6
4.1 Dosing Considerations ............................................................................................. 6
4.2 Recommended Dose and Dosage Adjustment ......................................................... 7
4.4 Administration ......................................................................................................... 9
4.5 Missed Dose............................................................................................................. 9
5 OVERDOSAGE ............................................................................................................... 9
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 10
7 WARNINGS AND PRECAUTIONS.................................................................................. 11
7.1 Special Populations ................................................................................................ 17
7.1.1 Pregnant Women ............................................................................................ 17
7.1.2 Breast-feeding................................................................................................. 17
7.1.3 Pediatrics ........................................................................................................ 17
7.1.4 Geriatrics......................................................................................................... 18
8 ADVERSE REACTIONS .................................................................................................. 18
8.1 Adverse Reaction Overview ................................................................................... 18
8.2 Clinical Trial Adverse Reactions ............................................................................. 18
8.2.1 Clinical Trial Adverse Reactions – Pediatrics ................................................... 23

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 8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 26
8.3.1 Less Common Clinical Trial Adverse Reactions-Pediatrics ............................... 27
8.5 Post-Market Adverse Reactions ............................................................................. 28
9 DRUG INTERACTIONS ................................................................................................. 29
9.1 Serious Drug Interactions....................................................................................... 29
9.2 Drug Interactions Overview ................................................................................... 30
9.4 Drug-Drug Interactions .......................................................................................... 30
9.5 Drug-Food Interactions .......................................................................................... 32
9.6 Drug-Herb Interactions .......................................................................................... 32
9.7 Drug-Laboratory Test Interactions ......................................................................... 32
10 CLINICAL PHARMACOLOGY......................................................................................... 32
10.1 Mechanism of Action ....................................................................................... 32
10.2 Pharmacodynamics .......................................................................................... 33
10.3 Pharmacokinetics ............................................................................................. 33
11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 36
PART II: SCIENTIFIC INFORMATION ........................................................................................ 37
13 PHARMACEUTICAL INFORMATION ............................................................................. 37
14 CLINICAL TRIALS ......................................................................................................... 37
14.1 Clinical Trials by Indication ............................................................................... 37
14.2 Comparative Bioavailability Studies ................................................................. 53
15 MICROBIOLOGY .......................................................................................................... 54
16 NON-CLINICAL TOXICOLOGY ....................................................................................... 54
PATIENT MEDICATION INFORMATION ................................................................................... 57

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PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

VYVANSE (lisdexamfetamine dimesylate) capsules and chewable tablets are indicated for the
treatment of:
• Attention Deficit Hyperactivity Disorder (ADHD).
• Moderate to Severe Binge Eating Disorder (BED) in adults.
Recurrent episodes of binge-eating are characterised by:
• consuming an abnormally large amount of food in a short period of time and
sense of lack of control overeating during the episode.
• marked distress about the behavior.
• feeling disgusted or guilty, or eating alone because of embarrassment.
Limitation of Use for BED:
Prescribers should consider that serious cardiovascular (CV) events have been reported with this
class of sympathomimetic drugs. The BED clinical trials were not designed to assess CV safety.
While there is an accumulation of safety data with VYVANSE use in the ADHD population, this is
of limited relevance regarding CV risk in the BED population. Given the higher CV risk associated
with obesity, the BED population may be at a higher risk (see 4.1 Dosing Considerations and 7
WARNINGS AND PRECAUTIONS, Cardiovascular).
The safety and effectiveness of VYVANSE for the treatment of obesity have not been
established. VYVANSE is not indicated or recommended for weight loss. Use of other
sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse
events.
ADHD
A diagnosis of ADHD (DSM-IV-TR®) implies the presence of hyperactive-impulsive and/or
inattentive symptoms that cause impairment and were present before the age of 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 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 six 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 six months (or adult
equivalent symptoms): 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.

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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 also 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
VYVANSE is indicated as an integral part of a total treatment program for ADHD that may
include other measures (psychological, educational/vocational, 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 a patient who exhibits symptoms secondary to
environmental factors and/or other primary psychiatric disorders, including psychosis.
Appropriate educational/vocational 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 and on the level of functional impairment.
Long-term Use
The physician who elects to use VYVANSE for extended periods should periodically re-evaluate
the long-term usefulness of the drug for the individual patient (see 4.2 Recommended Dose and
Dosage Adjustment).
The efficacy of VYVANSE has been evaluated separately in both children and adolescents for up
to four weeks, and in adults for up to ten weeks. In a separate controlled trial of a combined
population of children and adolescents, the efficacy of VYVANSE has been evaluated for up to
seven weeks.

1.1 Pediatrics

ADHD
Pediatrics (6 to 17 years of age): Based on the data submitted and reviewed by Health Canada,
the safety and efficacy of VYVANSE in this population has been established, and therefore
Health Canada has authorized its indication.
Pediatrics (< 6 years of age): No data are available to Health Canada; therefore, Health Canada
has not authorized an indication for children under the age of 6 years. Amphetamines should
not be used in pediatric patients with ADHD under six years of age.
BED
Safety and effectiveness in patients less than 18 years of age have not been established, and
therefore Health Canada has not authorized an indication for use in this population.

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 1.2 Geriatrics

VYVANSE has not been systematically studied in, and is therefore not indicated for use in, the
geriatric population (>65 years of age) (see 10.3 Pharmacokinetics). Subjects over 55 years of
age were excluded from the ADHD and BED clinical trials.

2 CONTRAINDICATIONS

VYVANSE 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.
VYVANSE is contraindicated in patients with the following conditions:
• Moderate to severe hypertension
• Advanced arteriosclerosis
• Symptomatic cardiovascular disease
• Hyperthyroidism
• Known hypersensitivity or idiosyncrasy to the sympathomimetic amines
• Allergy to amphetamines
• Glaucoma
• Agitated states
• Patients with History of drug abuse
• During or within 14 days following the administration of monoamine oxidase inhibitors
(MAOIs) (hypertensive crises may result) (see 9.4 Drug-Drug Interactions).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

• 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, Cardiovascular and Dependence/Tolerance, 16 NON-
CLINICAL TOXICOLOGY, special toxicology, non-clinical abuse data)

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Cardiovascular
VYVANSE should not be used in patients with symptomatic cardiovascular disease including
coronary artery disease nor in patients with moderate to severe hypertension (see 2
CONTRAINDICATIONS). Blood pressure and pulse should be measured prior to initiating
treatment and monitored in all patients taking VYVANSE (see 7 WARNINGS AND PRECAUTIONS,
Cardiovascular).

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VYVANSE should generally not be used in patients 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 or BED drugs (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS,
Cardiovascular).
Theoretically there exists a pharmacological potential for all ADHD drugs to increase the risk of
sudden/cardiac death. Although confirmation is lacking, prescribers should consider this
potential risk.
All drugs with sympathomimetic effects prescribed in the management of ADHD or BED 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 sympathomimetic medication treatment for ADHD or BED should
undergo a prompt cardiac evaluation.
Patients who are considered to need extended treatment with VYVANSE should undergo
periodic evaluation of their cardiovascular status (see 7 WARNINGS AND PRECAUTIONS,
Cardiovascular).
Tics
Careful clinical evaluation for motor or verbal tics of Tourette’s syndrome should be conducted
before initiating VYVANSE (see 7 WARNINGS AND PRECAUTIONS, Neurologic, Tics).
Induction of a Manic Episode in Patients with Bipolar Disorder
Prior to initiating VYVANSE treatment, screen patients for risk factors for developing a manic
episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar
disorder, and depression) (see 7 WARNINGS AND PRECAUTIONS, Psychiatric, Screening Patients
for Bipolar Disorder).

4.2 Recommended Dose and Dosage Adjustment

Dosage should be individualized according to the therapeutic needs and response of the
patient. VYVANSE should be administered at the lowest effective.
In patients with severe renal insufficiency (GFR 15 to <30 mL/min/1.73 m2), the maximum dose
should not exceed 50 mg/day. Further dosage reduction should be considered in patients
undergoing dialysis (see 7 WARNINGS AND PRECAUTIONS, Renal, 10.3 Pharmacokinetics, Special
Populations and Conditions).
Attention Deficit Hyperactivity Disorder (ADHD) in Children (≥ 6 years of age), Adolescents (13
to 17 years of age) and Adults (18 to 65 years of age)

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VYVANSE is not approved for pediatric patients under 6 years of age.
The usual starting dose is 30 mg once daily in the morning, whether a patient is starting ADHD
treatment for the first time or switching from another medication. When in the judgment of the
clinician a lower dose is appropriate, a patient may begin treatment with 20 mg once daily in
the morning.
If a dose increase is warranted in the judgment of the physician, daily dosage may be adjusted in
increments of 10 mg or 20 mg at approximately weekly intervals.
The maximum VYVANSE dose should not exceed 60 mg/day. In clinical studies, doses of up to 70
mg/day were shown to be effective, although no additional benefit was demonstrated at doses
greater than 30 mg/day, and adverse events and discontinuations were more frequent at higher
doses. Doses greater than 70 mg/day of VYVANSE have not been studied.
If improvement is not observed after appropriate dosage adjustment over a one-month period,
the drug should be discontinued.
The effectiveness of VYVANSE has not been studied in adults over 55 years of age (see 10.3
Pharmacokinetics).
Long-term Use
Pharmacological treatment of ADHD may be needed for extended periods. The efficacy of
VYVANSE in maintaining symptom response in children and adolescent patients (aged 6 to 17
years) with ADHD was studied in a 6-week, placebo-controlled randomized withdrawal trial in
subjects following treatment with open-label VYVANSE for at least 26 weeks. The efficacy of
VYVANSE in maintaining symptom response in adult patients (aged 18 to 55 years) with ADHD
was studied in a 6-week, placebo-controlled randomized withdrawal trial in subjects with
documentation of open-label treatment with VYVANSE for a minimum of 6 months. Subjects
assigned to VYVANSE in the randomized withdrawal phase continued on the same dose used to
confirm response in the open-label phase (see 14 Clinical Trials).
The efficacy of VYVANSE in ADHD has been evaluated separately in both children and
adolescents for up to four weeks, and in adults for up to ten weeks. In a separate controlled trial
of a combined population of children and adolescents, the efficacy of VYVANSE has been
evaluated for up to seven weeks.
The clinician who elects to use VYVANSE for extended periods in the treatment of ADHD should
periodically re evaluate the long-term usefulness of the drug for the individual patient. Where
possible, drug administration should be interrupted occasionally to determine if there is a
recurrence of behavioral symptoms sufficient to require continued therapy.
Moderate to Severe Binge Eating Disorder (BED) in Adults (18 to 65 years of age)
The recommended starting dose is 30 mg/day to be titrated in increments of 20 mg at
approximately weekly intervals to achieve the recommended target dose of 50 to 70 mg/day.
The maximum dose is 70 mg/day.
VYVANSE has not been studied, and is not recommended for use in pediatrics patients (less than
18 years of age) with BED. VYVANSE has not been studied in adults over 55 years of age.

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VYVANSE should be prescribed for the shortest duration that is clinically indicated in order to
minimize exposure to the CV risk in this population; the risk-benefit profile of the drug for the
individual patient should be periodically re-evaluated. (see 7 WARNINGS AND PRECAUTIONS,
Cardiovascular).

4.4 Administration

VYVANSE (lisdexamfetamine dimesylate) capsules or chewable tablets should be taken in the

morning. Afternoon doses should be avoided because of the potential for insomnia.
VYVANSE may be taken with or without food.
VYVANSE capsules may be taken whole, or the capsule may be opened and the entire contents
emptied and mixed with yogurt or in a glass of water or orange juice. If the contents of the
capsule include any compacted powder, a spoon may be used to break apart the powder in the
yogurt or liquid. The contents should be mixed until completely dispersed. The patient should
consume the entire mixture of yogurt or liquid immediately; it should not be stored. The active
ingredient dissolves completely once dispersed; however, a film containing the inactive
ingredients may remain in the glass or container once the mixture is consumed. The patient
should not take anything less than one capsule per day and a single capsule should not be
divided.
VYVANSE chewable tablets must be chewed thoroughly before swallowing. The patient should
not take anything less than one chewable tablet per day and a single chewable tablet should not
be divided.
VYVANSE capsules can be substituted with VYVANSE chewable tablets on a unit per unit / mg
per mg basis (for example, 30 mg capsules for 30 mg chewable tablet) (see 10.3
Pharmacokinetics).

4.5 Missed Dose

If a dose is missed in the morning, the patient should be instructed to wait until the next day
and take the usual dose at the usual time in the morning. Do not double dose.
Afternoon doses should be avoided because of the long-acting nature of the drug, including the
potential for insomnia.

5 OVERDOSAGE

Individual patient response to amphetamines varies widely. Toxic symptoms may occur
idiosyncratically at low doses.
Symptoms: Frequently observed signs and symptoms of overdose with amphetamines are
restlessness, tremor, hyperreflexia, rapid respiration, confusion, aggression, 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.

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Treatment: Management of acute amphetamine intoxication is largely symptomatic and
includes gastric lavage, administration of activated charcoal, administration of a cathartic and
sedation. 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.
The prolonged duration of action of VYVANSE should be considered when treating patients with
overdose.
Lisdexamfetamine and dextroamphetamine are not dialyzable.

