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VyvanseTM (lisdexamfetamine dimesylate) C- II Rx Only
AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION
OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO
DRUG DEPENDENCE. PARTICULAR ATTENTION SHOULD BE PAID TO THE
POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-
THERAPEUTIC USE OR DISTRIBUTION TO OTHERS AND THE DRUGS
SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY.
MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS
CARDIOVASCULAR ADVERSE EVENTS.
DESCRIPTION
Vyvanse (lisdexamfetamine dimesylate) is designed as a capsule for once-a-day oral
administration. The chemical designation for lisdexamfetamine dimesylate is (2S)-2,6-
diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide dimethanesulfonate. The molecular
formula is C15H25N3O•(CH4O3S)2, which corresponds to a molecular weight of 455.60. The
chemical structure is:
Lisdexamfetamine dimesylate is a white to off-white powder that is soluble in water (792
mg/mL). Vyvanse capsules contain 30 mg, 50 mg and 70 mg of lisdexamfetamine dimesylate
and the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, and
magnesium stearate. The capsule shells contain gelatin, titanium dioxide, and one or more of
the following: D&C Red #28, D&C Yellow #10, FC&C Blue #1 and FD&C Red #40.
CLINICAL PHARMACOLOGY
Mechanism of Action and Pharmacology
Vyvanse is a pro-drug of dextroamphetamine. After oral administration, lisdexamfetamine
dimesylate is rapidly absorbed from the gastrointestinal tract and converted to
dextroamphetamine, which is responsible for the drug’s activity. Amphetamines are non-
catecholamine sympathomimetic amines with CNS stimulant activity. The mode of
therapeutic action in Attention-Deficit/Hyperactivity Disorder (ADHD) is not known.
Amphetamines are thought to block the reuptake of norepinephrine and dopamine into the
presynaptic neuron and increase the release of these monoamines into the extraneuronal
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space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the
reuptake of norepinephrine and dopamine in vitro.
Pharmacokinetics
Pharmacokinetic studies of dextroamphetamine after oral administration of lisdexamfetamine
dimesylate have been conducted in healthy adult and pediatric (6–12 yrs) patients with
ADHD.
In 18 pediatric patients (6–12 yrs) with ADHD, the Tmax of dextroamphetamine was
approximately 3.5 hours following single-dose oral administration of lisdexamfetamine
dimesylate either 30 mg, 50 mg, or 70 mg after an 8-hour overnight fast. The Tmax of
lisdexamfetamine dimesylate was approximately 1 hour. Linear pharmacokinetics of
dextroamphetamine after single-dose oral administration of lisdexamfetamine dimesylate was
established over the dose range of 30 mg to 70 mg in children aged 6 to 12 years.
There is no accumulation of dextroamphetamine AUC at steady state in healthy adults and no
accumulation of lisdexamfetamine dimesylate after once-daily dosing for 7 consecutive days.
Food does not affect the observed AUC and Cmax of dextroamphetamine in healthy adults
after single-dose oral administration of 70 mg of Vyvanse capsules but prolongs Tmax by
approximately 1 hour (from 3.8 hrs at fasted state to 4.7 hrs after a high fat meal). After an 8-
hour fast, the AUC for dextroamphetamine following oral administration of lisdexamfetamine
dimesylate in solution and as intact capsules were equivalent.
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 7 days.
Weight/Dose normalized AUC and Cmax values were the same in girls and boys following
single doses of 30-70 mg.
Metabolism and Excretion
After oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the
gastrointestinal tract. Lisdexamfetamine dimesylate is converted to dextoamphetamine and L-
lysine, which is believed to occur by first-pass intestinal and/or hepatic metabolism.
Lisdexamfetamine is not metabolized by cytochrome P450 enzymes. Following the oral
administration of a 70 mg dose of radiolabeled lisdexamfetamine dimesylate to 6 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 dimesylate are
low and transient, generally becoming non-quantifiable by 8 hours after administration. The
plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in
studies of lisdexamfetamine dimesylate in volunteers.
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Dextroamphetamine is known to inhibit monoamine oxidase. The ability of
dextroamphetamine and its metabolites to inhibit various P450 isozymes and other enzymes
has not been adequately elucidated. In vitro experiments with human microsomes indicate
minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and
3A4 by one or more metabolites, but there are no in vivo studies of p450 enzyme inhibition.
Special Populations
The pharmacokinetics of dextroamphetamine is similar in pediatric (6-12 years) and
adolescent (13-17 years) ADHD patients, and healthy adult volunteers. Any differences in
kinetics seen after oral administration are a result of differences in mg/kg dosing.
Gender
Systemic exposure to dextroamphetamine is similar for men and women given the same
mg/kg dose.
