NEW ZEALAND DATA SHEET

VYVANSE has a potential for abuse, misuse, dependence, or diversion for non-therapeutic
uses. Physicians should assess the risk of abuse prior to prescribing and monitor for signs of
abuse and dependence while on therapy. VYVANSE should be prescribed cautiously to
patients with a history of substance abuse or dependence. Careful supervision is required
during withdrawal from abusive use since severe depression may occur. Withdrawal following
chronic therapeutic use may unmask symptoms of the underlying disorder that may require
follow-up.

1 VYVANSE capsules
VYVANSE 20 mg capsule
VYVANSE 30 mg capsule
VYVANSE 40 mg capsule
VYVANSE 50 mg capsule
VYVANSE 60 mg capsule
VYVANSE 70 mg capsule

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

VYVANSE capsules contains 20mg, 30 mg, 40mg, 50 mg, 60mg or 70 mg of lisdexamfetamine
dimesilate as the active ingredient.
For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM
Capsule.
VYVANSE (lisdexamfetamine dimesilate) was developed as a capsule for once-a-day oral
administration. The chemical designation for lisdexamfetamine dimesilate is (2S)-2,6-diamino-N-
[(1S)-1-methyl-2-phenylethyl] hexanamide dimethanesulfonate. Lisdexamfetamine dimesilate is a
white to off-white powder that is highly soluble in water. Lisdexamfetamine dimesilate has a 2-
octanol/water partition coefficient (logP) of -1.76; pKa1 of 10.5 / pKa2 of 7.7; and pH of 4.1 when
dissolved in water.
Chemical structure:
O
H3C S OH H2N O
O CH3
HN
O
H3C S OH H2N
O

Formula: C17H33N3O7S2
Molecular weight: 455.59
CAS numbers: lisdexamfetamine: 608137-32-2
lisdexamfetamine dimesilate: 608137-33-3

Appearance
VYVANSE 20 mg capsule: ivory opaque body and ivory opaque cap, printed ‘S489’ and ‘20 mg’ in
black ink.
VYVANSE 30 mg capsule: white opaque body and pink opaque cap, printed ‘S489’ and ‘30 mg’ in

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black ink.
VYVANSE 40 mg capsule: white opaque body and blue/green opaque cap, printed ‘S489’ and ‘40 mg’
in black ink.
VYVANSE 50 mg capsule: white opaque body and blue opaque cap, printed ‘S489’ and ‘50 mg’ in
black ink.
VYVANSE 60 mg capsule: aqua blue opaque body and aqua blue opaque cap, printed ‘S489’ and ‘60
mg’ in black ink.
VYVANSE 70 mg capsule: blue opaque body and pink opaque cap, printed ‘S489’ and ‘70 mg’ in black
ink.

4 CLINICAL PARTICULARS
4.1 Therapeutic indications
VYVANSE is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults,
adolescents and children aged 6 years and older. Treatment should be commenced by a specialist.
A diagnosis of ADHD implies the presence of hyperactive-impulsive or inattentive symptoms that
caused impairment and were present before 12 years of age.
Need for comprehensive treatment programme: VYVANSE is indicated as an integral part of a total
treatment program for ADHD that may include other measures (psychological, educational and
social) for patients with this syndrome. Stimulants are not intended for use in the patient who
exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders,
including psychosis. Appropriate educational placement is essential and psychosocial intervention is
often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant
medication will depend upon the physician’s assessment of the chronicity and severity of the
patient’s symptoms.
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.
4.2 Dose and method of administration
Patients should be reviewed at least annually to assess if there is an ongoing requirement for
treatment with VYVANSE. Blood pressure and cardiovascular status should also be regularly
reviewed.
VYVANSE should be administered orally at the lowest possible dosage and should then be slowly
adjusted to the lowest effective dose for each individual. VYVANSE should be taken in the morning
with or without food; avoid afternoon doses because of the potential for insomnia.
VYVANSE capsules may be taken whole, or the capsule may be opened and the entire contents
emptied and mixed with a soft food such as 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 soft food or liquid. The contents should be mixed until completely dispersed. The
patient should consume the entire mixture of soft food 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.
Dose
In patients who are either starting treatment for the first time or switching from another
medication, 30 mg once daily in the morning is the recommended starting dose. If the decision is
made to increase the dose beyond 30 mg/day, daily dosage may be adjusted in increments of 10 mg

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 NEW ZEALAND DATA SHEET
or 20 mg in intervals no more frequently than weekly. When in the judgment of the clinician a lower
initial dose is appropriate, patients may begin treatment with 20 mg once daily in the morning. The
maximum recommended dose is 70 mg/day; doses greater than 70 mg/day of VYVANSE have not
been studied. VYVANSE has not been studied in children under 6 years of age. The effectiveness of
VYVANSE has not been studied in adults over 55 years of age. 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 section 4.4 Special warnings and precautions for use – Renal impairment, and section 5.2
Pharmacokinetic properties – Special populations.
Lisdexamfetamine and dexamphetamine are not dialysable.