For management of a suspected drug overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table – Dosage Forms, Strengths, Composition and Packaging

Route of Dosage Form / Strength

Non-medicinal Ingredients
Administration / Composition
Oral Capsules: croscarmellose sodium, magnesium
stearate, microcrystalline cellulose
10 mg, 20 mg, 30 mg,
Capsule shells which contain edible ink,
40 mg, 50 mg, 60 mg,
gelatin, titanium dioxide (E171), and one or
70 mg
more of the following: FD&C Yellow #6
(E110), FD&C Blue #1 (E133), FD&C Red #3
(E127), FDA/E172 Black Iron Oxide,
FDA/E172 Yellow Iron Oxide.
Chewable tablets: artificial strawberry flavouring, colloidal
silicon dioxide, croscarmellose sodium, guar
10 mg, 20 mg, 30 mg,
gum, magnesium stearate, mannitol,
40 mg, 50 mg, 60 mg
microcrystalline cellulose, and sucralose.
VYVANSE capsules and chewable tablets are designed for once-a-day oral administration.
VYVANSE capsules / chewable tablets contain 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg and 70
mg* of lisdexamfetamine dimesylate. Corresponding dextroamphetamine base equivalence as
follows:

Lisdexamfetamine
10 mg 20 mg 30 mg 40 mg 50 mg 60 mg 70 mg*
dimesylate
dextroamphetamine
3.0 mg 5.9 mg 8.9 mg 11.9 mg 14.8 mg 17.8 mg 20.8 mg*
base equivalence
* Not applicable to chewable tablets

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VYVANSE capsules 10 mg: pink body/pink cap (imprinted S489 10 mg), bottles of 100.
VYVANSE capsules 20 mg: ivory body/ivory cap (imprinted S489 20 mg), bottles of 100.
VYVANSE capsules 30 mg: white body/orange cap (imprinted S489 30 mg), bottles of 100.
VYVANSE capsules 40 mg: white body/blue green cap (imprinted S489 40 mg), bottles of 100.
VYVANSE capsules 50 mg: white body/blue cap (imprinted S489 50 mg), bottles of 100.
VYVANSE capsules 60 mg: aqua blue body/aqua blue cap (imprinted S489 60 mg), bottles of
100.
VYVANSE capsules 70 mg: blue body/orange cap (imprinted S489 70 mg), bottles of 100.
VYVANSE chewable tablets 10 mg: white to off-white round shaped tablet debossed with ‘10’
on one side and ‘S489’ on the other, bottles of 100.
VYVANSE chewable tablets 20 mg: white to off-white hexagonal shaped tablet debossed with
‘20’ on one side and ‘S489’ on the other, bottles of 100.
VYVANSE chewable tablets 30 mg: white to off-white arc triangular shaped tablet debossed
with ‘30’ on one side and ‘S489’ on the other, bottles of 100.
VYVANSE chewable tablets 40 mg: white to off-white capsule shaped tablet debossed with ‘40’
on one side and ‘S489’ on the other, bottles of 100.
VYVANSE chewable tablets 50 mg: white to off-white arc square shaped tablet debossed with
‘50’ on one side and ‘S489’ on the other, bottles of 100.
VYVANSE chewable tablets 60 mg: white to off-white arc diamond shaped tablet debossed with
‘60’ on one side and ‘S489’ 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. VYVANSE should be used with caution in
patients who use other sympathomimetic drugs.
Carcinogenesis and Mutagenesis
See 16 NON-CLINICAL TOXICOLOGY for discussion on animal data.
Cardiovascular
Serious cardiovascular events have been reported with the use of sympathomimetic drugs,
including VYVANSE, in the ADHD population (as below). Given the higher CV risk associated with
obesity, the BED population may be at a higher risk. Prescribers should consider this potential
risk when treating BED (see 1 INDICATIONS, Limitation of Use for BED).
Limited CV safety information is provided by the BED clinical trials, given the exclusion of higher
risk patients (e.g., diabetes, moderate to severe hypertension, and cardiovascular disease; older
than 55 years of age) combined with limited patient numbers and limited treatment duration.
As VYVANSE was not developed to the regulatory standard of a weight-loss drug, and is not
indicated for weight loss, a post-approval cardiac safety assessment (e.g., a dedicated CV
outcome study) is not planned.

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Misuse and Serious Cardiovascular Adverse Events:
The misuse of amphetamines may cause serious cardiovascular adverse events and sudden
death.
Hypertension and Other Cardiovascular Conditions:
CNS stimulants such as VYVANSE are known to cause increases in blood pressure and heart rate.
In clinical trials, modest mean increases are seen (about 2-4 mmHg and 3-6 bpm, respectively),
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.
Patients with moderate to severe hypertension, symptomatic CV disease, or advanced
arteriosclerosis should not be treated with VYVANSE (see 2 CONTRAINDICATIONS). Blood
pressure and pulse should be measured prior to initiating treatment, and monitored at
appropriate intervals in patients taking VYVANSE, especially patients with hypertension. 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.
QTc Prolongation: Lisdexamfetamine dimesylate has been shown to prolong QTc interval in
some patients (see 8.5 Post-Market Adverse Reactions). It should be used with caution in
patients with QTc prolongation interval, in patients treated with drugs affecting the QTc interval
or in patients with relevant pre-existing cardiac disease or electrolyte disturbances.
Lisdexamfetamine dimesylate is contraindicated in patients with symptomatic cardiovascular
disease and also in patients with moderate to severe hypertension (see 2
CONTRAINDICATIONS).
Binge Eating Disorder
VYVANSE should be prescribed for the shortest duration that is clinically indicated in order to
minimize exposure to CV risk in this population; the risk-benefit profile of the drug for the
individual patient should be periodically re-evaluated.
Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart
Problems:
Children and 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, sympathomimetic drugs generally should not be used in children/adolescents with
known serious structural cardiac abnormalities or other serious cardiac 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 death, stroke, and myocardial infarction have been reported in adults taking stimulant

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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).
Assessing Cardiovascular Status in Patients Being Treated with Sympathomimetic Medications
Theoretically there exists a pharmacological potential for all ADHD drugs to increase the risk of
sudden/cardiac death. Although confirmation is lacking, prescribers should consider this
potential risk.
All drugs with sympathomimetic effects prescribed in the management of ADHD or BED 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. Patients who
are being considered for treatment with sympathomimetic medications should have a careful
history (including assessment for a family history of sudden death or ventricular arrhythmia)
and physical exam to assess for the presence of cardiac disease and should receive further
cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and
echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained
syncope, or other symptoms suggestive of cardiac disease during sympathomimetic medication
treatment for ADHD or BED should undergo a prompt cardiac evaluation (see 2
CONTRAINDICATIONS).
Dependence/Tolerance
Amphetamines have been extensively abused (see 3 SERIOUS WARNINGS AND PRECAUTION
BOX, 14 CLINICAL TRIALS, Drug Abuse and Dependence Studies, 16 NON-CLINICAL TOXICOLOGY,
non-clinical abuse data). 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 the excessive use, should be kept in mind. Therefore, care should be used in
the selection of candidates for VYVANSE 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.
For details on abuse liability studies, refer to 14 CLINICAL TRIALS, Drug Abuse and Dependence
Studies.
Driving and Operating Machinery
Patients should find out how VYVANSE will affect them before engaging in activities such as

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operating machinery or vehicles, as VYVANSE may impair the ability to engage in these
activities.
Endocrine and Metabolism
ADHD Population: Suppression of Growth:
CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric
patients (see 8.1 Adverse Reactions Overview). Closely monitor growth (weight and height) in
pediatric patients treated with CNS stimulants, including VYVANSE. Patients who are not
growing or gaining weight as expected may need to have their treatment interrupted.
Children and Adolescents in VYVANSE ADHD Clinical Trials
In a 4-week controlled trial of lisdexamfetamine in children ages 6 to 12 years with ADHD, mean
weight loss from baseline to endpoint was -0.9, -1.9, and -2.5lbs, respectively, for patients
assigned to receive 30 mg, 50 mg, and 70 mg of lisdexamfetamine, compared to a 1.0lb weight
gain for patients receiving placebo. Higher doses were associated with greater weight loss with
four weeks of treatment. Careful follow-up for weight in children ages 6 to 12 years who
received lisdexamfetamine over 12 months suggests that consistently medicated children (i.e.,
treatment for seven days per week throughout the year) have a slowing in growth rate
measured by body weight as demonstrated by an age- and sex-normalized mean change from
baseline in percentile of -13.4 over one year (average percentiles at baseline and 12 months
were 60.9 and 47.2, respectively).
In a 4-week controlled trial of VYVANSE in adolescents aged 13 to 17 years with ADHD, mean
weight change from baseline to endpoint was -2.7, -4.3, and -4.8lbs, respectively, for patients
assigned to receive 30 mg, 50 mg, and 70 mg of VYVANSE, compared to a 2.0lb weight gain for
patients receiving placebo. Careful follow-up for weight in adolescents aged 13 to 17 years who
received lisdexamfetamine over 12 months suggests that consistently medicated adolescents
(i.e., treatment for 7 days per week throughout the year) have a slowing in growth rate
measured by body weight as demonstrated by an age- and sex-normalized mean change from
baseline in percentile of -6.5 over 1 year. The average percentile at baseline (n=265) and 12
months (n=156), were 66.0 and 61.5, respectively.
Stimulant Use in Adolescents and Children with ADHD
Published data for other stimulants report that in children aged 7 to 10 years there is a
temporary slowing in growth rate without evidence of growth rebound during this period of
development. In a controlled trial of amphetamine (d- to l-enantiomer ratio of 3:1) in
adolescents, mean weight change from baseline within the initial four weeks of therapy was –
1.1lbs and –2.8lbs, respectively, for patients receiving 10 mg and 20 mg of amphetamine (d- to l-
enantiomer ratio of 3:1). Higher doses were associated with greater weight loss within the initial
four weeks of treatment. Published data are inadequate to determine whether the chronic use
of amphetamines in children may be causally associated with suppression of growth.
Neurologic
Seizures

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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.
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 patients and
their families should precede use of stimulant medications.
Serotonin toxicity/Serotonin syndrome
Serotonin toxicity also known as serotonin syndrome is a potentially life-threatening condition
and has been reported with amphetamines, including VYVANSE, 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-
HT1 receptor agonists (triptans), and 5-HT3 receptor antagonist antiemetics (see 9.4 Drug-Drug
Interactions).
Serotonin toxicity is characterized 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
• Hypotonia and body temperature ≥38˚C and ocular clonus or inducible clonus.
If concomitant treatment with VYVANSE and other serotonergic agents is clinically warranted,
careful observation of the patient is advised, particularly during treatment initiation and dose
increases. If serotonin toxicity is suspected, discontinuation of the serotonergic agent should be
considered. (See 9.2 Drug Interaction Overview, 9.4 Drug-Drug Interactions).
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

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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 with ADHD 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 post-marketing 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 of 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, 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 in patients with severe renal insufficiency (GFR 15 to <30
mL/min/1.73m2), the maximum dose should not exceed 50 mg/day. Further dosage reduction
should be considered in patients undergoing dialysis (see 4.2 Recommended Dose and Dosage
Adjustment; 10.3 Pharmacokinetics, Special Populations and Conditions).
Lisdexamfetamine and dextroamphetamine are not dialyzable.
Reproductive Health: Female and Male Potential
See 7.1.1 Pregnant Women.
Fertility

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See 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology.
Teratogenic Risk
There are no adequate and well controlled studies 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 dextroamphetamine sulfate with lovastatin
during the first trimester of pregnancy. See 16 NON-CLINICAL TOXICOLOGY, Reproductive and
Developmental Toxicology.
Vascular
Peripheral Vasculopathy, Including Raynaud’s Phenomenon
Stimulants, such as VYVANSE, are associated with peripheral vasculopathy, including Raynaud’s
phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare
sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral
vasculopathy, including Raynaud’s phenomenon, were observed in post marketing reports at
different times and at therapeutic doses in all age groups throughout the course of treatment.
Signs and symptoms generally improve after reduction in dose or discontinuation of drug.
Careful observation for digital changes is necessary during treatment with stimulants. Further
clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

7.1 Special Populations

7.1.1 Pregnant Women

The effects of VYVANSE on labour and delivery in humans are unknown.

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.
VYVANSE should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
See 7 WARNINGS AND PRECAUTIONS, Reproductive Health: Female and Male Potential and 16
NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology.

7.1.2 Breast-feeding

Amphetamines are excreted in human milk. Long-term neurodevelopmental effects on infants

from amphetamine exposure are unknown. Because of the potential for serious adverse
reactions in nursing infants, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.

7.1.3 Pediatrics

ADHD

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Pediatrics (6 to 17 years old): VYVANSE is indicated for use in children 6 years of age and older.
Pediatrics (≤ 6 years of age): No data are available to Health Canada; therefore, Health Canada
has not authorized an indication for use in children younger than 6 years of age. Long term
effects of amphetamines in children have not been well established (see 1.1 Pediatrics; 7
WARNINGS AND PRECAUTIONS, Endocrine and Metabolism; 16 NON-CLINICAL TOXICOLOGY,
Juvenile Toxicity).
BED
Pediatrics (0-18 years of age): No data are available to Health Canada; therefore, Health Canada
has not authorized an indication for pediatric use.

7.1.4 Geriatrics

VYVANSE has not been systematically studied in, and is therefore not indicated for use in, the
geriatric population (>65 years of age) (see 10.3 Pharmacokinetics). Subjects over 55 years of
age were excluded from the ADHD and BED clinical trials.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Attention Deficit Hyperactivity Disorder (ADHD)

Adverse drug reactions (ADRs) observed with VYVANSE treatment mainly reflect side effects
commonly associated with amphetamine use. In ADHD clinical trials, approximately a third of
pediatric, adolescent and adult subjects treated with VYVANSE reported decreased appetite and
insomnia. Other very common adverse drug reactions include dry mouth, headache and upper
abdominal pain. Stimulant side effects generally occur early in treatment and tend to decrease
over time.
Small increases in heart rate were observed with VYVANSE use. These changes were small in
magnitude and are known effects of amphetamine use. No significant differences were
observed among the treatment groups in systolic blood pressure and diastolic blood pressure.
Binge Eating Disorder (BED)
The most commonly observed adverse events reported with exposure to VYVANSE in BED
across the five studies (>5%) were: dry mouth, insomnia, headache, decreased appetite, nausea,
upper respiratory tract infection, nasopharyngitis, tachycardia, constipation, irritability, anxiety,
feeling jittery, fatigue and diarrhea. The commonly occurring TEAEs are generally consistent
with the known safety profile of VYVANSE.