Clinical Trials
A double-blind, randomized, placebo-controlled, parallel-group study was conducted in
children aged 6–12 (N=290) who met DSM-IV® criteria for ADHD (either the combined type
or the hyperactive-impulsive type). Patients were randomized to fixed dose treatment groups
receiving final doses of 30, 50, or 70 mg of Vyvanse or placebo once daily in the morning for
four weeks. Significant improvements in patient behavior, based upon investigator ratings on
the ADHD Rating Scale (ADHD-RS), were observed at endpoint for all Vyvanse doses
compared to patients who received placebo. Mean effects at all doses were fairly similar,
although the highest dose (70 mg/day) was numerically superior to both lower doses (30 and
50 mg/day). The effects were maintained throughout the day based on parent ratings
(Connor’s Parent Rating Scale) in the morning (approximately 10 am), afternoon
(approximately 2 pm), and early evening (approximately 6 pm).
A double-blind, placebo-controlled, randomized, crossover design, analog classroom study
was conducted in children aged 6-12 (N=52) who met DSM-IV® criteria for ADHD (either
the combined type or the hyperactive-impulsive type). Following a 3-week open-label dose
titration with ADDERALL XR®, patients were randomly assigned to continue the same dose
of ADDERALL XR® (10, 20, or 30 mg), Vyvanse (30, 50, and 70 mg), or placebo once daily
in the morning for 1 week each treatment. A significant difference in patient behavior, based
upon the average of investigator ratings on the Swanson, Kotkin, Agler, M.Flynn and Pelham
(SKAMP)-Deportment scores across the 8 sessions of a 12 hour treatment day, was observed
between patients who received Vyvanse compared to patients who received placebo. The drug
effect was similar for all 8 sessions.
INDICATIONS AND USAGE
Vyvanse is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).
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The efficacy of Vyvanse in the treatment of ADHD was established on the basis of two
controlled trials in children aged 6 to 12, who met DSM-IV® criteria for ADHD (see
CLINICAL TRIALS).
A diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD; DSM-IV®) implies the
presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were
present before age 7 years. The symptoms must cause clinically significant impairment, in
social, academic, or occupational functioning, and be present in two or more settings, e.g., at
school (or work) and at home. The symptoms must not be better accounted for by another
mental disorder. For the Inattentive Type, at least six of the following symptoms must have
persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained
attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks
requiring sustained mental effort; loses things; easily distracted; forgetful. For the
Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for
at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty
with quiet activities; “on the go”; excessive talking; blurting answers; can’t wait turn;
intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to
be met.
Special Diagnostic Considerations: Specific etiology of this syndrome is unknown, and
there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but
of special psychological, educational, and social resources. Learning may or may not be
impaired. The diagnosis must be based upon a complete history and evaluation of the child
and not solely on the presence of the required number of DSM-IV® characteristics.
Need for Comprehensive Treatment Program: Vyvanse is indicated as an integral part of a
total treatment program for ADHD that may include other measures (psychological,
educational, social) for patients with this syndrome. Drug treatment may not be indicated for
all children with this syndrome. Stimulants are not intended for use in the child who exhibits
symptoms secondary to environmental factors and/or other primary psychiatric disorders,
including psychosis. Appropriate educational placement is essential and psychosocial
intervention is often helpful. When remedial measures alone are insufficient, the decision to
prescribe stimulant medication will depend upon the physician’s assessment of the chronicity
and severity of the child’s symptoms.
Long-Term Use: The effectiveness of Vyvanse for long-term use, i.e., for more than 4 weeks,
has not been systematically evaluated in controlled trials. Therefore, 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.
CONTRAINDICATIONS
Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe
hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the
sympathomimetic amines, glaucoma.
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Agitated states.
Patients with a history of drug abuse.
During or within 14 days following the administration of monoamine oxidase
inhibitors (hypertensive crises may result).
WARNINGS
Serious Cardiovascular Events
Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other
Serious Heart Problems
Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual
doses in children and adolescents with structural cardiac abnormalities or other serious
heart problems. Although some serious heart problems alone carry an increased risk
of sudden death, stimulant products generally should not be used in children or
adolescents with known serious structural cardiac abnormalities, cardiomyopathy,
serious heart rhythm abnormalities, or other serious cardiac problems that may place
them at increased vulnerability to the sympathomimetic effects of a stimulant drug
(see CONTRAINDICATIONS).
Adults
Sudden deaths, stroke, and myocardial infarction have been reported in adults taking
stimulant drugs at usual doses for ADHD. Although the role of stimulants in these
adult cases is also unknown, adults have a greater likelihood than children of having
serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm
abnormalities, coronary artery disease, or other serious cardiac problems. Adults with
such abnormalities should also generally not be treated with stimulant drugs (see
CONTRAINDICATIONS).