4.3 Contraindications
VYVANSE is contraindicated in patients with:
• Advanced arteriosclerosis
• Symptomatic cardiovascular disease including cardiac arrhythmia, ischaemic heart disease
• Moderate to severe hypertension
• Hyperthyroidism
• Known hypersensitivity or idiosyncratic reaction to sympathomimetic amines or any of the
excipients
• Glaucoma
• Agitated states such as severe anxiety, tension and agitation
• During or within 14 days following the administration of monoamine oxidase inhibitors
(hypertensive crises may result)
• Phaeochromatocytoma
• Tics, Tourette’s syndrome
• Patients who currently exhibit severe depression, anorexia nervosa, psychotic symptoms or
suicidal tendency
• Patients with known drug dependence or alcohol abuse
4.4 Special warnings and precautions for use
Drug abuse and dependence
Note: Because of the potential for abuse, drugs of the amphetamine type are subject to special
restrictions on their availability.
Amphetamines have a high potential for drug abuse. Care should be exercised in the selection of
patients for amphetamine therapy and prescription size should be limited to that required to
achieve the therapeutic goal. Patients should be cautioned against increasing the recommended
dosage. Should psychological dependence occur, gradual withdrawal of the medication is
recommended. Abrupt cessation following prolonged high dosage results in extreme fatigue and
mental depression; changes have also been noted on the sleep EEG.
Manifestations of chronic intoxication with amphetamines include severe dermatoses, marked
insomnia, irritability, hyperactivity and personality changes. The most severe manifestation of
chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.
Pre-treatment assessment
Before starting treatment with VYVANSE, it is important to consider the patient's personal and
family cardiac and psychiatric history. In patients with identified or potential cardiovascular or
psychiatric risk factors, further investigation or specialist review may be considered.

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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.
Cardiovascular disease
Sudden death and pre-existing structural cardiac abnormalities or other serious heart problems
Children and adolescents:
Sudden death has been reported in children and adolescents taking CNS stimulants at usual doses,
including those 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.
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.
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.
Psychiatric disorders
Pre-existing psychosis
Administration of stimulants may exacerbate symptoms of behaviour 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.

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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.
Aggression
Aggressive behaviour 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, including VYVANSE. Stimulants may cause aggressive behaviour or hostility.
Patients beginning treatment for ADHD should be monitored for the appearance of or worsening of
aggressive behaviour or hostility.
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.
Tics
Stimulants have been reported to exacerbate motor and phonic tics and Tourette’s syndrome (see
section 4.8). Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their
families should precede use of stimulant medications. VYVANSE is contraindicated in individuals
with tics or Tourette's syndrome (see section 4.3).
Long-term suppression of growth (height and weight)
VYVANSE was associated with dose-related reductions in weight in children, adolescents and adults
in short-term studies. Although a causal relationship has not been established, suppression of
growth (i.e. weight and/or height) has been reported with the long-term use of stimulants in
children. Therefore, patients requiring long-term therapy should be carefully monitored. Patients
who are not growing or gaining weight as expected should have their treatment interrupted.
Prescribing and dispensing
The least amount of VYVANSE feasible should be prescribed or dispensed at one time in order to
minimise the possibility of overdosage. Consideration should be given when using VYVANSE in
patients who use other sympathomimetic drugs.
Children under 6 years
VYVANSE should not be used in children under the age of 6 years. Safety and efficacy in this age
group has not been established.
Adult patients aged over 55 years
Safety and efficacy has not been established in adult patients over the age of 55 years.
Impaired hepatic function
No studies have been conducted in patients with hepatic impairment.
Renal impairment

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 NEW ZEALAND DATA SHEET
Due to reduced clearance 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 section 5.2 Pharmacokinetic properties – Special populations]
Lisdexamfetamine and dexamphetamine are not dialysable.
Effect on laboratory test
Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is
greatest in the evening. Amphetamine may interfere with urinary steroid determinations.
4.5 Interaction with other medicines and other forms of interaction
In vitro and In vivo enzyme inhibition and induction
Lisdexamfetamine dimesilate was not an in vitro inhibitor of the major human CYP450 isoforms
(CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) in human hepatic
microsomal suspensions, nor was it an in vitro inducer of CYP1A2, CYP2B6 or CYP3A4/5 in cultured
fresh human hepatocytes. Lisdexamfetamine dimesilate was not an in vitro substrate for P-gp in
MDCKII cells nor an in vitro inhibitor of P-gp in Caco-2 cells and is therefore unlikely to be involved in
clinical interactions with drugs transported by the P-gp pump.
In an in vivo human study, the co-administration of a single dose of lisdexamfetamine dimesilate did
not result in any clinically meaningful effect on the pharmacokinetics of single doses of drugs
metabolised by CYP1A2, CYP2D6, CYP2C19, or CYP3A.
Agents whose blood levels may be affected by VYVANSE
Extended release guanfacine: In a drug interaction study, administration of an extended release
guanfacine in combination with VYVANSE 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 dexamphetamine
exposure was observed following coadministration of extended release guanfacine and VYVANSE.
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. VYVANSE
(dexamphetamine) may be a weak inhibitor of CYP2D6. Lisdexamfetamine has no effect on the AUC
and Cmax of the composite of venlafaxine and o-desmethylvenlafaxine. These small changes are not
expected to be clinically meaningful. In this study, no effect on dexamphetamine exposure was
observed following coadministration of extended release venlafaxine and VYVANSE.
Agents and conditions that alter urinary pH and impact the urinary excretion and half-life of
amphetamine
Ascorbic acid and other agents or conditions that acidify urine increase urinary excretion and
decrease half-life of amphetamine. Sodium bicarbonate and other agents or conditions that
alkalinise urine decrease urinary excretion and extend the half-life of amphetamine.
Monoamine oxidase inhibitors
Do not administer VYVANSE concomitantly with monoamine oxidase inhibitors or within 14 days
after discontinuing MAOI treatment. Concomitant use of MAOIs and CNS stimulants can cause
hypertensive crisis. Severe outcomes including death may occur. [See section 4.3 Contraindications]
Serotonergic drugs
Serotonin syndrome can occur in association with the use of amphetamines such as VYVANSE, when
given in conjunction with serotonergic drugs, including selective serotonin reuptake inhibitors