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

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real-world use.
Attention Deficit Hyperactivity Disorder (ADHD)
The ADHD pre-marketing development program for VYVANSE included exposures in a total of
992 participants in clinical trials (345 pediatric patients aged 6 to 12 years, 233 adolescent
patients aged 13 to 17 years, 358 adult patients and 56 healthy adult subjects). Of these, 345
pediatric patients (aged 6 to 12 years) were evaluated in two controlled clinical studies (one
parallel group and one crossover), one open label extension study, and one single dose clinical
pharmacology study, 233 adolescent (aged 13 to 17 years) patients were evaluated in one
controlled clinical study, and 358 adult patients were evaluated in one controlled clinical study
and one open-label extension study.
The safety information for the ADHD indication is based on data from the 4-week parallel group
controlled clinical trials in children, adolescent and adult patients with ADHD. Adverse reactions
were assessed by collecting adverse events, results of physical examinations, vital signs,
weights, laboratory analyses, and ECGs.
Adverse events during exposure were obtained primarily by general inquiry and recorded by
clinical investigators using terminology of their own choosing. Consequently, it is not possible to
provide a meaningful estimate of the proportion of individuals experiencing adverse events
without first grouping similar types of events into a smaller number of standardized event
categories. In the tables and listings that follow, MedDRA terminology has been used to classify
reported adverse events.
The stated frequencies of adverse events represent the proportion of individuals who
experienced, at least once, a treatment-emergent adverse event of the type listed.
Adverse reactions reported in the ADHD controlled trials in patients treated with VYVANSE
(incidence of 1% or greater) and greater than that observed in placebo treated patients are
presented as follows: Children (aged 6 to 12 years) – Table 3, adolescents (aged 13 to 17 years)
– Table 4, and Adults – Table 1.
Long-Term Extension Studies in ADHD
Three long-term, open-label extension studies were conducted over 12 months in 274 children
(aged 6-12 years; 147 subjects completed), 269 adolescents (aged 13-17 years; 156 subjects
completed), and 349 adults (aged 18-55 years; 191 subjects completed), respectively. VYVANSE
was generally safe and well tolerated in each study with a safety profile consistent with
stimulant treatment.
ADHD in Adult Patients
Four hundred and twenty (420) adult subjects with ADHD were enrolled in a Phase 3,
randomized, double-blind, multi-center, placebo-controlled, parallel-group, forced-dose
titration, safety and efficacy study of VYVANSE. The most common ADRs (≥5.0%) reported with
VYVANSE treatment reflected side effects commonly associated with amphetamine use. These
included decreased appetite, dry mouth, headache, insomnia, nausea, diarrhea, anxiety,
anorexia and initial insomnia; there was no apparent dose effect for these events among
VYVANSE treatment groups. Most ADRs tended to occur early during the course of treatment

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and their incidence generally decreased over time despite the forced-dose titration schedule of
the study.
Table 1 Adverse Drug Reactions Reported by 1% or More of Adult Patients with
ADHD Taking VYVANSE in a 4 Week Clinical Trial
VYVANSE Placebo
Body System
n = 358 n = 62
Preferred Term
(%) (%)
Cardiac Disorders
Palpitations 2 0
Tachycardia 1 0
Gastrointestinal Disorders
Dry Mouth 26 3
Nausea 7 0
Diarrhea 7 0
Abdominal Pain Upper 3 2
General Disorder and Administration Site
Conditions
Feeling Jittery 4 0
Investigations
Weight Decreased 3 0
Blood Pressure Increased 3 0
Metabolism and Nutrition Disorders
Decreased Appetite 27 2
Anorexia 5 0
Nervous System Disorders
Headache 21 13
Tremor 2 0
Psychiatric Disorders
Insomnia 19 5
Anxiety 6 0
Initial Insomnia 5 3
Middle Insomnia 4 0
Agitation 3 0
Restlessness 3 0
Libido Decreased 1 0
Logorrhea 1 0
Reproductive System and Breast
Disorders Erectile Dysfunction 1 0

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 VYVANSE Placebo
Body System
n = 358 n = 62
Preferred Term
(%) (%)
Respiratory, Thoracic and Mediastinal
Disorders
Dyspnea 2 0
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis 3 0
Rash 1 0
Note: This table includes those events for which the incidence in patients taking VYVANSE
was greater than the incidence in patients taking placebo. ADRs for which the incidence was
greater or equal in patients taking placebo: Dizziness, Fatigue and Irritability.
Adverse Events Associated with Discontinuation of Treatment in ADHD Clinical Trials
In the controlled adult trial, 6% (21/358) of VYVANSE-treated patients discontinued due to
adverse events compared to 2% (1/62) who received placebo. The most frequent adverse
events leading to discontinuation and considered to be drug-related (i.e., leading to
discontinuation in at least 1% of VYVANSE-treated patients and at a rate at least twice that of
placebo) were insomnia (8/358; 2%), tachycardia (3/358; 1%), irritability (2/358; 1%),
hypertension (4/358; 1%), headache (2/358; 1%), anxiety (2/358; 1%), and dyspnea (3/358; 1%).
Weight Loss in Adults with ADHD
In the 4-week adult trial, the dose-dependent effect of VYVANSE on body weight was similar to
the pediatric studies.
Binge Eating Disorder (BED)
The clinical development program for VYVANSE in treatment of BED included exposure in a total
of 1252 patients with BED, aged 18 to 55, in five clinical trials, including an open-label extension.
Of these, 288 BED patients received the drug for at least a year, and 608 patients for at least six
months. Patients with cardiovascular risk factors other than obesity and smoking were
excluded.
Adverse events were assessed by collecting adverse events, results of physical examinations,
vital signs, weights, laboratory analyses, and ECGs.
Adverse events during exposure were obtained primarily by general inquiry and recorded by
clinical investigators using terminology of their own choosing. Consequently, it is not possible to
provide a meaningful estimate of the proportion of individuals experiencing adverse events
without first grouping similar types of events into a smaller number of standardized event
categories. In the tables and listings that follow, MedDRA terminology has been used to classify
reported adverse events.
The stated frequencies of adverse events represent the proportion of individuals who
experienced, at least once, a treatment-emergent adverse event of the type listed.

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Treatment-emergent adverse events reported in VYVANSE-treated patients, with an incidence
of 2% or greater and greater than that observed in placebo treated patients, from two 12-week
randomized, double-blind, multicenter, parallel-group, placebo-controlled dose-optimization
studies in adults aged 18-55 years with moderate to severe BED, are presented in Table 2.
Table 2 Treatment-Emergent Adverse Events Reported by 2% or More of Adult
Patients with BED Taking VYVANSE, and at incidence rates greater than for
placebo, in 12 Week Clinical Trials
VYVANSE Placebo
Body System
n = 373 n = 372
Preferred Term
(%) (%)
Cardiac Disorders
Palpitations 3 2
Gastrointestinal Disorders
Dry Mouth 36 7
Nausea 9 6
Constipation 6 1
Diarrhea 4 2
Abdominal Pain Upper 2 0
Dyspepsia 2 1
Vomiting 2 1
General Disorder and Administration Site
Conditions
Irritability 7 5
Feeling Jittery 6 1
Fatigue 6 5
Energy Increased 2 0
Infections and Infestations
Urinary Tract Infection 2 0
Gastroenteritis 2 1
Investigations
Increased Heart Ratea 7 1
Weight Decreased 4 0
Blood Pressure Increased 3 2
Metabolism and Nutrition Disorders
Decreased Appetiteb 8 2

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 VYVANSE Placebo
Body System
n = 373 n = 372
Preferred Term
(%) (%)
Nervous System Disorders
Headache 16 9
Paraesthesia, Hypoaesthesia 3 1
c
Dysgeusia 2 1
Psychiatric Disorders
Insomniad 20 7
Anxiety 5 1
Nightmare 2 0
Restlessness 2 0
Reproductive System and Breast
Disorders
Erectile dysfunctione 2 0
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis 4 0
Pruritis 2 1
a
Includes the preferred terms Heart Rate Increased and Tachycardia.
b
Decreased appetite includes preferred terms Anorexia and Decreased appetite.
c
Dysgeusia includes preferred terms of dysgeusia, ageusia, hypogeusia and hypergeusia
d
Insomnia includes preferred terms of Insomnia, Initial Insomnia and Middle Insomnia.
e
Denominator includes only male subjects (VYVANSE n=49, Placebo n=56)
Adverse Events Leading to Discontinuation of Treatment in BED Clinical Trials
The discontinuation rate due to adverse events was 9% in 1252 BED patients. The more
common events leading to discontinuation were: blood pressure increased/hypertension
(0.8%), insomnia (0.7%), anxiety (0.6%), tachycardia (0.6%) and irritability (0.5%).

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

ADHD in Children Aged 6 to 12 Years of age

The children clinical trial was a Phase 3, randomized, multi center, double blind, parallel group,
placebo-controlled study in 290 children aged 6 to 12 years with ADHD. Adverse drug reactions
with the highest subject incidence rates (≥5.0%) in VYVANSE treatment groups combined were
decreased appetite, insomnia, upper abdominal pain, headache, irritability, weight decreased,
vomiting, nausea and dizziness. All these adverse drug reactions are typical side effects of
amphetamine products. 54.1% of these adverse drug reactions occurred within the first week of
treatment with VYVANSE, when all the active-treated subjects received VYVANSE 30 mg.

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Table 3 Adverse Drug Reactions Reported by 1% or More of Child Patients with
ADHD (Aged 6 to 12 Years) Taking VYVANSE in a 4 Week Clinical Trial
VYVANSE Placebo
Body System
n = 218 n = 72
Preferred Term
(%) (%)
Gastrointestinal Disorders
Abdominal Pain Upper 12 6
Vomiting 9 4
Nausea 6 3
Dry Mouth 5 0
General Disorder and Administration Site
Conditions
Pyrexia 2 1
Investigations
Weight Decreased 9 1
Metabolism and Nutrition Disorders
Decreased Appetite 39 4
Anorexia 2 0
Nervous System Disorders
Headache 12 10
Dizziness 5 0
Somnolence 2 1
Psychomotor Hyperactivity 1 0
Psychiatric Disorders
Insomnia 19 3
Irritability 10 0
Initial Insomnia 4 0
Affect Lability 3 0
Tic 2 0
Aggression 1 0
Agitation 1 0
Obsessive-Compulsive Symptoms 1 0
Skin and Subcutaneous Tissue Disorders
Rash 3 0
Note: This table includes those events for which the incidence in patients taking VYVANSE
was greater than the incidence in patients taking placebo. ADRs for which the incidence was
greater or equal in patients taking placebo: Fatigue.

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Adverse Events Associated with Discontinuation of Treatment in ADHD Clinical Trials
Nine percent (20/218) of VYVANSE-treated children aged 6 to 12 years discontinued due to
adverse events compared to 1% (1/72) who received placebo. The most frequent adverse
events leading to discontinuation and considered to be drug-related (i.e., leading to
discontinuation in at least 1% of VYVANSE-treated patients and at a rate at least twice that of
placebo) were ECG voltage criteria for ventricular hypertrophy, tic, vomiting, psychomotor
hyperactivity, decreased appetite, insomnia, and rash (2/218 each; 1%).
Weight Loss and Suppression of Growth in Pediatric Patients with ADHD
In the studies conducted in children (aged 6-12 years), VYVANSE demonstrated a dose-
dependent effect on subjects’ body weight over four weeks (see 7 WARNINGS AND
PRECAUTIONS, Endocrine and Metabolism).
ADHD in Adolescents Aged 13 to 17 Years
Three hundred and fourteen (314) adolescent subjects (aged 13 to 17 years) with ADHD were
enrolled in a Phase 3, randomized, double-blind, multi-center, placebo-controlled, parallel
group, forced-dose titration, safety and efficacy study of VYVANSE. The most common ADRs
(≥5.0%) reported with VYVANSE treatment reflected side effects commonly associated with
amphetamine use. These included decreased appetite, headache, insomnia, weight decreased
and irritability; there was no apparent dose effect for these events among VYVANSE treatment
groups. Most ADRs tended to occur early during the course of treatment and their incidence
generally decreased over time despite the forced-dose titration schedule of the study.
Table 4 Adverse Drug Reactions Reported by 1% or More of Adolescent Patients with
ADHD (Aged 13 to 17 Years) Taking VYVANSE in a 4-Week Clinical Trial
VYVANSE Placebo
Body System
n = 233 n = 77
Preferred Term
(%) (%)
Cardiac Disorders
Palpitations 2 1
Gastrointestinal Disorders
Dry Mouth 4 1
Nausea 4 3
General Disorder and Administration Site
Conditions
Fatigue 4 3
Investigations
Weight Decreased 9 0
Blood Pressure Increased 1 0
Metabolism and Nutrition Disorders
Decreased Appetite 34 3
Anorexia 2 0

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 VYVANSE Placebo
Body System
n = 233 n = 77
Preferred Term
(%) (%)
Nervous System Disorders
Headache 15 13
Tremor 2 0
Psychiatric Disorders
Insomnia 11 4
Irritability 7 4
Initial Insomnia 3 0
Affect Lability 1 0
Respiratory, Thoracic and Mediastinal
Disorders
Dyspnea 1 0
Note: This table includes those events for which the incidence in patients taking VYVANSE
was greater than the incidence in patients taking placebo. ADRs for which the incidence was
greater or equal in patients taking placebo: Diarrhea, Dizziness and Vomiting.
Adverse Events Associated with Discontinuation of Treatment in ADHD Clinical Trials
In the controlled adolescent (aged 13 to 17 years) trial, 4% (10/233) of VYVANSE-treated
patients discontinued due to adverse reactions compared to 1% (1/77) who received placebo.
The most frequent adverse events leading to discontinuation in at least 1% of VYVANSE-treated
patients and considered to be drug related were irritability (3/233; 1%), decreased appetite, and
insomnia (2/233 each; 1%).
Weight Loss and Suppression of Growth in Pediatric Patients with ADHD
In the studies conducted in adolescents (aged 13-17 years), VYVANSE demonstrated a dose-
dependent effect on subjects’ body weight over four weeks (see 7 WARNINGS AND
PRECAUTIONS, Endocrine and Metabolism).

8.3 Less Common Clinical Trial Adverse Reactions

ADHD in adult patients

Uncommon adverse drug reactions (reported by ≥0.1% to <1% of adult patients with ADHD
taking VYVANSE) in a 4-week clinical trial include:
Eye Disorders: Vision blurred
Gastrointestinal Disorders: Vomiting
General Disorders and Administration Site Conditions: Pyrexia
Psychiatric Disorders: Affect lability, depression, dermatillomania, dysphoria, euphoria, tic
Nervous System Disorders: Psychomotor hyperactivity, somnolence
Skin and Subcutaneous Tissue Disorders: Urticaria
BED in adult patients

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Less Common Clinical Trial Adverse Events: The adverse events listed below are based on
evaluation of data from pre-marketing phase 2-3 studies based on a pooled database of a total
of 4 placebo-controlled studies (including open-label portion when applicable). In these studies,
multiple doses of VYVANSE were administered to 988 patients. All reported events are included
except those already listed in Table 2, those too general to be informative, and those not
reasonably associated with the use of the drug. In some cases, separate event terms have been
consolidated to facilitate meaningful presentation. Events are further classified within System
Organ Class categories and enumerated in order of decreasing frequency using the following
definitions: common (occurring in less than 10/100 patients, but at least 1/100), uncommon
(occurring in less than 1/100, but at least 1/1000 patients) or rare (occurring in less than 1/1000
but at least in 1/10,000 patients).