Hypertension and other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4
mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger
increases. While the mean changes alone would not be expected to have short-term
consequences, all patients should be monitored for larger changes in heart rate and
blood pressure. Caution is indicated in treating patients whose underlying medical
conditions might be compromised by increases in blood pressure or heart rate, e.g.,
those with pre-existing hypertension, heart failure, recent myocardial infarction, or
ventricular arrhythmia (see CONTRAINDICATIONS).
Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications
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Children, adolescents, or adults who are being considered for treatment with stimulant
medications should have a careful history (including assessment for a family history of
sudden death or ventricular arrhythmia) and physical exam to assess for the presence
of cardiac disease, and should receive further cardiac evaluation if findings suggest
such disease (e.g. electrocardiogram and echocardiogram). Patients who develop
symptoms such as exertional chest pain, unexplained syncope, or other symptoms
suggestive of cardiac disease during stimulant treatment should undergo a prompt
cardiac evaluation.
Psychiatric Adverse Events
Pre-Existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and
thought disorder in patients with pre-existing psychotic disorder.
Bipolar Illness
Particular care should be taken in using stimulants to treat ADHD patients with
comorbid bipolar disorder because of concern for possible induction of mixed/manic
episode in such patients. Prior to initiating treatment with a stimulant, patients with
comorbid depressive symptoms should be adequately screened to determine if they are
at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional
thinking, or mania in children and adolescents without prior history of psychotic
illness or mania can be caused by stimulants at usual doses. If such symptoms occur,
consideration should be given to a possible causal role of the stimulant, and
discontinuation of treatment may be appropriate. In a pooled analysis of multiple
short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4
patients with events out of 3482 exposed to methylphenidate or amphetamine for
several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-
treated patients.
Aggression
Aggressive behavior or hostility is often observed in children and adolescents with
ADHD, and has been reported in clinical trials and the postmarketing experience of
some medications indicated for the treatment of ADHD. Although there is no
systematic evidence that stimulants cause aggressive behavior or hostility, patients
beginning treatment for ADHD should be monitored for the appearance of or
worsening of aggressive behavior or hostility.
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Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were
randomized to either methylphenidate or non-medication treatment groups over 14
months, as well as in naturalistic subgroups of newly methylphenidate-treated and
non-medication treated children over 36 months (to the ages of 10 to 13 years),
suggests that consistently medicated children (i.e., treatment for 7 days per week
throughout the year) have a temporary slowing in growth rate (on average, a total of
about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years),
without evidence of growth rebound during this period of development. In a controlled
trial of amphetamine (d to l enantiomer ratio of 3:1) in adolescents, mean weight
change from baseline within the initial 4 weeks of therapy was –1.1 lbs. and –2.8 lbs.,
respectively, for patients receiving 10 mg and 20 mg of amphetamine (d to l
enantiomer ratio of 3:1). Higher doses were associated with greater weight loss within
the initial 4 weeks of treatment. In a controlled trial of lisdexamfetamine in children
ages 6 to 12 years, mean weight loss from baseline after 4 weeks of therapy was
-0.9, -1.9, and -2.5 lb, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of
lisdexamfetamine, compared to a 1 lb weight gain for patients receiving placebo.
Higher doses were associated with greater weight loss with 4 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 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 -13.4 over 1 year (average percentile at baseline
and 12 months, were 60.6 and 47.2, respectively). Therefore, growth should be
monitored during treatment with stimulants, and patients who are not growing or
gaining weight as expected may need to have their treatment interrupted.
Seizures
There is some clinical evidence that stimulants may lower the convulsive threshold in
patients with prior history of seizure, in patients with prior EEG abnormalities in
absence of seizures, and very rarely, in patients without a history of seizures and no
prior EEG evidence of seizures. In the presence of seizures, the drug should be
discontinued.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with
stimulant treatment.
PRECAUTIONS
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General: The least amount of Vyvanse 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.
Tics: Amphetamines have been reported to exacerbate motor and phonic tics and
Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome
in children and their families should precede use of stimulant medications.
Information for Patients: Amphetamines may impair the ability of the patient to
engage in potentially hazardous activities such as operating machinery or vehicles; the
patient should therefore be cautioned accordingly.
Prescribers or other health professionals should inform patients, their families, and
their caregivers about the benefits and risks associated with treatment with
lisdexamfetamine and should counsel them in its appropriate use. A patient
Medication Guide is available for Vyvanse. The prescriber or health professional
should instruct patients, their families, and their caregivers to read the Medication
Guide and should assist them in understanding its contents. Patients should be given
the opportunity to discuss the contents of the Medication Guide and to obtain answers
to any questions they may have. The complete text of the Medication Guide is
reprinted at the end of this document.
Drug Interactions:
Urinary acidifying agents—These agents (ammonium chloride, sodium acid
phosphate, etc.) increase the concentration of the ionized species of the amphetamine
molecule, thereby i
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