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(SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). It has also been reported in
association with overdose of amphetamines, including VYVANSE. [See section 4.9 Overdose]
Agents whose effects may be reduced by amphetamines
Antihypertensives: Amphetamines may decrease the effectiveness of antihypertensive medications.
Agents whose effects may be potentiated by amphetamines
Amphetamines potentiate the analgesic effect of narcotic analgesics.
Agents that may reduce the effects of amphetamines
Chlorpromazine: Chlorpromazine blocks dopamine and noradrenaline receptors, thus inhibiting the
central stimulant effects of amphetamines.
Haloperidol: Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of
amphetamines.
Lithium carbonate: The anorectic and stimulatory effects of amphetamines may be inhibited by
lithium carbonate.
4.6 Fertility, pregnancy and lactation
Effects on fertility
A fertility study of lisdexamfetamine dimesilate has not been conducted. Amphetamine (d- to l-
enantiomer ratio of 3:1) did not adversely affect fertility or early embryonic development in the rat
at oral doses of up to 20 mg total amphetamine base/kg/day. This dose resulted in a plasma
amphetamine AUC which was 4 (males) and 6 (females) fold the AUC expected in adults at the
maximum recommended dose of 70 mg.
Use in pregnancy (Category B3)
The effects of VYVANSE on labour and delivery in humans are unknown.
There are no adequate and well-controlled studies with VYVANSE in pregnant women. VYVANSE
should be used during pregnancy only if the potential benefit justifies the potential risk to foetus.
Infants born to mothers taking amphetamines should be monitored for symptoms of withdrawal
such as feeding difficulties, irritability, agitation and excessive drowsiness.
Lisdexamfetamine dimesilate had no apparent effects on embryofoetal development or survival
when administered orally to pregnant rats and rabbits throughout the period of organogenesis at
doses of up to 40 and 120 mg/kg/day respectively. These doses resulted in respective plasma
dexamphetamine AUC values which were 5 and 2 fold the AUC expected in adults at the maximum
recommended dose of 70 mg, and respective plasma lisdexamfetamine AUC values which were 12
and 40 fold the AUC expected in adults at the maximum recommended dose.
A study of lisdexamfetamine dimesilate has not been conducted in rats treated throughout gestation
and lactation. Amphetamine sulphate (d- to l- enantiomer ratio of 3:1), when given orally to rats
from early gestation through to weaning at doses of 2, 6 and 10 mg total amphetamine base/kg/day,
reduced the number of liveborn pups and pup viability during lactation. Body weight gain of
offspring was reduced during lactation and after weaning, development was delayed, and increases
in locomotor activity were observed. The reproductive performance of the offspring was also
reduced. Some effects were observed at the 2 mg/kg/day dose, which was associated with a plasma
amphetamine AUC about half that expected in adults at the maximum recommended dose of 70 mg.
Use in lactation
Amphetamines are excreted in human milk. Mothers taking VYVANSE should be advised to refrain
from breast feeding.

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Oral administration of amphetamine sulfate to rats from early gestation through to weaning was
associated with adverse effects on offspring. [See Use in pregnancy].
4.7 Effects on ability to drive and use machines
VYVANSE can cause dizziness, drowsiness and visual disturbances including difficulties with
accommodation, diplopia and blurred vision. These are uncommon but could have a moderate
influence on the ability to drive and use machines. If affected, patients should avoid potentially
hazardous activities such as driving or operating machinery.
4.8 Undesirable effects
Adverse drug reactions observed with VYVANSE treatment mainly reflect side effects commonly
associated with amphetamine use. Tables 1-3 present common adverse drug reactions (ADRs)
reported in parallel-group, controlled clinical trials of children, adolescents and adults who received
VYVANSE. Table 4 presents common ADRs reported in long-term, open-label clinical trials in
children, adolescents and adults who received VYVANSE.