Ear and Labyrinth Disorders: Uncommon: vertigo, tinnitus

Eye Disorders: Uncommon: vision blurred
Gastrointestinal Disorders: Common: abdominal discomfort, abdominal pain; Uncommon: post-
tussive vomiting
General Disorders and Administration Site Conditions: Uncommon: chest pain, pyrexia
Investigations: Uncommon: blood pressure diastolic increased, blood pressure systolic
increased
Musculoskeletal and Connective Tissue Disorders: Uncommon: myalgia
Nervous System Disorders: Common: tremor; Uncommon: psychomotor hyperactivity, memory
impairment, syncope, dizziness postural, resting tremor
Psychiatric Disorders: Common: bruxism, nervousness; Uncommon: depressed mood,
loggorhea, agitation, affect lability, depression, tachyphrenia, euphoric mood, libido decreased,
dermatillomania, depressive symptoms, dysphoria, hypomania, loss of libido, major depression
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: dyspnea, dyspnea exertional
Skin and Subcutaneaous Tissue Disorders: Uncommon: rash, alopecia, rash pruritic
Vascular Disorders: Uncommon: hypertension, diastolic hypertension, Raynaud’s Phenomenon

Multiple events may have been reported by a single patient. It is important to emphasize that
although the events reported did occur during treatment with VYVANSE, they were not
necessarily caused by it.

8.3.1 Less Common Clinical Trial Adverse Reactions-Pediatrics

ADHD in children 6-12 years of age

Uncommon adverse drug reactions (reported by ≥0.1% to <1% of pediatric patients with ADHD
taking VYVANSE) in a 4-week clinical trial include:
Cardiac Disorders: Palpitation, tachycardia
Eye Disorders: Mydriasis, vision blurred
Gastrointestinal Disorders: Diarrhea
General Disorders and Administration Site Conditions: Feeling jittery
Immune System Disorders: Hypersensitivity

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Investigations: Blood pressure increased
Psychiatric Disorders: Depression, dysphoria, logorrhea
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea
ADHD in children 12-17 years of age
Uncommon adverse drug reactions (reported by ≥0.1% to <1% of adolescent patients with
ADHD taking VYVANSE) in a 4-week clinical trial include:
Cardiac Disorders: Tachycardia
Gastrointestinal Disorders: Abdominal pain upper
General Disorders and Administration Site Conditions: Feeling jittery, pyrexia
Psychiatric Disorders: Aggression, anxiety, dermatillomania, restlessness
Nervous System Disorders: Psychomotor hyperactivity, somnolence
Skin and Subcutaneous Tissue Disorders: Rash, urticaria
Reproductive System and Breast Disorders: Erectile dysfunction

8.5 Post-Market Adverse Reactions

Table 5 Post-Market Adverse Reactions

System Organ Class Preferred Term

Cardiac Disorders Cardiomyopathy
Palpitations
Eye Disorders Diplopia
Mydriasis
Vision Blurred
Gastrointestinal Disorders Constipation, Intestinal
Ischemia
General Disorders and Administration Site Chest Pain
Disorders Fatigue
Hepatobiliary Disorders Eosinophilic Hepatitis
Immune System Disorders Anaphylactic Reaction
Hypersensitivity
Investigations QTc Prolongation
Musculoskeletal and Connective Tissue Disorders Rhabdomyolysis
Nervous System Disorders Dysgeusia
Dyskinesia
Restlessness
Seizure
Somnolence
Tremor

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 System Organ Class Preferred Term
Psychiatric Disorders Aggression
Agitation
Anxiety
Bruxism
Depression
Dermatillomania
Dysphoria
Euphoria
Hallucination
Logorrhea
Mania
Psychotic Episodes
Suicidal Behavior
Tic
Skin and Subcutaneous Tissue Disorders Angioedema
Hyperhidrosis
Stevens-Johnson Syndrome
Urticaria
Vascular Disorders Raynaud’s Phenomenon,
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).

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

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 9.2 Drug Interactions Overview

Lisdexamfetamine is not metabolized by cytochrome P450 (CYP) enzymes. The pharmacokinetic

parameters of dextroamphetamine, the active metabolite of lisdexamfetamine, were minimally
or not affected when VYVANSE was co-administered with omeprazole, extended-release
guanfacine, or extended-release venlafaxine (9.4 DRUG-DRUG INTERACTIONS). Due to the risk
of serotonergic syndrome, VYVANSE should be used with caution in combination with
serotonergic and/or neuroleptic drugs, e.g., triptans, certain tricyclic antidepressants and opiate
analgesics, lithium, St. John’s Wort, MAOIs (see 2 CONTRAINDICATIONS, 7 WARNINGS AND
PRECAUTIONS, Neurologic and 9.4 Drug-Drug Interactions).

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).
Proton Pump Inhibitors
These agents act on proton pumps by blocking acid production thereby reducing gastric acidity.
A proton pump inhibitor (omeprazole) had no effect on the pharmacokinetics of VYVANSE
(lisdexamfetamine dimesylate).
In Vivo Study on Cytochrome P450 (CYP) Substrates
An in vivo human study of lisdexamfetamine dimesylate (70 mg) in healthy adults did not result
in any clinically meaningful effect on the pharmacokinetics of drug substrates metabolized by
CYP1A2 (200 mg caffeine), CYP2D6 (30 mg dextromethorphan), CYP2C19 (40 mg omeprazole),
or CYP3A (0.025 mg/kg midazolam).
Agents Whose Blood Levels May be Impacted by VYVANSE
Extended-release guanfacine: In a drug interaction study, administration of an extended-release
guanfacine (4 mg) to healthy adult volunteers in combination with VYVANSE (50 mg) induced a
19% increase in guanfacine maximum plasma concentrations; whereas exposure (area under
the curve; AUC) was increased by 7%. These small changes are not expected to be clinically
meaningful. In this study, no effect on dextroamphetamine exposure was observed following
co-administration of extended-release guanfacine and VYVANSE. Drug interaction studies have
not been conducted with higher doses of lisdexamfetamine dimesylate.
Extended-release venlafaxine: In a drug interaction study, administration of 225 mg extended-
release venlafaxine, a CYP2D6 substrate, in combination with 70 mg VYVANSE induced a 9%
decrease in the Cmax and 17% decrease in the AUC for the primary active metabolite
o-desmethylvenlafaxine and a 10% increase in Cmax and 13% increase in AUC for venlafaxine.
These small changes are not expected to be clinically meaningful. In this study, no effect on
dextroamphetamine exposure was observed following co-administration of extended-release
venlafaxine and VYVANSE. VYVANSE (dextroamphetamine) may be a weak inhibitor of CYP2D6.
Lisdexamfetamine has no effect on the AUC and Cmax of the composite of venlafaxine and
o-desmethylvenlafaxine.

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Agents and Conditions that Alter Urinary pH and Impact the Urinary Excretion and Half Life of
Amphetamines
Ascorbic acid and other agents and conditions that acidify urine increase urinary excretion and
decrease the half-life of amphetamines. Sodium bicarbonate and other agents and conditions
that alkalinize urine, decrease urinary excretion and extend the half-life of amphetamines.
Monoamine Oxidase Inhibitors (MAOIs)
VYVANSE is contraindicated during or within 14 days following the administration of MAOIs.
MAOIs and amphetamines, when co-administered, can increase the release of norepinephrine
and other monoamines. This can cause severe headaches and other signs of hypertensive crisis.
A variety of toxic neurological effects and malignant hyperpyrexia can occur, sometimes with
fatal results (see 2 CONTRAINDICATIONS).
Serotonergic Drugs
On rare occasions, serotonin syndrome has occurred in association with the use of
amphetamines, such as VYVANSE, when given in conjunction with serotonergic drugs, including
selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake
inhibitors (SNRIs). It has also been reported in association with overdose of amphetamines,
including VYVANSE (see 5 OVERDOSAGE and 7 WARNINGS AND PRECAUTIONS, Neurologic).
There were no reported cases of serotonin syndrome when VYVANSE was administered with
SSRIs and SNRIs in clinical trials.
As this syndrome 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.
VYVANSE should be used with caution in combination with serotonergic and/or neuroleptic
drugs (e.g., triptans, certain tricyclic antidepressants and opiate analgesics, lithium, St. John’s
Wort, MAOIs) due to the risk of serotonergic syndrome (see 2 CONTRAINDICATIONS and 7
WARNINGS AND PRECAUTIONS, Neurologic).
Agents Whose Effects May be Reduced by Amphetamines
• Adrenergic blockers: As expected by their pharmacologic action, adrenergic blockers are
inhibited by amphetamines.
• Antihypertensives: Amphetamines may antagonize the hypotensive effects of
antihypertensives.
Agents Whose Effects May be Potentiated by Amphetamines
• Norepinephrine: Amphetamines enhance the adrenergic effect of norepinephrine.
• Modafinil: Modafinil with amphetamines may cause increases in blood pressure and heart
rate and may result in additive effects; their concomitant use is not recommended.
Agents that May Reduce the Effects of Amphetamines

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• Chlorpromazine: Chlorpromazine blocks dopamine and norepinephrine receptors, thus
inhibiting the central stimulant effects of amphetamines.
• Haloperidol: Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant
effects of amphetamines.
• Pimozide: Pimozide may block the action of amphetamines, and concomitant use of the two
medications is not recommended.

9.5 Drug-Food Interactions

Capsule Formulation
Food (a high fat meal or yogurt) or orange juice does not affect the observed AUC and Cmax of
dextroamphetamine in healthy adults after single-dose oral administration of 70 mg of
VYVANSE capsules. Food prolongs Tmax by approximately 1 hour (from 3.8 hrs at fasted state to
4.7 hrs after a high-fat meal or to 4.8 hours with orange juice). After an 8 hour fast, the AUC for
dextroamphetamine following oral administration of lisdexamfetamine dimesylate in solution
and as intact capsules were equivalent.
Chewable Tablet Formulation
Food (a high-fat meal) does not affect the Cmax, AUClast, and AUC0-∞ of dextroamphetamine in
healthy adults (N=23) after a single 60 mg dose of VYVANSE chewable tablets. Food delays the
mean Tmax of dextroamphetamine by approximately 1 hour (from 3.90 hours at fasted state to
4.89 hours after a high fat meal).

9.6 Drug-Herb Interactions

VYVANSE should be used with caution in combination with St. John’s Wort (see 9.4 Drug-Drug
Interaction, Serotonergic Drugs).

9.7 Drug-Laboratory Test Interactions

Amphetamines can cause a significant elevation in plasma corticosteroid levels particularly in

the evening, and thus may affect urinary steroid determinations.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Lisdexamfetamine dimesylate is a prodrug of dextroamphetamine. Amphetamines are non-

catecholamine sympathomimetic amines with CNS stimulant activity. Amphetamines block the
reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release
of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does
not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro. The
mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.

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 10.2 Pharmacodynamics

Binding assays showed that lisdexamfetamine dimesylate lacked affinity for human recombinant
DAT and NET transporter sites. Lisdexamfetamine dimesylate was also tested against 62 specific
receptor and enzyme sites that could potentially mediate adverse side effects.
Lisdexamfetamine dimesylate did not bind significantly to any of these sites.
In pharmacodynamic studies, the effects of orally administered lisdexamfetamine dimesylate
were generally comparable to dextroamphetamine. These studies demonstrated that the total
extent of the pharmacological effect of lisdexamfetamine dimesylate (increased locomotor
activity) over time was increased while the onset of effect was delayed, compared with an
equivalent dose of amphetamine sulphate. This delayed onset is consistent with gradual
hydrolysis of lisdexamfetamine dimesylate to release dextroamphetamine. Parenteral (IV or IN)
administration of lisdexamfetamine dimesylate resulted in minimal pharmacological effect as
compared to that induced by an equivalent dextroamphetamine sulphate dose.

10.3 Pharmacokinetics

Pharmacokinetic studies of dextroamphetamine after oral administration of lisdexamfetamine

dimesylate have been conducted in healthy adult (capsule and chewable tablet formulations)
and pediatric (aged 6 to 12 years) (capsule formulation) patients with ADHD. Linear
pharmacokinetics of dextroamphetamine after single dose oral administration of VYVANSE
capsules was established over the dose range of 30 mg to 70 mg in children aged 6 to 12 years;
and in adults over a range of 50 mg to supratherapeutic dose of 150 mg. There is no
accumulation of dextroamphetamine (as measured by AUC) at steady state in healthy adults
and no accumulation of lisdexamfetamine dimesylate after once-daily dosing for seven
consecutive days.
Absorption
After oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the
gastrointestinal tract.
Capsule Formulation
In 18 pediatric patients (aged 6 to 12 years) with ADHD, the Tmax of dextroamphetamine was
approximately 3.5 hours following single-dose oral administration of lisdexamfetamine
dimesylate 30 mg, 50 mg, or 70 mg after an 8 hour overnight fast. The Tmax of lisdexamfetamine
dimesylate was approximately one hour.
Food (a high fat meal or yogurt) or orange juice does not affect the observed AUC and Cmax of
dextroamphetamine in healthy adults after single-dose oral administration of 70 mg of
VYVANSE capsules. Food prolongs Tmax by approximately one hour (from 3.8 hrs at fasted state
to 4.7 hrs after a high-fat meal or to 4.8 hrs with orange juice). After an 8 hour fast, the AUC for
dextroamphetamine following oral administration of lisdexamfetamine dimesylate in solution
and as intact capsules were equivalent.