Table 1: Adverse Drug Reactions Occurring in ≥5% of Children who Received VYVANSE in Short-term,
Parallel-group, Controlled Studies
NRP104.301 SPD489-325
(forced dose; 4 weeks) (dose optimisation; 7 weeks)
VYVANSE Placebo VYVANSE Placebo Concerta
System Organ Class N=218 N=72 N=77 N=79 N=80
Preferred Term (n [%]) (n [%]) (n [%]) (n [%]) (n [%])
Gastrointestinal disorders
Abdominal pain upper 25 (11.5) 4 (5.6) 6 (7.8) 5 (6.3) 6 (7.5)
Diarrhoea 1 (0.5) 2 (2.8) 4 (5.2) 1 (1.3) 2 (2.5)
Nausea 13 (6.0) 2 (2.8) 8 (10.4) 2 (2.5) 6 (7.5)
Vomiting 19 (8.7) 3 (4.2) 3 (3.9) 1 (1.3) 2 (2.5)
General disorders and administration site conditions
Irritability 21 (9.6) 0 3 (3.9) 0 3 (3.8)
Pyrexia 5 (2.3) 1 (1.4) 3 (3.9) 0 4 (5.0)
Investigations
Weight decreased 21 (9.6) 2 (2.8) 10 (13.0) 0 4 (5.0)
Metabolism and nutrition disorders
Anorexia 16 (7.3) 1 (1.4) 8 (10.4) 2 (2.5) 3 (3.8)
Decreased appetite 72 (33.0) 2 (2.8) 19 (24.7) 3 (3.8) 14 (17.5)
Nervous system disorders
Dizziness 11 (5.0) 0 1 (1.3) 1 (1.3) 1 (1.3)
Headache 26 (11.9) 7 (9.7) 9 (11.7) 12 (15.2) 13 (16.3)
Psychiatric disorders
Aggression 3 (1.4) 0 4 (5.2) 1 (1.3) 3 (3.8)
Initial insomnia 8 (3.7) 0 2 (2.6) 1 (1.3) 4 (5.0)
Insomnia 42 (19.3) 2 (2.8) 12 (15.6) 0 6 (7.5)
Note: Subjects are only counted once within each treatment group and by system organ class and preferred term.
Percentages are based on the number of subjects in the Safety Population for each treatment group.

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Table 2: Adverse Drug Reactions Occurring in ≥5% of Adolescents who Received VYVANSE or Active
Treatment in Short-term, Parallel-group, Controlled Studies
SPD489-305 SPD489-325
(forced dose; 4 weeks) (dose optimisation; 7 weeks)
VYVANSE Placebo VYVANSE Placebo Concerta
System Organ Class N=233 N=77 N=34 N=31 N=31
Preferred Term (n [%]) (n [%]) (n [%]) (n [%]) (n [%])
Gastrointestinal disorders
Abdominal pain upper 2 (0.9) 3 (3.9) 2 (5.9) 1 (3.2) 3 (9.7)
Dry mouth 11 (4.7) 1 (1.3) 2 (5.9) 0 1 (3.2)
Nausea 9 (3.9) 2 (2.6) 4 (11.8) 1 (3.2) 2 (6.5)
Vomiting 3 (1.3) 4 (5.2) 1 (2.9) 0 2 (6.5)
General disorders and administration site
conditions
Fatigue 10 (4.3) 2 (2.6) 2 (5.9) 1 (3.2) 0
Irritability 17 (7.3) 3 (3.9) 1 (2.9) 0 1 (3.2)
Investigations
Weight decreased 24 (10.3) 0 5 (14.7) 0 1 (3.2)
Metabolism and nutrition disorders
Anorexia 4 (1.7) 0 4 (11.8) 0 3 (9.7)
Decreased appetite 80 (34.3) 2 (2.6) 9 (26.5) 0 3 (9.7)
Nervous system disorders
Dizziness 10 (4.3) 3 (3.9) 3 (8.8) 0 1 (3.2)
Headache 34 (14.6) 10 (13.0) 7 (20.6) 10 (32.3) 9 (29.0)
Psychiatric disorders
Initial insomnia 6 (2.6) 0 1 (2.9) 0 3 (9.7)
Insomnia 26 (11.2) 3 (3.9) 4 (11.8) 0 3 (9.7)
Note: Subjects are only counted once within each treatment group and by system organ class and preferred term.
Percentages are based on the number of subjects in the Safety Population for the treatment group.

Table 3: Adverse Drug Reactions Occurring in ≥5% of Adults who Received VYVANSE in Short-term,
Parallel-group, Controlled Studies
VYVANSE Placebo
N=493 N=202
Preferred Term (n [%]) (n [%])
Gastrointestinal disorders
Decreased appetite 122 (24.7) 6 (3.0)
Dry mouth 113 (22.9) 8 (4.0)
Diarrhoea 29 (5.9) 2 (1.0)
Nausea 26 (5.3) 5 (2.5)
Nervous system disorders
Headache 100 (20.3) 13 (6.4)
General disorders and administration site conditions
Irritability 31 (6.3) 7 (3.5)
Fatigue 25 (5.1) 7 (3.5)
Feeling jittery 25 (5.1) 0
Investigations
Weight decreased 19 (3.9) 0
Psychiatric disorders
Insomnia 79 (16.0) 12 (5.9)

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Initial insomnia 26 (5.3) 6 (3.0)
Anxiety 25 (5.1) 0
Note: Subjects were counted once within each preferred term and treatment group.
Percentages are based on the number of subjects in the Safety Population for each treatment group.
Adverse events were coded using Medical Dictionary for Regulatory Activities Version 11.1.

Table 4: Adverse Drug Reactions Occurring in > 5% of Children, Adolescents or Adults who Received
VYVANSE in Long-term, Open-label Studies
NRP104.302 SPD489-306 NRP104.304
(children) (adolescents) (adults)
(52 weeks open-label (52 weeks; open-label (52 weeks; open-label
VYVANSE) VYVANSE) VYVANSE)
System Organ Class N=270 N=265 N=349
Preferred Term (n [%]) (n [%]) (n [%])
Gastrointestinal disorders
Abdominal pain upper 28 (10.4) 8 (3.0) 5 (1.4)
Dry mouth 0 14 (5.3) 58 (16.6)
Vomiting 23 (8.5) 7 (2.6) 3 (0.9)
General disorders and administration site conditions
Irritability 26 (9.6) 33 (12.5) 39 (11.2)
Investigations
Weight decreased 44 (16.3) 43 (16.2) 21 (6.0)
Metabolism and nutrition disorders
Decreased appetite 84 (31.1) 56 (21.1) 50 (14.3)
Nervous system disorders
Dizziness 0 14 (5.3) 15 (4.3)
Headache 48 (17.8) 55 (20.8) 60 (17.2)
Psychiatric disorders
Affect lability 17 (6.3) 0 2 (0.6)
Anxiety 3 (1.1) 3 (1.1) 29 (8.3)
Insomnia 48 (17.8) 32 (12.1) 68 (19.5)
Note: Subjects are only counted once within each study and by system organ class and preferred term.
Percentages are based on the number of subjects in each study.

In addition the following adverse reactions have been identified in clinical trials of VYVANSE:
agitation, logorrhoea, libido decreased, dysphoria, euphoria, psychomotor hyperactivity, bruxism,
mania, hallucinations, restlessness, tremor, somnolence, tachycardia, dyspnoea, hyperhidrosis, rash,
increased blood pressure, erectile dysfunction and constipation.
Suppression of growth in paediatric patients with ADHD
Weight
Weight change compared to placebo has been evaluated in 4-week trials for children (age 6- 12) and
adolescents (age 13-17). Higher doses were associated with greater weight loss. In children, mean
weight loss from baseline to endpoint was -0.39, -0.84, and -1.12kg, respectively, for patients
assigned to receive 30 mg, 50 mg, and 70 mg of VYVANSE, compared to a 0.46 kg weight gain for
patients receiving placebo. In adolescents, mean weight change from baseline to endpoint was -
1.24, -1.94, and -2.16 kg, respectively, for patients assigned to receive 30 mg, 50 mg, and 70 mg of
VYVANSE, compared to a 0.9 kg weight gain for patients receiving placebo.
In children and adolescents who received VYVANSE over 12 months, careful monitoring of weight
suggested that consistent medication (i.e., treatment for 7 days per week throughout the year)
resulted in a slowing of growth as measured by body weight. In children, the average weight
percentiles at baseline (n=271) and 12 months (n=146), were 60.9 and 47.2, respectively. The age-

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and sex-normalised mean change from baseline in percentile over 1 year was -13.4. In adolescents,
the average weight percentiles at baseline (n=265) and 12 months (n=156), were 66.0 and 61.5,
respectively. The age- and sex-normalised mean change from baseline in percentile over 1 year was -
6.5. [See section 4.4 Special warnings and precautions for use]
Long term growth
Long term controlled height and weight data with use of VYVANSE are not available. In a long-term
study, careful follow-up of weight and height in children ages 7 to 10 years who were randomised to
either methylphenidate or non-medication treatment groups over 14 months, as well as in
naturalistic subgroups of newly methylphenidate-treated and nonmedication treated children over
36 months (to the ages of 10 to 13 years) (total of all subgroups n=370), 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.
Postmarketing experience
The following adverse reactions have been identified during post approval use of VYVANSE. These
events are as follows: palpitations, cardiomyopathy, mydriasis, blurred vision, eosinophilic hepatitis,
anaphylactic reaction, hypersensitivity, chest pain, dyskinesia, dysgeusia, tics, depression, affect
lability, dermatillomania, psychotic episodes, Tourette’s Disorder, Stevens-Johnson Syndrome,
alopecia, angioedema, urticaria, seizures, QTc prolongation, Raynaud’s phenomenon, epistaxis and
intestinal ischemia.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows
continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are
asked to report any suspected adverse reactions https://pophealth.my.site.com/carmreportnz/s/
4.9 Overdose
Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia,
rapid respiration, confusion, aggression, hallucinations, panic states, hyperpyrexia, rhabdomyolysis
and other features of serotonin syndrome. 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, diarrhoea, and abdominal
cramps. Fatal poisoning is usually preceded by convulsions and coma.
Management of acute amphetamine intoxication is largely symptomatic and includes administration
of activated charcoal and sedation. 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.
Lisdexamfetamine and dexamphetamine are not dialysable. Acidification of the urine increases
amphetamine excretion but is believed to increase risk of acute renal failure if myoglobinuria is
present.
The prolonged release of VYVANSE in the body should be considered when treating patients with
overdose.
For advice on the management of overdose please contact the National Poisons Centre on 0800
POISON (0800 764766).