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Chewable Tablet Formulation
In healthy adult subjects (N=18), the chewable lisdexamfetamine dimesylate tablet formulation,
as evaluated by Cmax, AUClast, and AUC0-∞ of dextroamphetamine has shown comparable
bioavailability when compared to the capsule formulation after a single-dose oral
administration under fasting condition. The mean Tmax (SD) of dextroamphetamine was 4.4
(1.18) hours following a single 60 mg dose of lisdexamfetamine dimesylate administered in
chewable tablet form after a 10-hour overnight fast. The Tmax of lisdexamfetamine was
approximately 1 hour. The dextroamphetamine Cmax pharmacokinetic parameter following
administration of the 60 mg chewable tablet in adults exhibited low inter-subject (20.89% [95%
CI: 14.85, 31.57]), intra-subject (8.37% [95% CI: 6.62, 11.37]) and subject by treatment
interaction (4.15% [95% CI: 1.39, 7.34]) variability.
Food (a high-fat meal) does not affect Cmax, AUClast, and AUC0-∞ of dextroamphetamine in
healthy adults (N=23) after a single-dose of 60 mg of VYVANSE chewable tablets. Food delays
the mean Tmax of dextroamphetamine by approximately 1 hour (from 3.90 hrs in fasted state to
4.89 hours after a high fat meal).
Metabolism:
Lisdexamfetamine dimesylate is hydrolyzed in the blood to dextroamphetamine, which is
responsible for the drug’s activity, and L-lysine. Lisdexamfetamine is not metabolized by
cytochrome P450 enzymes.
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.
Elimination
Following the oral administration of a 70 mg dose of radiolabeled lisdexamfetamine dimesylate
to six healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the
urine and only 0.3% recovered in the feces over a period of 120 hours. Of the radioactivity
recovered in the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and
2% intact lisdexamfetamine. Plasma concentrations of unconverted lisdexamfetamine are low
and transient, generally becoming non-quantifiable by eight hours after administration. The
plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in studies
of lisdexamfetamine dimesylate in volunteers.
In Vitro and Animal Pharmacokinetics
Oral administration of lisdexamfetamine dimesylate in comparison to dextroamphetamine
sulfate demonstrated that the bioavailability (AUC) of dextroamphetamine from the prodrug

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was approximately equivalent near therapeutic human equivalent doses (HEDs). At high doses
well above the therapeutic range, however, both AUC and Cmax of dextroamphetamine from
lisdexamfetamine dimesylate were substantially decreased in comparison to AUC and Cmax of
dextroamphetamine from dextroamphetamine sulfate.
Absorption of lisdexamfetamine dimesylate orally administered increased non-linearly with
increasing dose. The clearance of lisdexamfetamine dimesylate was greater than that of
dextroamphetamine following oral administration. When lisdexamfetamine dimesylate is
administered via parenteral routes, there is delayed and gradual release of dextroamphetamine
with substantially attenuated peak concentrations when compared to immediate-release
dextroamphetamine.
Oral administration of lisdexamfetamine dimesylate demonstrated that lisdexamfetamine
dimesylate was not detected in rat brain tissue. The major metabolites of lisdexamfetamine
dimesylate following oral administration were glucuronidated amphetamine and amphetamine.
These two moieties comprised >90% of the total metabolites in plasma after oral dosing.
Following intravenous administration, small amounts of hydroxylated lisdexamfetamine
dimesylate were observed in plasma. As in the case of oral administration, the major
metabolites from intravenous administration of lisdexamfetamine dimesylate were similar,
glucuronidated amphetamine and amphetamine.
In vitro experiments demonstrated that incubation of lisdexamfetamine dimesylate in human
hepatic microsomal suspensions resulted in no significant inhibition of a panel of CYP450
isoforms that included CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, nor
induction of CYP1A2, CYP2B6 or CYP3A4/5 in cultured fresh human hepatocytes.
Lisdexamfetamine dimesylate was stable in the presence of human microsomes and fresh
human and rat hepatocytes. No metabolites of lisdexamfetamine dimesylate were observed.
In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by
amphetamine and minor inhibition of CYP1A2, CYP2D6, and CYP3A4 by one or more
metabolites. Although the clinical significance of this interaction is likely to be minimal,
consideration should be given when medications metabolised by these pathways are
administered.
Lisdexamfetamine dimesylate and dextroamphetamine are not in vitro substrates for P-gp nor
in vitro inhibitors of P-gp transport in monolayers and therefore are unlikely to be involved in
clinical interactions with drugs transported by the P-gp pump.
Urinary excretion was the predominant route of elimination accounting for approximately 77%
and 87% of the administered dose in males and females, respectively. Excretion in feces
accounted for only 10.9% and 3.9% in males and females, respectively. Elimination of
radioactivity in urine and feces occurred largely in the first 48 hours post-dose.
Excretion of radioactive labeled lisdexamfetamine dimesylate was evaluated in intact and bile
duct cannulated rats. Lisdexamfetamine dimesylate was rapidly eliminated following oral or
intravenous administration. Cumulative biliary excretion for the first 48 hours post-dose
accounted for approximately 14% and 12% of the dose in male and female rats, respectively.
The majority of radioactivity excreted in bile occurred within 8 hours post-dose. The AUC(last) for

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prodrug was similar for intact and bile duct cannulated rats with no gender differences. On the
basis of these findings, bile excretion does not play a major role in lisdexamfetamine dimesylate
elimination.
Special Populations and Conditions
Pediatrics: The pharmacokinetics of dextroamphetamine is similar in pediatric (aged 6 to 12
years) and adolescent (aged 13 to 17 years) ADHD patients, and healthy adult volunteers. Any
differences in kinetics seen after oral administration are a result of differences in mg/kg dosing.
Geriatrics: In a study of 47 subjects aged 55 years of age or older, amphetamine clearance was
approximately 0.7 L/hr/kg for subjects 55-74 years of age and 0.55 L/hr/kg for subjects ≥75
years of age. This is slightly reduced compared to younger adults (approximately 1 L/hr/kg for
subjects 18-45 years of age). Reduced amphetamine clearance does not appear to be related to
kidney function as measured by creatinine clearance.
Sex: Systemic exposure to dextroamphetamine is similar for men and women given the same
mg/kg dose. Weight/Dose normalized AUC and Cmax were 22% and 12% lower, respectively, in
adult females than in males on Day 7 following a 70 mg/day dose of lisdexamfetamine for seven
days. Weight/Dose normalized AUC and Cmax values were the same in girls and boys following
single doses of 30 mg to 70 mg.
Ethnic Origin: Formal pharmacokinetic studies for race have not been conducted.
Hepatic Insufficiency: No studies have been conducted in patients with hepatic impairment.
Renal Insufficiency: In a pharmacokinetic study of lisdexamfetamine in subjects with normal
and impaired renal function, dextroamphetamine 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 m2) (see 4.2 Recommended Dose and Dosage Adjustment; 7 WARNINGS AND
PRECAUTIONS, Renal).

11 STORAGE, STABILITY AND DISPOSAL

Capsule Formulation
Dispense in a tight, light-resistant container as defined in the USP.
Store at 15-30°C (59-86°F).
Chewable Tablet Formulation
Store at 15-30°C (59-86°F).

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PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance
Proper name: lisdexamfetamine dimesylate
Chemical name: (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide
dimethanesulfonate
Molecular formula and molecular mass: C15H25N3O•(CH4O3S)2 455.60
Structural formula:

Physicochemical properties: White to off-white powder that is highly soluble in water.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Attention Deficit Hyperactivity Disorder (ADHD)

Table 6 - Summary of patient demographics for clinical trials in ADHD

Study Mean
Dosage, route of
Study # Study design subject age Sex
administration and duration
s (n) (Range)
NRP104 Randomized, Patients were randomized to n=285 9.0 Male:
.301 double-blind, fixed dose treatment groups years 69.1%
placebo-controlled, receiving final doses of 30, (6 to Female:
parallel-group study 50, or 70 mg of VYVANSE or 12) 30.9%
conducted in placebo once daily in the
children aged 6 to morning for four weeks.
12 years who met
DSM-IV criteria for
ADHD (either the
combined type or
the hyperactive-
impulsive type).

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 Study Mean
Dosage, route of
Study # Study design subject age Sex
administration and duration
s (n) (Range)
NRP104 Double-blind, Following a 3-week open- n=50 9.1 Male:
.201 placebo- and active- label dose titration with years 62%
controlled, mixed salts amphetamine (6 to Female:
randomized, extended-release capsules, 12) 38%
multi-dose, 3-period patients were randomized
and 3-treatment with respect to treatment
crossover, study of sequence for the same dose
children aged 6 to of mixed salts amphetamine
12 years who met extended-release capsules
DSM-IV criteria for (10, 20, or 30 mg), VYVANSE
ADHD (either the (30, 50, or 70 mg), or
combined type or placebo once daily in the
the hyperactive- morning for one week each
impulsive type) treatment.
conducted in a
laboratory
classroom setting.
SPD489- Double-blind, In this 4-week study, n=310 14.6 Male:
305 randomized, patients were randomized in years 70.3%
placebo-controlled, a 1:1:1:1 ratio to a daily (13 to Female:
parallel-group study morning dose of VYVANSE 17) 29.7%
conducted in (30, 50 or 70 mg/day) or
adolescents aged 13 placebo for a double-blind
to 17 years who met stepwise forced-dose
DSM-IV criteria for titration (3 weeks) followed
ADHD. by a 1-week Dose
Maintenance Period. All
subjects receiving VYVANSE
were initiated on 30 mg for
the first week of treatment.
Subjects assigned to the
50 mg and 70 mg dose
groups were titrated by
20 mg per week until they
achieved their assigned
dose.

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 Study Mean
Dosage, route of
Study # Study design subject age Sex
administration and duration
s (n) (Range)
NRP104 Double-blind, In this 4-week forced-dose n=420 35.1 Male:
.303 randomized, titration study, subjects years 54.3%
placebo-controlled, were randomly assigned in a (18 to Female:
parallel-group, 2:2:2:1 ratio of each of the 55) 45.7%
forced dose titration three active doses vs.
study conducted in placebo to a daily morning
adults aged 18 to 55 dose of VYVANSE or placebo
years who met for four weeks. All VYVANSE
DSM-IV criteria for groups started at 30 mg/day.
ADHD (either the Subjects randomized to
combined type or 70 mg titrated to that dose
the over a 2-week period; those
hyperactive-impulsiv randomized to 50 mg
e type). titrated to that dose over a
1-week period; those
randomized to 30 mg began
dosing on 30 mg/day during
Week 1 and remained on
that dose throughout the
study.

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Study Results in ADHD
Children with ADHD
Table 7 - Results of study NRP104.301 in ADHD (Children Aged 6 to 12 Years)

Associated value and Associated value and

Primary Endpoints statistical significance for statistical significance for
Drug at specific dosages Placebo or active control
ADHD Rating Scale Significant improvement in
(ADHD-RS) total score change patient behavior was
from baseline at treatment observed at endpoint for all
endpoint for the ITT active treatment groups.
population LS Mean (SE)*
LS Mean (SE)*
-6.2 (1.56)
30 mg: -21.8 (1.60)
50 mg: -23.4 (1.56)
70 mg: -26.7 (1.54)
Comparison (placebo-
adjusted difference):
LS Mean (95% CI†)
-15.58 (-20.78, -10.38)
p<0.0001
-17.21 (-22.33, -12.08)
p<0.0001
-20.49 (-25.63, -15.36)
p<0.0001
* Treatment effect: p<0.0001 (2-way ANCOVA)
† Dunnett’s test
CI: Confidence Interval; SE: Standard Error; LS: Least Squares

Significant improvements in ADHD symptoms, based upon investigator ratings on the ADHD
Rating Scale (ADHD-RS), were observed at Week 1 and continued throughout the entire 4-week
treatment period for all VYVANSE doses compared to placebo in children aged 6 to 12 years
(Table 7). Parents (based on Conner’s Parent Rating Scale) reported significant improvement in
behavior throughout the day at approximately 10 am, 2 pm, 6 pm in the VYVANSE group when
compared to placebo.

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Table 8 - Results of study NRP104.201 in ADHD (Children Aged 6 to 12 Years)

Associated value and statistical Associated value and statistical

Primary Endpoints significance for Drug at specific significance for Placebo or active
dosages control
Average of SKAMP- LS Mean (SE) LS Mean (SE)
deportment scores 0.8 (0.1) mixed salts amphetamine
across the treatment extended release capsules (10
assessment day, using mg, 20 mg, and 30 mg
a mixed effects model combined): 0.8 (0.1)
of analysis of variance
Placebo: 1.7 (0.1)
(ANOVA) for the ITT
population Difference in LS Mean (95% CI) Difference in LS Mean (95% CI) of
of VYVANSE vs. placebo: mixed salts amphetamine
-0.9 (-1.1, -0.7)* extended release capsules vs.
placebo:
Difference in LS Mean (95% CI)
-0.9 (-1.1, -0.7)*
of VYVANSE vs. mixed salts
amphetamine extended-release
capsules:
-0.1 (-0.3, 0.1)
* p<0.0001 (2-way ANOVA with treatment and period effects)
CI: Confidence Interval; LS: Least Squares; SE: Standard Error

A significant improvement in patient (aged 6 to 12 years) behavior, based upon the average of
investigator ratings on the Swanson, Kotkin, Agler, M.Flynn and Pelham (SKAMP)-deportment
scores across the eight sessions of a 12-hour treatment day (assessments conducted at 1, 2, 3,
4.5, 6, 8, 10, and 12 hours post-dose), was observed between patients who received VYVANSE
compared to patients who received placebo (Table 8).
The results of the secondary efficacy measures (SKAMP-Attention, Clinical Global Impression
Improvement [CGI-I], number of math problems attempted [PERMP-A] and number of math
problems worked correctly [PERMP-C]) were supportive of the primary efficacy endpoint. On
the CGI-I scale, both VYVANSE and mixed salts amphetamine extended-release capsules scores
indicated significant improvement compared with placebo. In addition, LS means of Permanent
Product Measure of Performance [PERMP] average scores for combined doses of active
treatments across the treatment day were highly significant compared with placebo, with both
associated with robust increases in the number of attempted and correct math problems.
Analog Classroom Study
A second double-blind, placebo-controlled, randomized, crossover design, analog classroom
study was conducted in children aged 6 to 12 years (n=129) who met DSM-IV criteria for ADHD
(either the combined type or the hyperactive-impulsive type). Following a 4 week open label
dose titration with VYVANSE (30, 50, 70 mg), patients were randomly assigned to continue

VYVANSE® (lisdexamfetamine dimesylate) Page 41 of 67

VYVANSE or placebo once daily in the morning for one week each treatment. A significant
difference in patient behavior, based upon the average of investigator ratings on the SKAMP-
deportment scores at 1.5 hours post dose (primary endpoint) and across all seven post dose
sessions of a 13-hour treatment day (assessments conducted at 1.5, 2.5, 5.0, 7.5, 10.0, 12.0 and
13.0 hours post dose), was observed between patients who received VYVANSE compared to
patients who received placebo.
Adolescent with ADHD
Table 9 - Results of study SPD489-305 in ADHD (Adolescents Aged 13 to 17 Years)

Associated value and Associated value and

Primary Endpoints statistical significance for statistical significance for
Drug at specific dosages Placebo or active control
ADHD Rating Scale Significant improvements in
(ADHD-RS) total score change ADHD symptoms were
from baseline at treatment observed at endpoint for all
endpoint for the FAS VYVANSE doses compared to
population placebo. LS Mean (SE)*
LS Mean (SE)* -12.8 (1.25)
30 mg: -18.3 (1.25)
50 mg: -21.1 (1.28)
7 0 mg: -20.7 (1.25)
Comparison (placebo-
adjusted difference):
LS Mean (95% CI†)
-5.5 (-9.7, -1.3) p=0.0056
-8.3 (-12.5, -4.1) p<0.0001
-7.9 (-12.1, -3.8) p<0.0001
* Treatment effect: p<0.0001 (2-way ANCOVA)
† Dunnett’s test
CI: Confidence Interval; FAS: Full Analysis Set; LS: Least Squares; SE: Standard Error

Significant improvements in ADHD symptoms, based upon investigator ratings on the ADHD
Rating Scale (ADHD-RS), were observed at endpoint for all VYVANSE doses compared to placebo
in adolescents aged 13 to 17 years (Table 9). The improvement in the ADHD-RS-IV total score
demonstrated in the primary efficacy analysis was supported by the results of the ADHD-RS-IV
hyperactivity/impulsivity and inattentiveness subscale analyses at endpoint. Consistent with the
primary efficacy result, efficacy was demonstrated at endpoint and at every study visit for all
three VYVANSE treatment groups. The mean ADHD-RS-IV hyperactivity/impulsivity and
inattentiveness subscale scores consistently decreased from Visit 1 to Visit 4, and at every visit
there was a consistently larger reduction in the subscale scores in VYVANSE treatment groups

VYVANSE® (lisdexamfetamine dimesylate) Page 42 of 67

compared to placebo. At endpoint and at all study visits, the mean change from baseline in the
ADHD-RS-IV subscale scores for all three VYVANSE treatment groups was statistically
significantly different from placebo, representing an improvement in ADHD symptomatology
compared to placebo.