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5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: centrally acting sympathomimetics, ATC code: N06 BA12.
Pharmacodynamic effects
Lisdexamfetamine is a pharmacologically inactive prodrug of dexamphetamine, which is a central
nervous system stimulant.
After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract and
hydrolysed primarily in whole blood to dexamphetamine, which is responsible for the drug’s activity.
Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The
mode of therapeutic action of amphetamine in ADHD is not fully established, however it is thought
to be due to its ability to block the reuptake of noradrenaline 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 noradrenaline and
dopamine in vitro.
Clinical trials
The effects of VYVANSE in the treatment of ADHD have been demonstrated in two controlled trials
in children aged 6 to 12 years, one controlled study in adolescents aged 13 to 17 years, one
controlled study in children and adolescents (6 to 17 years), two controlled trials in adults, one
maintenance trial in children and adolescents and one maintenance trial in adults.
In clinical studies conducted in children and adults, the effects of VYVANSE were ongoing at 13 hours
after dosing in children and at 14 hours in adults when the product was taken once daily in the
morning (data presented below).
In dose optimisation studies, the mean daily dose of VYVANSE tended to be slightly lower in studies
in children (range 44.3-50.5 mg) than in adolescents (range 53.5-58.8 mg) or adults (range 52.3-56.8
mg). This observation is consistent with the lower weights of children.
Children aged from 6 to 12 years

A double-blind, randomised, placebo-controlled, parallel-group study was conducted in children

aged 6 to 12 (N=290) who met DSM-IV criteria for ADHD (either the combined type or the
hyperactive-impulsive type). Patients were randomised 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. All
subjects receiving VYVANSE were initiated on 30 mg for the first week of treatment. Subjects
assigned to the 50 and 70 mg dose groups were titrated by 20 mg per week until they achieved their
assigned dose. 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
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 (Conners’ Parent Rating Scale) in the
morning (approximately 10 am), afternoon (approximately 2 pm), and early evening (approximately
6 pm). ADHD-RS results for Study NRP104.301 are shown in the following table:

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Table 5: ADHD-RS Total Score at Endpoint (Children; Study NRP104.301; Full Analysis Set)

Baseline Change from Baseline ≥50% Response a

LS
LS Mean (SE)
Treatment n Mean (SD) n Means 95% CI p-valueb n Percent p-valuec
Change
Diff.

Placebo 72 42.4 (7.13) 72 -6.2 (1.56) 72 12.5

VYVANSE
69 43.2 (6.68) 69 -21.8 (1.60) -15.58 (-20.78 -10.38) <0.0001 71 52.1 <0.001
30mg
VYVANSE
71 43.3 (6.74) 71 -23.4 (1.56) -17.21 (-22.33, -12.08) <0.0001 74 60.8 <0.001
50mg
VYVANSE
73 45.1 (6.82) 73 -26.7 (1.54) -20.49 (-25.63, -15.36) <0.0001 73 71.2 <0.001
70mg
a
Defined as a ≥50% decrease from baseline in ADHD-RS Total Score at endpoint.
b
p-value is adjusted based on Dunnett’s multiple comparison procedure for comparing the active doses to placebo.
c
p-value is based on Cochran-Mantel-Haenszel test comparing each active dose to placebo controlling for pooled site.
Note: Endpoint is the last post-randomisation treatment week for which a valid ADHD-RS-IV Total Score is obtained.
Note: Response is defined as a percentage reduction from baseline in the ADHD-RS-IV Total Score of ≥50%
Full Analysis Set=full analysis set (all subjects who took at least 1 dose of investigational product and who had a valid baseline
and at least 1 post-baseline ADHD-RS total score); SE=standard error.