The results of the secondary efficacy measure were supportive of the primary efficacy endpoint.
On the CGI-I scale, VYVANSE scores indicated significant improvement compared with placebo.

Children and Adolescents with ADHD

A double-blind, randomized, placebo- and active-controlled parallel-group, dose-optimization
study was conducted in children and adolescents aged 6 to 17 years (total 317 subjects [Full
Analysis Set population], 229 (72.2%) subjects aged 6 to 12 years and 88 (27.8%) subjects aged
13 to 17 years) who met DSM-IV criteria for ADHD; subjects previously treated with the active
control who had not responded were not enrolled into the study. In this eight-week study,
patients were randomized to a daily morning dose of VYVANSE (30, 50 or 70 mg/day), active
control (included for trial sensitivity) or placebo (1:1:1). The study consisted of 3 periods, as
follows: a Screening and Washout Period (up to 42 days), a 7-week Double-blind Evaluation
Period (consisting of a 4-week Dose-Optimization Period followed by a 3-week Dose
Maintenance Period), and a 1-week Washout and Follow-up Period. During the 4-week Dose
Optimization Period, subjects were titrated until an optimal dose, based on TEAEs and clinical
judgment, was reached.
Significant improvements in ADHD symptoms, based upon investigator ratings on the ADHD
Rating Scale (ADHD-RS), were observed for VYVANSE at endpoint compared to placebo (Table
10). The results of the secondary efficacy measures (CGI-I, change in CHIP-CE: PRF Achievement
Domain) were supportive of the primary efficacy endpoint and statistically significantly different
from placebo.

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Table 10 – Results of Study SPD489-325 in ADHD (Children and Adolescents Aged 6 to 17
Years)

Associated value and statistical Associated value and

Primary Endpoints significance for Drug at specific statistical significance for
dosages Placebo or active control
ADHD Rating Scale Significant improvements in
(ADHD-RS) total score change ADHD symptoms were observed
from baseline at treatment at endpoint compared to
LS Mean (SE)*
endpoint for the FAS placebo.
population -5.7 (1.13)
LS Mean (SE)*
-24.3 (1.16)

Comparison (placebo-adjusted
difference):
LS Mean (95% CI)
-18.6 (-21.5, -15.7) p<0.001
* Treatment effect: p<0.001 (2-way ANCOVA)
CI: Confidence Interval; FAS: Full Analysis Set; LS: Least Squares; SE: Standard Error

Randomized Withdrawal Study (6 weeks double-blind randomized withdrawal in subjects

following treatment with open-label VYVANSE for at least 26 weeks)
A double-blind, placebo-controlled, randomized withdrawal study was conducted in children
and adolescents aged 6 to 17 years who met the diagnosis of ADHD (DSM-IV criteria). A total of
276 patients were enrolled into the study, 236 patients participated in the preceding study
SPD489-325 and 40 subjects directly enrolled. A total of 262 subjects were in the open-label Full
Analysis Set population, 185 (70.6%) subjects aged 6 to 12 years and 77 (29.4%) subjects aged
13 to 17 years. In order to ensure that the appropriate population was included in the
randomized withdrawal period to evaluate the long-term maintenance of efficacy, subjects
were treated with open-label VYVANSE for an extended period (at least 26 weeks) prior to being
assessed for entry into the randomized withdrawal period. Eligible patients had to demonstrate
treatment response as defined by CGI-S <3 and Total Score on the ADHD-RS ≤22. ADHD-RS Total
Score is a measure of core symptoms of ADHD. Of patients that maintained open-label
treatment response, 157 were randomized to ongoing treatment with the same dose of
VYVANSE (n=78) or switched to placebo (n=79) during the double-blind phase. Patients were
observed for relapse (treatment failure) during the 6-week double-blind phase. Maintenance of
efficacy was demonstrated based on the significantly lower proportion of treatment failure
among VYVANSE subjects (15.8%) compared to placebo (67.5%) at endpoint of the randomized
withdrawal period (see Figure 1). The endpoint measurement was defined as the last post-
randomization treatment week at which a valid ADHD-RS Total Score and CGI-S were observed.
Treatment failure was defined as a ≥50% increase (worsening) in the ADHD-RS Total Score and a

VYVANSE® (lisdexamfetamine dimesylate) Page 44 of 67

≥2-point increase in the CGI-S score compared to scores at entry into the double blind
randomized withdrawal phase. For the majority of subjects (70.3%) who were treatment
failures, ADHD symptoms worsened at or before the Week 2 visit following randomization.

Figure 1 Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure (children

and adolescents)

VYVANSE® (lisdexamfetamine dimesylate) Page 45 of 67

Adults with ADHD
Table 11 – Results of Study NRP104.303 in ADHD (Adults Aged 18 to 55 Years)

Associated value and

Associated value and statistical
statistical significance
Primary Endpoints significance for Drug at specific
for Placebo or active
dosages
control
ADHD Rating Scale Significant improvement in ADHD
(ADHD-RS) total score change symptoms was observed at
from baseline at treatment endpoint for all VYVANSE doses.
LS Mean (SE)*
endpoint for the ITT LS Mean (SE)*
population -8.2 (1.43)
30 mg: -16.2 (1.06)
50 mg: -17.4 (1.05)
70 mg: -18.6 (1.03)
Comparison (placebo-adjusted
difference):
LS Mean (95% CI†)
-8.04 (-12.14, -3.95) p<0.0001
-9.16 (-13.25, -5.08) p<0.0001
-10.41 (-14.49, -6.33) p<0.0001
* Treatment effect: p<0.0001 (2-way ANCOVA)
† Dunnett’s test
CI: Confidence Interval; LS: Least Squares; SE: Standard Error

Significant improvements in ADHD symptoms, based upon investigator ratings on the ADHD
Rating Scale (ADHD-RS), were observed at Week 1 and were seen throughout the entire 4-week

VYVANSE® (lisdexamfetamine dimesylate) Page 46 of 67

treatment period for all VYVANSE doses compared to placebo in adults aged 18 to 55 years
(Table 11).
The results of the secondary efficacy measure were supportive of the primary efficacy endpoint.
On the CGI-I scale, VYVANSE scores indicated significant improvement compared with placebo.
Adult Workplace Environment Study
A second double-blind, placebo-controlled, randomized, crossover design, multi-centered, adult
workplace environment (AWE) study, a modified analog classroom study of VYVANSE to
simulate a workplace environment, was conducted in adults (n=142) who met DSM-IV-TR
criteria for ADHD. Following a 4-week open-label dose optimization with VYVANSE (30, 50, 70
mg), patients were randomly assigned to continue VYVANSE or placebo once daily in the
morning for one week each treatment. Significant improvements in patient performance, based
upon the Permanent Product Measure of Performance (PERMP) scores, a skill-adjusted math
test that measures attention in ADHD, were demonstrated at all post dose time points
measured between patients who received VYVANSE compared to patients who received
placebo. The PERMP assessments were administered at pre dose (-0.5 hours) and at 2, 4, 8, 10,
12, and 14 hours post-dose.
At the optimized dose strength, significant improvements based upon the PERMP-A (number of
math problems attempted) score and PERMP-C (number of math problems answered correctly)
scores were demonstrated at all post dose time points measured between patients who
received VYVANSE compared to patients who received placebo. Secondary measures of Adult
ADHD-RS with prompts total score, hyperactivity/impulsivity subscale score, and the
inattentiveness subscale score were also supportive of the primary efficacy endpoint and
statistically significantly different from placebo. On the CGI-I scale, a significantly larger
percentage of subjects receiving VYVANSE were improved compared to placebo during the
crossover visits.
Randomized Withdrawal Study (6 weeks double-blind randomized withdrawal in subjects with
documentation of open-label treatment with VYVANSE for a minimum of 6 months)
A double-blind, placebo-controlled, randomized withdrawal design study was conducted in
adults aged 18 to 55 years (n=123) who met DSM-IV criteria for ADHD. At study entry, subjects
must have had documentation of treatment with VYVANSE for a minimum of 6 months and had
to demonstrate treatment response as defined by CGI-S ≤3 and Total Score on the ADHD-RS
with adult prompts <22. ADHD-RS Total Score is a measure of core symptoms of ADHD. Subjects
that maintained treatment response at Week 3 of the open-label treatment phase (n=116) were
eligible to enter the double-blind randomized withdrawal phase (6 weeks duration), and
received their entry dose of VYVANSE (n=56) or placebo (n=60). The efficacy for subjects
maintaining treatment with VYVANSE was demonstrated by the significantly lower proportion of
treatment failure (<9%) compared to subjects receiving placebo (75%) in the double-blind
randomized withdrawal phase (see Figure 2). Treatment failure was defined as a ≥50% increase
in the ADHD-RS with adult prompts Total Score and ≥2-point increase in the CGI-S score
compared to scores at entry into the double-blind randomized withdrawal phase.

VYVANSE® (lisdexamfetamine dimesylate) Page 47 of 67

Figure 2 Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure (adults)
Executive Function (Self-regulation) Behaviors Study in ADHD
A 10-week, double-blind, placebo-controlled study was conducted to evaluate change in
executive function behaviors, key quality of life outcomes, and ADHD symptoms in adults with
ADHD. The study enrolled adults aged 18 to 55 years (n=161) who met DSM-IV criteria for ADHD
and had a total score of ≥65 on Behavior Rating Inventory of Executive Function – Adult Version
(BRIEF A) Global Executive Composite (GEC) T-score by subject-report and a score of ≥28 using
the Adult ADHD-RS with prompts at the Baseline visit. The difference in LS mean change from
baseline to week 10 for subject-reported BRIEF-A GEC T-score (-11.2) was significantly better in
the VYVANSE group compared with placebo (p<0.0001). Secondary efficacy measures of Adult
ADHD Impact Module (AIM-A), ADHD-RS with adult prompts, CGI and the ADHD Index T-score of
the Conners’ Adult ADHD Rating Scale – Observer: Short Version (CAARS-O:S) were all
significantly better in the VYVANSE group compared with placebo.

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Binge Eating Disorder (BED)
Table 12 - Summary of patient demographics for clinical trials in BED

Dosage, route
Study Mean
of
Study # Study design subjects age Sexb
administration
(n) a (Range)b
and duration
SPD489- Multicenter, Randomized, VYVANSE n=374 38.1 Male:
343 Double-blind, Parallel-group, 30, 50, and years 13.5%
Placebo-controlled, Dose- 70mg (19 to Female:
optimization Study to Evaluate 55) 86.5%
oral, once daily
the Efficacy, Safety, and
capsules
Tolerability of VYVANSE in
Adults Aged 18-55 Years with Placebo
Moderate to Severe Binge oral, once daily
Eating Disorder. This study capsules
consisted of a screening phase,
a double-blind treatment phase
(including dose-optimization Duration of
and dose-maintenance treatment: 12
periods), and a follow-up visit. weeks

SPD489- Multicenter, Randomized, VYVANSE n=350 37.9 Male:

344 Double-blind, Parallel-group, 30, 50, and years 14.8%
Placebo-controlled, Dose- 70mg (18 to Female:
optimization Study to Evaluate 56) 85.2%
oral, once daily
the Efficacy, Safety, and
capsules
Tolerability of VYVANSE in
Adults Aged 18-55 Years with Placebo
Moderate to Severe Binge oral, once daily
Eating Disorder. This study capsules
consisted of a screening phase,
a double-blind treatment phase
(including dose-optimization Duration of
and dose-maintenance treatment: 12
periods), and a follow-up visit. weeks

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 Dosage, route
Study Mean
of
Study # Study design subjects age Sexb
administration
(n) a (Range)b
and duration
SPD489- Multicenter, Double-blind, VYVANSE n=267 38.7 Male:
346 Placebo-controlled, 30, 50, and years 12.6%
Randomized-withdrawal Study 70mg (18 to Female:
to Evaluate the Maintenance of 55) 87.4%
oral, once daily
Efficacy of VYVANSE in Adults
capsules
Aged 18-55 Years with
Moderate to Severe Binge Placebo
Eating Disorder. This study oral, once daily
consisted of a screening phase, capsules
an open-label treatment phase
(dose optimization followed by
dose maintenance), a double- Duration of
blind withdrawal phase (26 treatment: 38
weeks), and a follow-up visit. weeks
a Based on the full analysis set
b Based on the safety analysis set

Study Results in BED

Adults with Moderate to Severe BED
The efficacy of VYVANSE in the treatment of BED was demonstrated in two 12-week
randomized, double-blind, multi-center, parallel-group, placebo-controlled, dose-optimization
studies in adults aged 18-55 years with moderate to severe BED (Study SPD489-343: N=374,
Study SPD489-344: N=350). A diagnosis of BED was confirmed using DSM-IV criteria for BED.
Requirement of moderate to severe BED was based on having at least 3 binge days per week (as
assessed for 2 weeks prior to the baseline visit) and a Clinical Global Impression Severity [CGI-S]
score ≥4 at the baseline visit. For both studies, a binge day was defined as a day with at least 1
binge episode, as determined from the subject’s daily binge diary and confirmed by the
clinician.
Exclusion criteria related to CV safety included moderate or severe hypertension, diabetes, and
cardiovascular diseases, such that obesity and smoking were permissible CV risk factors.
Comorbid Axis I or Axis II psychiatric disorders that were either controlled with prohibited
medications or were uncontrolled and associated with significant symptoms were excluded.
Psychotherapy (e.g., supportive psychotherapy, cognitive behavior therapy, interpersonal
therapy) or weight loss support (e.g., Weight Watchers) for BED that began ≥3 months prior to
the screening visit was allowed, but initiation or change during the study was prohibited; 9
patients (6 on placebo, and 3 on drug) were receiving psychotherapy for BED at the time of
informed consent. The majority of patients were women (87%), White (75%), and recruited in
sites in the USA (around 90%).