A second double-blind, placebo-controlled, randomised, crossover design, analog classroom study

was conducted in children aged 6 to 12 (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 or placebo once
daily in the morning for 1 week each treatment. A significant difference in patient behaviour, based
upon the average of investigator ratings on the SKAMP-Deportment scores across all 7 assessments
conducted at 1.5, 2.5, 5.0, 7.5, 10.0, 12.0, and 13.0 hours post-dose, were observed between
patients who received VYVANSE compared to patients who received placebo. Significant differences
at all assessments from 1.5 hours through 13 hours post-dose were observed between patients who
received VYVANSE compared to patients who received placebo.
Adolescents aged from 13 to 17 years

A double-blind, randomised, placebo-controlled, parallel-group study was conducted in adolescents

aged 13 to 17 (N=314) who met DSM-IV criteria for ADHD. In this four-week study, patients were
randomised in a 1:1:1:1 ratio to a daily morning dose of VYVANSE (30, 50 or 70 mg/day) or placebo
for a double-blind stepwise forced dose titration (3 weeks) followed 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 and 70 mg dose groups were titrated by 20 mg per week until they
achieved their assigned dose. 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. ADHD-RS results for Study SPD489-305 are shown in the following table:

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Table 6: ADHD-RS Total Score at Endpoint (Adolescents; Study SPD489-305; Full Analysis Set)

Baseline Change from Baseline ≥50% Response a

LS
LS Mean (SE)
Treatment n Mean (SD) n Means 95% CI p-valueb n Percent p-valuec
Change
Diff.

Placebo 77 38.5 (7.11) 76 -12.8 (1.25) 77 33.8

VYVANSE
78 38.3 (6.71) 76 -18.3 (1.25) -5.5 (-9.7, -1.3) 0.0056 78 50.0 0.041
30mg
VYVANSE
76 37.3 (6.33) 72 -21.1 (1.28) -8.3 (-12.5, -4.1) <0.0001 77 59.7 0.001
50mg
VYVANSE
78 37.0 (7.30) 75 -20.7 (1.25) -7.9 (-12.1, -3.8) <0.0001 78 56.4 0.005
70mg
a
Defined as a ≥50% decrease from baseline in ADHD-RS Total Score at endpoint.
b
p-value is adjusted based on Dunnett’s multiple comparison procedure for comparing the active doses to placebo.
c
p-value is based on Cochran-Mantel-Haenszel test comparing each active dose to placebo controlling for pooled site
Note: Endpoint is the last post-randomisation treatment week for which a valid ADHD-RS-IV Total Score is obtained.
Note: Response is defined as a percentage reduction from baseline in the ADHD-RS-IV Total Score of ≥50%
Full Analysis Set=full analysis set (all subjects who took at least 1 dose of investigational product and who had a valid baseline
and at least 1 post-baseline ADHD-RS total score); SE=standard error.

Children and adolescents aged from 6 to 17 years

A double-blind, randomised, placebo- and active-controlled parallel-group, dose-optimisation study
was conducted in children and adolescents aged 6 to 17 years (N=336) who met DSM-IV criteria for
ADHD. In this eight-week study, patients were randomised to a daily morning dose of VYVANSE (30,
50 or 70 mg/day), a long-acting methylphenidate formulation (Concerta) (18 mg, 36 mg or 54
mg/day) 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-
Optimisation Period followed by a 3-week Dose-Maintenance Period), and a 1-week Washout and
Follow-up Period. During the 4-week Dose Optimisation Period, subjects were titrated until an
optimal dose, based on TEAEs and clinical judgment, was reached.
VYVANSE showed significantly greater efficacy than placebo. The placebo-adjusted mean reduction
from baseline in the ADHD-RS-IV total score was 18.6 (p<0.001). With regard to functional outcome,
78.0% of subjects on VYVANSE showed Improvement (“very much improved” or “much improved”)
on the Clinical Global Impression-Improvement (CGI-I) rating scale. VYVANSE also showed significant
improvement in child achievement in academic performance, as measured by the Health Related
Quality of Life instrument CHIP-CE:PRF Achievement Domain, VYVANSE demonstrated a significant
improvement compared to placebo from baseline (VYVANSE: 9.4 vs. Placebo -1.1) with a mean
difference between the two treatment groups of 10.5 (p<0.001). Outcome results for Study SPD489-
325 are shown in the following table:

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Table 7: Results for Study SPD489-325 at Endpoint (Children and Adolescents; Full Analysis Set)

VYVANSE Placebo Concerta

Change in ADHD-RS IV Total Score
Least Square Mean -24.3 -5.7 -18.7
Effect size (versus Placebo) 1.804 N/A 1.263
P-value (versus Placebo) <0.001 N/A <0.001

Percent with ≥50% Responsea 65.4 13.2 49.5

P-value (versus Placebo) <0.001 <0.001
Analysis of CGI-I
Patients Showing Improvementb 78% (78/100) 14% (15/104) 61% (63/104)
Difference in improvement from placebo (percentage
64 N/A 46
point improvement)
P-value (versus Placebo) <0.001 N/A <0.001
Change in CHIP-CE: PRF Achievement Domain
Least Square Mean 9.4 -1.1 6.4
Effect size (versus Placebo) 1.28 N/A 0.912
P-value (versus Placebo) <0.001 N/A <0.001
a
Defined as a ≥50% decrease from baseline in ADHD-RS Total Score at endpoint
b
Improvement (“very much improved” or “much improved”)
Note: Endpoint is defined as the last on-treatment post-Baseline visit of the dose optimisation or dose maintenance Period
(Visits 1-7) with a valid value