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Both 12-week studies consisted of a 4-week dose-optimization period and an 8-week dose-
maintenance period. During dose-optimization, subjects assigned to VYVANSE began treatment
at the titration dose of 30 mg/day and, after 1 week of treatment, were subsequently titrated to
50 mg/day. Additional increases to 70 mg/day were made as tolerated and clinically indicated.
Following the dose-optimization period, subjects continued on their optimized dose for the
duration of the dose-maintenance period.
The primary efficacy outcome for the two studies was defined as the LS mean change from
baseline at Week 11/12 in the number of binge days per week. Baseline is defined as the weekly
average of the number of binge days per week for the 14 days prior to the Baseline visit.
Based upon per-protocol MMRM analysis, subjects from both studies on VYVANSE had a
statistically significantly greater reduction from baseline compared to placebo in mean number
of binge days per week at Weeks 11/12 (Table 13).
Table 13 – Summary of Primary Efficacy Results in BED

Primary Efficacy Measure: Binge Days per Week at Week

12
Study Placebo-
Treatment Group LS Mean Change
Number Mean Baseline subtracted
from Baseline Differencea
Score (SD)
(SE) (95% CI)

SPD489- VYVANSE 4.79 (1.27) -3.87 (0.12) -1.35 (-1.70, -1.01)

343 (50 or 70
mg/day)*
Placebo 4.60 (1.21) -2.51 (0.13) --
SPD489- VYVANSE 4.66 (1.27) -3.92 (0.14) -1.66 (-2.04, -1.28)
344 (50 or 70
mg/day)*
Placebo 4.82 (1.42) -2.26 (0.14) --
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence
interval.
a
Difference (drug minus placebo) in least-squares mean change from baseline.
* Doses statistically significantly superior to placebo.

In addition, subjects on VYVANSE showed greater improvement as compared to placebo across

key secondary outcomes with higher proportion of subject rated improved on the CGI-I rating
scale, higher proportion of subjects with 4-week binge cessation, and greater reduction on

VYVANSE® (lisdexamfetamine dimesylate) Page 51 of 67

obsessive/compulsive binge eating symptoms as measured by the Yale-Brown Obsessive
Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) total score in both studies.
Randomized Withdrawal Study
A double-blind, placebo-controlled, randomized withdrawal design study was conducted to
evaluate maintenance of efficacy based on time to relapse between VYVANSE and placebo in
adults aged 18 to 55 years (n=267) with moderate to severe BED (DSM-IV-TR diagnosis), who at
baseline reported 3 or more binge eating days per week during each of the 2 weeks prior to
baseline, and had a CGI-S score of 4 or more.
Exclusion criteria and use of psychotherapy or weight loss support in this study were as
described above for the pivotal studies. Two patients were receiving psychotherapy for BED at
the time of informed consent. The majority of patients were women (87%), White (84%), and
recruited in sites in the USA (around 80%).
The 12-week open-label treatment phase consisted of 4 weeks of dose-optimization and 8
weeks of dose-maintenance. Subjects began treatment at the titration dose of 30 mg/day for 1
week of treatment, and were subsequently titrated to 50 mg/day for the second week.
Additional increases to 70 mg/day were made as tolerated and clinically indicated. If, at the end
of the third week of dose optimization, the 70 mg dose level was not tolerated, the subject
could have been down-titrated to 50 mg; no further dose adjustments were permitted after this
time. During the randomised-withdrawal phase, patients received VYVANSE (n=137) or placebo
(n=138), at the same optimised dose level as at the end of the open-label phase (50 or 70
mg/day), for up to 26 weeks.
Patients who had responded to VYVANSE in the preceding 12-week open-label treatment phase
were randomized to continuation of VYVANSE or placebo for up to 26 weeks of observation for
relapse. Response in the open-label phase was defined as 1 or fewer binge days each week for
four consecutive weeks prior to the last visit at the end of the 12-week open-label phase and a
CGI-S score of 2 or less at the same visit. Relapse during the double-blind phase was defined as
having 2 or more binge days each week for two consecutive weeks (14 days) prior to any visit
and having an increase in CGI-S score of 2 or more points compared to the randomized-
withdrawal baseline.
VYVANSE was superior over placebo as measured by time to relapse, the primary efficacy
outcome. At the end of the randomized-withdrawal phase, the group continuing on VYVANSE
had a lower proportion of relapse (5/136, 3.7%) as compared to the placebo group (42/131,
32.1%). The proportion of patients who completed the randomized withdrawal phase of the
study (that is, neither relapsed nor discontinued for other reasons) was 74.5% (102/137) on
VYVANSE compared to 36.2% (50/138) on placebo.
Drug Abuse and Dependence Studies
In a human abuse liability study, when equivalent oral doses of 100 mg lisdexamfetamine
dimesylate and 40 mg immediate-release dextroamphetamine sulfate were administered to
individuals with a history of drug abuse, lisdexamfetamine dimesylate 100 mg produced
subjective responses on a scale of “Drug Liking Effects” (primary endpoint) that were
significantly less than dextroamphetamine immediate-release 40 mg. However, oral

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administration of 150 mg lisdexamfetamine dimesylate produced increases in positive
subjective responses on this scale that were statistically indistinguishable from the positive
subjective responses produced by 40 mg of oral immediate-release dextroamphetamine and
200 mg of diethylpropion.
Intravenous administration of 50 mg lisdexamfetamine dimesylate to individuals with a history
of drug abuse produced positive subjective responses on scales measuring "Drug Liking",
"Euphoria", "Amphetamine Effects", and "Benzedrine Effects" that were not significantly
different from placebo. Administration of a dose of 20 mg of intravenous dextroamphetamine
produced significant positive subjective responses on these scales.

14.2 Comparative Bioavailability Studies

There have been no clinical efficacy studies using VYVANSE chewable tablets. However, in a
randomized, open-label, 2-sequence, 4-period replicated crossover study, the bioavailability of
dextroamphetamine (the primary active lisdexamfetamine metabolite) was compared after a
single 60 mg dose administration of VYVANSE chewable tablet versus VYVANSE capsule. The
products were administered to healthy adult male and female subjects under fasting conditions.
The results from the 18 subjects who completed all four periods of the study are presented
below.
Table 14 - summary table of the comparative bioavailability data
dextroamphetamine
(1 x 60 mg lisdexamfetamine dimesylate)
From measured data
Geometric Mean
Arithmetic Mean (CV %)
VYVANSE % Ratio of
VYVANSE 90% Confidence
Parameter Chewable Geometric
Capsule Interval
Tablet Means
AUCT(0-96h) 1047.5 1052.9
99.5 95.7 - 103.4
(ng·h/mL) 1079 (24.0) 1087 (24.0)
AUCI 1135.5 1126.2
100.8 97.4 - 104.4
(ng·h/mL) 1168 (23.1) 1161 (23.4)
Cmax 55.5 55.9
99.2 96.1 - 102.4
(ng/mL) 56.9 (25.8) 56.7 (17.8)
§
Tmax
4.00 (2.0 - 8.0) 4.00 (2.0 - 6.0)
(h)
T½€
12.7 (18.5) 12.3 (19.4)
(h)
§
Expressed as the median (range).
€
Expressed as the arithmetic mean (CV%)

VYVANSE® (lisdexamfetamine dimesylate) Page 53 of 67

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:
Acute Toxicity Studies: The LD50 value for lisdexamfetamine diHCl in rats was >1000 mg/kg.
Lisdexamfetamine diHCl has a 39.9% inherent dextroamphetamine content. On the basis of this
value, the LD50 value would be equivalent to either >399 mg/kg of dextroamphetamine or >548
mg/kg dextroamphetamine sulfate. Therefore, lisdexamfetamine diHCl is approximately 5-fold
less lethal by the oral route than dextroamphetamine sulfate (LD50 value of 96.8 mg/kg).
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.
Subacute and Subchronic Toxicity Studies: In the pivotal 28 day repeat dose rat study, animals
were administered lisdexamfetamine dimesylate 20, 40 or 80 mg/kg/day or
dextroamphetamine sulfate at 16 mg/kg/day. There was no mortality, no effects on
hematological parameters, and only isolated changes associated with clinical chemistry values
for mid- and high-dose group animals. The effects noted at the mid dosage of lisdexamfetamine
dimesylate were similar to those of an equimolar dose of dextroamphetamine sulfate. No
histological findings were present at any dosage of lisdexamfetamine dimesylate.
In the 6-month repeat dose rat study with a 4-week recovery period, animals were administered
lisdexamfetamine dimesylate (20 and 40 mg/kg/day) or dextroamphetamine sulfate (8 and 16
mg/kg/day). No treatment-related pathological changes were apparent, including evaluation of
Ki-67 immunolabeling for potential proliferative changes in the liver. Overall there were no
toxicologically significant differences between the two test articles.
In the pivotal 28 day repeat dose dog study, animals were administered lisdexamfetamine
dimesylate 3, 6 and 12 mg/kg/day or dextroamphetamine sulfate at 2.4 mg/kg/day. There was
no mortality, and no effects on clinical pathology, ophthalmology, ECG, gross necropsy, and
histopathology were observed. Other reported effects associated with lisdexamfetamine
dimesylate administration were consistent with the known pharmacological effects of
dextroamphetamine. The mid dose of lisdexamfetamine dimesylate demonstrated
pharmacological effects similar to those of an equimolar dose of dextroamphetamine sulfate.
Juvenile toxicity studies were performed in the rat (4, 10 and 40 mg/kg/day lisdexamfetamine
dimesylate) and dog (2, 5 and 12 mg/kg/day). No adverse effects were observed upon nervous
system development or reproductive function in the rat or on neurotoxicity or male
reproductive endpoints in the dog.

VYVANSE® (lisdexamfetamine dimesylate) Page 54 of 67

Genotoxicity:
Mutagenicity Studies: Lisdexamfetamine dimesylate was not clastogenic in the mouse bone
marrow micronucleus test in vivo and was negative when tested in the E. coli and S.
typhimurium components of the Ames test and in the L5178Y/TK+- mouse lymphoma assay in
vitro.
Carcinogenicity:
Carcinogenicity studies have not been performed with lisdexamfetamine dimesylate.
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 two 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.
Reproductive and Developmental Toxicology:
In animal reproduction studies, lisdexamfetamine dimesylate 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 40 and 120 mg/kg/day,
respectively. These doses are approximately 3.2 and 19.2 times (child) and 6.5 and 38.9 times
(adult) respectively the maximum recommended dose of 60 mg/day for the treatment of ADHD
and 5.6 and 33.4 times (adults) respectively the maximum recommended human daily dose of
70 mg for the treatment of BED, on a mg/m2 body surface area basis.
The effects of lisdexamfetamine dimesylate on fertility and early embryonic development have
not been investigated in animal reproductive studies. Amphetamine (d to l enantiomer 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.
The effects of lisdexamfetamine dimesylate on pre- and post-natal development have not been
investigated in animal reproductive studies. 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.
Special Toxicology:
Non-Clinical Abuse Data: Non-clinical abuse studies indicate that lisdexamfetamine produced
behavioural and subjective effects in rats and monkeys that are qualitatively similar to those of
the CNS stimulant dextroamphetamine, but that are delayed in onset. The rewarding effects, as
determined in self-administration studies, are lower than those of methylphenidate or cocaine,
but are greater than those of modafinil or placebo.

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Juvenile Toxicity:
Effects on Growth: A study was conducted in which juvenile rats received oral doses of 4, 10, or
40 mg/kg/day of lisdexamfetamine from Day 7 to Day 63 of age. These doses are approximately
0.3, 0.8, and 3.2 times the maximum recommended human daily dose of 60 mg for the
treatment of ADHD, on a mg/m2 basis. Dose related decreases in food consumption,
bodyweight gain, and crown-rump length were seen; after a four week drug-free recovery
period bodyweights and crown-rump lengths had significantly recovered in females but were
still substantially reduced in males. Time to vaginal opening was delayed in females at the
highest dose, but there were no drug effects on fertility when the animals were mated
beginning on Day 85 of age.
In a study in which juvenile dogs received lisdexamfetamine for six months beginning at 10
weeks of age, decreased bodyweight gain was seen at all doses tested (2, 5, and 12 mg/kg/day,
which are approximately 0.5, 1.3, and 3.2 times the maximum recommended human daily dose
of 60 mg on a mg/m2 basis). This effect partially or fully reversed during a 4 week drug free
recovery period.

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PATIENT MEDICATION INFORMATION

READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

VYVANSE®
lisdexamfetamine dimesylate capsules
lisdexamfetamine dimesylate chewable tablets
Read this carefully before you start taking VYVANSE 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
VYVANSE.

Serious Warnings and Precautions

Drug dependence: Like other stimulants, VYVANSE has the potential to be abused. This can
lead to you becoming dependent on VYVANSE or feeling like you need to take more of it over
time.

What is VYVANSE used for?

VYVANSE is used to treat:
• Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age or older,
adolescents and adults. Treatment with VYVANSE for ADHD should be combined with
other measures, such as psychological counselling, educational and social measures, as
part of a total treatment program. VYVANSE is NOT recommended for use in children
with ADHD under 6 years of age.
• moderate to severe Binge Eating Disorder (BED) in adults. VYVANSE is NOT
recommended for use in children with BED under 18 years of age.

Use of other stimulant drugs for weight loss has been associated with serious heart-related
problems. It is not known if VYVANSE is safe and effective for weight loss.
How does VYVANSE work?
VYVANSE belongs to a group of medicines called central nervous system stimulants. VYVANSE is
a prodrug, which means that the medicinal ingredient lisdexamfetamine dimesylate is inactive
until the body breaks it down into its active form called dextroamphetamine. It works by raising
the levels of chemicals in the brain called dopamine and norepinephrine.
• This helps to increase attention and decrease impulsiveness and hyperactivity in patients
with ADHD;
• This may help to reduce the number of binge eating days in adults with BED.

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What are the ingredients in VYVANSE?
Medicinal ingredients: Lisdexamfetamine dimesylate
Non-medicinal ingredients:
• VYVANSE capsules: Croscarmellose sodium, magnesium stearate and microcrystalline
cellulose. The capsule shells contain edible ink, gelatin, titanium dioxide (E171), and one or
more of the following: FD&C Yellow #6 (E110), FD&C Blue #1 (E133), FD&C Red #3 (E127),
FDA/E172 Black Iron Oxide, FDA/E172 Yellow Iron Oxide.
• VYVANSE chewable tablets: artificial strawberry flavouring, colloidal silicon dioxide,
croscarmellose sodium, guar gum, magnesium stearate, mannitol, microcrystalline cellulose,
and sucralose.
VYVANSE comes in the following dosage forms:
• Capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg and 70 mg
• Chewable Tablets: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg and 60 mg
Do not use VYVANSE if you/your child:
• are allergic to amphetamines, the medicinal ingredient lisdexamfetamine dimesylate or
its active form (i.e., dextroamphetamine), or any of the other ingredients in VYVANSE.
• are sensitive to, allergic to or had a reaction to other stimulant medicines.
• have advanced arteriosclerosis (hardened arteries).
• have symptoms of heart disease.
• have moderate to severe high blood pressure.
• are agitated.
• have glaucoma (an eye disease with increased pressure in the eye).
• have hyperthyroidism (an overactive thyroid gland).
• are taking or have recently taken (in the past 14 days) any medications from the group
called monoamine oxidase inhibitors (MAOIs).
• have a history of drug abuse.
To help avoid side effects and ensure proper use, talk to your healthcare professional before
you take VYVANSE. Talk about any health conditions or problems you may have, including if
you/your child:
• have structural heart abnormalities, cardiomyopathy, serious heart rhythm
abnormalities or other serious heart problems.
• have a family history of sudden cardiac death or death related to heart problems.
• have mild high blood pressure.
• do strenuous exercise.
• have a history of seizures (convulsions, epilepsy) or have had abnormal brainwave tests
(electroencephalogram; EEGs).
• have or have a family history of tics (movements or sounds that you cannot control) or
Tourette’s syndrome.

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 • take other medications for ADHD.
• take blood pressure medications or other medicines that can affect blood pressure.
• have or have a family history of mental health problems, including:
− psychosis,
− mania,
− bipolar disorder,
− depression, or
− suicide.
• have severe kidney problems, including if you are undergoing dialysis.
• have a history of drug abuse or alcoholism.
• are pregnant, think you are pregnant or are planning to become pregnant.
• are breastfeeding or plan to breastfeed.

Other warnings you should know about:

Dependence and tolerance:
• Amphetamines, such as VYVANSE, 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 behavior
- psychosis
- schizophrenia
• Doctor supervision is needed when you or your child stop taking VYVANSE. Suddenly
ending treatment when taking higher doses of VYVANSE for a long period of time can
cause:
- extreme fatigue
- depression
- changes in sleep patterns
• VYVANSE should only be given under close medical supervision to patients whose
condition has been properly diagnosed.

Driving and using machines: VYVANSE can affect your ability to drive and use tools or
machinery. You should not drive or use tools or machinery until you know how you respond to
VYVANSE.
Pregnancy and breastfeeding:
• Taking VYVANSE during pregnancy can harm your unborn baby. It should not be used
during pregnancy unless your healthcare professional has determined the potential

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 benefits outweigh the potential risks to your baby. Your healthcare professional will
discuss these risks with you. If you discover that you are pregnant while taking VYVANSE,
tell your healthcare professional right away.
• VYVANSE can pass through your breast milk and may harm your baby. You should
consult with your healthcare professional to determine if you should stop breastfeeding
or discontinue VYVANSE.
The following have been reported with use of VYVANSE and other medicines used to treat
ADHD.
Growth in children: Slower growth (in weight and/or height) has been reported with the use of
VYVANSE in children. This risk increases as the dose of VYVANSE increases. Your healthcare
professional will carefully watch your child’s height and weight. If your child is not growing or
gaining weight as expected, your healthcare professional may stop treatment.
Heart-related problems: The following heart related problems have been reported in people
taking medications to treat ADHD, like VYVANSE:
• Sudden death in patients 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 association with stimulant drugs for ADHD treatment in
children and adolescents with structural heart abnormalities. VYVANSE generally should not be
used in children, adolescents or adults with known structural heart abnormalities. There may be
additional heart-related risks if you are overweight or obese.
Tell your healthcare professional if you/your child have any heart problems, heart defects, high
blood pressure, or a family history of these problems.
Your healthcare professional will check:
• you/your child for heart problems before starting VYVANSE.
• your/your child’s blood pressure and heart rate before and regularly during treatment
with VYVANSE.
Seek immediate medical help if you/your child have any signs of heart problems such as chest
pain, shortness of breath, or fainting while taking VYVANSE.
Mental health problems: The following mental health problems have been reported in people
taking stimulant medicines like VYVANSE:
• New or worse thoughts or feelings related to suicide (thinking about or feeling like killing
yourself) and suicidal actions (suicide attempt, suicidal ideation and completed suicide).
• New or worse symptoms of bipolar disorder (extreme mood swings, with periods of
impulsiveness or unusual excitement, switching between periods of sadness).
• New or worse aggressive behavior or hostility.
• New psychotic symptoms (such as hearing voices, believing things that are not true,
being suspicious) or new mania (unusually excited, over-active or un-inhibited).
These new or worse mental symptoms may be more likely to occur if you/your child have
mental disorders that you may or may not know about. Tell your doctor about any mental

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problems or about any personal or family history of suicide, bipolar illness, or depression you or
your child have.
A small number of patients taking ADHD medicines may experience unusual feelings of
agitation, hostility or anxiety, or have impulsive or disturbing thoughts such as thoughts of
suicide, self-harm or harm to others. Those suicidal thoughts or behaviors may occur at any time
during treatment, particularly at the start or during dose changes, and also after stopping
VYVANSE. Should this happen to you, or to those in your care if you are a caregiver or
guardian, consult your doctor immediately. Close observation by a doctor is necessary in this
situation.
Serotonin toxicity (also known as Serotonin Syndrome): Serotonin toxicity is a rare but
potentially life-threatening condition. It can cause serious changes in how your brain, muscles
and digestive system work. You may develop serotonin toxicity if you take VYVANSE with certain
anti-depressants or migraine medications. Serotonin toxicity 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.
Raynaud’s Phenomenon (episodes of reduced blood flow): Stimulant medicines, such as
VYVANSE, are associated with Raynaud’s Phenomenon. During treatment with VYVANSE, your
healthcare professional may check for problems with the circulation in your fingers and toes,
including numbness, feeling cold or pain.
Tell your healthcare professional about all the medicines you take, including any drugs,
vitamins, minerals, natural supplements or alternative medicines.
Serious Drug Interactions
Do not take VYVANSE 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 VYVANSE:

• other medications used to treat ADHD such as guanfacine.
• medicines used to treat depression or anxiety such as:
− certain tricyclic antidepressants,
− selective serotonin reuptake inhibitors (SSRIs), and
− serotonin and noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine.
• certain medicines used to treat migraines such as sumatriptan, rizatriptan or
zolmitriptan.

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 • medicines used to manage psychotic symptoms such as pimozide, haloperidol and
chlorpromazine.
• medicines that make the urine more acidic such as ammonium chloride and sodium acid
phosphate, as well as the dietary supplement ascorbic acid (vitamin C).
• medicines that make urine more alkaline such as sodium bicarbonate, acetazolamide,
and thiazides.
• blood pressure medications or other medicines that can affect blood pressure such as
beta blockers and norepinephrine.
• opioid medicines, used to relieve pain.
• lithium, used to treat manic episodes in bipolar disorder.
• modafinil, used to treat sleepiness due to narcolepsy.
• St John’s Wort, a herbal remedy.

How to take VYVANSE:

• Take VYVANSE once each day in the morning, with or without food.
• Avoid taking VYVANSE in the afternoon as it may cause insomnia.
• If you/your child were prescribed VYVANSE capsules:
− swallow the capsule whole with water; or
− for patients with problems swallowing medicines, the capsule can be opened and
all of the medication powder can be sprinkled over yogurt, water, or orange
juice. Mix the medication powder thoroughly until the powder is completely
dispersed. Make sure to break up any lumps of powder with a spoon. Eat the
entire yogurt or drink all of the water or orange juice immediately. Do not store it
for future use. Do not be alarmed if you see a film on the inside of the glass or
container; this film contains non-medicinal ingredients. Do not divide the dose.
• If you/your child were prescribed VYVANSE chewable tablets, you/your child must chew
the tablet thoroughly before swallowing. The entire tablet should be taken. Do not
divide the dose.
• As with all medicines, never share VYVANSE with anyone else.

Usual dose:
• To treat Attention Deficit Hyperactivity Disorder (ADHD) (children 6 years of age or
older, adolescents and adults):
Your healthcare professional will decide the dose that is right for you/your child. Always
follow the directions of your healthcare professional and never change the dose or stop
taking VYVANSE without discussing it with your healthcare professional first.

VYVANSE® (lisdexamfetamine dimesylate) Page 62 of 67

 The usual dose is 20 mg to 60 mg once a day. Take VYVANSE in the morning exactly as
prescribed. Your healthcare professional may adjust the dose until it is right for you/your
child. The maximum daily dose is 60 mg.

From time to time, your healthcare professional may interrupt your/your child’s
treatment to check your/your child’s symptoms while you/your child are not taking the
medicine.

• To treat moderate to severe Binge Eating Disorder (BED) (adults):

The recommended starting dose is 30 mg once a day in the morning. Your healthcare
professional will then gradually increase your daily dose by 20 mg each week. They will
do this until you’re taking 50 mg to 70 mg once a day in the morning. The maximum daily
dose is 70 mg.

Overdose:
If you think you, or a person you are caring for, have taken too much VYVANSE, 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 day and
take or have him or her take the usual dose at the usual time in the morning. Do not take an
afternoon dose. Do not double the dose to make up for the missed dose.

What are possible side effects from using VYVANSE?

These are not all the possible side effects you may have when taking VYVANSE. If you
experience any side effects not listed here, tell your healthcare professional.
Side effects may include:
• headache, dizziness, feeling like your environment is moving or spinning (vertigo)
• dry mouth, decreased appetite, anorexia (eating disorder)
• trouble sleeping or falling asleep, feeling sleepy
• upper abdominal pain, constipation or diarrhea, vomiting or nausea, indigestion
• numbness, or pricking or tingling sensations in the hands, arms, legs or feet
• fever, upper respiratory tract infection, stuffy nose or sore throat
• feeling irritable, anxious or jittery, lack or abundance of energy, rapid and sometimes
exaggerated changes in mood
• decreased sex drive, inability to get or keep an erection
• bladder infection
• skin rash, hives, itchy skin
• ringing in the ears
• unusual dilation or widening of the pupils

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 • weight changes
• changes in taste
• excessive sweating
• nightmares
• clenching of teeth
• hair loss
• memory problems
• muscle aches and pain

Serious side effects and what to do about them

Talk to your healthcare Stop taking drug
professional and get
Symptom / effect
Only if immediate
In all cases
severe medical help
COMMON
Anxiety ✓
New or worsening tics: movements or
✓
sounds that you cannot control
Slowing of growth (height and weight) in
✓
children
Palpitation (fast-beating, fluttering or
✓
pounding heart)
UNCOMMON
Aggressive behaviour or hostility ✓
Allergic reaction: difficulty swallowing or
breathing, and throwing up, swelling of
✓
the face, lips, tongue or throat, hives or
rash
Depression (sad mood that won’t go
away): difficulty sleeping or sleeping too
much, changes in appetite or weight,
feelings of worthlessness, guilt, regret,
helplessness or hopelessness, withdrawal
from social situations, family, gatherings ✓
and activities with friends, reduced libido
(sex drive) and thoughts of death or
suicide. If you have a history of
depression, your depression may become
worse
New or worsening mental health
problems: paranoia, delusions, ✓
hallucinations (seeing, feeling or hearing

VYVANSE® (lisdexamfetamine dimesylate) Page 64 of 67

 Serious side effects and what to do about them
Talk to your healthcare Stop taking drug
professional and get
Symptom / effect
Only if immediate
In all cases
severe medical help
things that are not there), mania (feeling
unusually excited, over-active, or
uninhibited), compulsions
Vision problems: changes in vision or
✓
blurry vision
UNKNOWN FREQUENCY
Epistaxis and Contusion: unexplained
✓
nosebleeds or bruising
Heart attack: severe, crushing chest pain
that can radiate into the arm and/or jaw,
upper back or neck, palpitation,
shortness of breath, nausea, vomiting, ✓
sweating, indigestion, heartburn,
dizziness, extreme fatigue, upper body
discomfort
Seizures (fits): uncontrollable shaking
✓
with or without loss of consciousness
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
Liver Disorder yellowing of the skin or
whites of the eyes (jaundice), dark urine
✓
and pale stools, abdominal pain, nausea,
vomiting, loss of appetite
Raynaud’s phenomenon (episodes of
reduced blood flow): cold feeling in
fingers and toes (and sometimes nose, ✓
lips and ears), prickly or stinging feeling,
change in skin colour to white then blue
Stevens-Johnson syndrome (SJS) (severe
skin rash): redness, blistering and/or ✓
peeling of the skin and/or inside of the

VYVANSE® (lisdexamfetamine dimesylate) Page 65 of 67

 Serious side effects and what to do about them
Talk to your healthcare Stop taking drug
professional and get
Symptom / effect
Only if immediate
In all cases
severe medical help
lips, eyes, mouth, nasal passages or
genitals, accompanied by fever, chills,
headache, cough, body aches or swollen
glands
Suicidal behaviour: thoughts or actions
✓
about hurting or killing yourself
Serotonin toxicity (also known as
Serotonin Syndrome): feeling of
agitation or restlessness, flushing, muscle
✓
twitching, involuntary eye movements,
heavy sweating, high body temperature
(above 38°C), rigid muscles
Cerebrovascular disorders (problems
with the blood vessels in the brain,
stroke): severe headaches, weakness or
✓
paralysis of any body part, or problems
with coordination, vision, speaking,
finding words or with your memory
Rhabdomyolysis (breakdown of
damaged muscle): muscle weakness,
✓
muscle pain, muscle spasms, red-brown
coloured urine
Hypertension (high blood pressure):
shortness of breath, fatigue, dizziness or
fainting, chest pain or pressure, swelling
✓
in your ankles and legs, bluish colour to
your lips and skin, racing pulse or fast or
uneven heartbeat.
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.

VYVANSE® (lisdexamfetamine dimesylate) Page 66 of 67

 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:
• Capsules: Store at 15 to 30°C. Protect from light.
• Chewable Tablets: Store at 15 to 30°C.
• Keep out of reach and sight of children.

If you want more information about VYVANSE:

• 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/vyvansepm, 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 20, 2024

VYVANSE® and the VYVANSE Logo®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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