The long-acting methylphenidate formulation (Concerta) was included as a reference arm to validate
the results of the trial.
Maintenance of Efficacy Study - A double-blind, placebo-controlled, randomised withdrawal study
was conducted in children and adolescents aged 6 to 17 years (N=276) 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. In order to ensure
that the appropriate population was included in the randomised 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 randomised 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 randomised 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
randomised withdrawal period (p<0.001). The endpoint measurement was defined as the last post-
randomisation 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 ≥2-
point increase in the CGI-S score compared to scores at entry into the double-blind randomised
withdrawal phase. For the majority of subjects (70.3%) who were treatment failures ADHD
symptoms worsened at or before the week 2 visit following randomisation.
Adults

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A double-blind, randomised, placebo-controlled, parallel-group study was conducted in adults
(N=420) who met DSM-IV criteria for ADHD. In this four-week study, patients were randomised to
fixed dose treatment groups receiving final doses of 30, 50, or 70 mg of VYVANSE or placebo. All
subjects receiving VYVANSE were initiated on 30 mg for the first week of treatment. Subjects
assigned to the 50 and 70 mg dose groups were titrated by 20 mg per week until they achieved their
assigned dose. 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. ADHD-RS results for Study NRP104.303 are shown in the following table:

Table 8: ADHD-RS Total Score at Endpoint (Adults; Study NRP104.303; Full Analysis Set)

Baseline Change from Baseline ≥50% Responsea

LS
LS Mean (SE)
Treatment n Mean (SD) n Means 95% CI p-valueb n Percent p-valuec
Change
Diff.

Placebo 62 39.4 (6.42) 62 -8.2 (1.43) 62 12.9

VYVANSE
115 40.5 (6.21) 115 -16.2 (1.06) -8.04 (-12.14, -3.95) <0.0001 119 36.1 0.002
30mg
VYVANSE
117 40.8 (73.0) 117 -17.4 (1.05) -9.16 (-13.25, -5.08) <0.0001 117 40.2 <0.001
50mg
VYVANSE
120 41.0 (6.02) 120 -18.6 (1.03) -10.41 (-14.49, -6.33) <0.0001 122 44.3 <0.001
70mg
a
Defined as a ≥50% decrease from baseline in ADHD-RS Total Score at endpoint
b
p-value is adjusted based on Dunnett’s multiple comparison procedure for comparing the active doses to placebo.
c
p-value is based on Cochran-Mantel-Haenszel test comparing each active dose to placebo controlling for pooled site
Note: Endpoint is the last post-randomisation treatment week for which a valid ADHD-RS-IV Total Score is obtained.
Note: Response is defined as a percentage reduction from baseline in the ADHD-RS-IV Total Score of ≥50%
Full Analysis Set=full analysis set (all subjects who took at least 1 dose of investigational product and who had a valid baseline
and at least 1 post-baseline ADHD-RS total score); SE=standard error.

The second study was a multi-centre, randomised, double-blind, placebo-controlled, crossover

design, modified analog classroom study of VYVANSE to simulate a workplace environment in 142
adults who met DSM-IV-TR criteria for ADHD. There was a 4-week open-label, dose optimisation
phase with VYVANSE (30, 50, or 70 mg/day in the morning). Subjects were then randomised to one
of two treatment sequences: 1) VYVANSE (optimised dose) followed by placebo, each for one week,
or 2) placebo followed by VYVANSE, each for one week. Efficacy assessments occurred at the end of
each week, using the Permanent Product Measure of Performance (PERMP). The PERMP is a skill-
adjusted mathematics test that measures attention in ADHD. VYVANSE treatment, compared to
placebo, resulted in a statistically significant improvement in attention across all post-dose time
points, as measured by average PERMP total scores over the course of one assessment day, as well
as at each time point measured. The PERMP assessments were administered at pre-dose (-0.5 hours)
and at 2, 4, 8, 10, 12, and 14 hours post-dose. In this study most subjects (> 80%) required a dose
greater than 30 mg. The majority of subjects (~50%) had a final dose of 50 mg.
Maintenance of Efficacy Study - A double-blind, placebo-controlled, randomised withdrawal design
study was conducted in adults aged 18 to 55 (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 with adult prompts Total Score is a measure of core
symptoms of ADHD. Subjects that maintained treatment response at week 3 of open label treatment
phase (N=116) were eligible to enter the 6 week double-blind randomised withdrawal phase, and
received their entry dose of VYVANSE (N=56) or placebo (N=60). Maintenance of efficacy for subjects
treated with VYVANSE was demonstrated by the significantly lower proportion of treatment failure
(<9%) compared to subjects receiving placebo (75%) in the double-blind randomised withdrawal

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phase (p<0.0001). 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 randomised withdrawal phase. For subjects receiving VYVANSE, the median and mean
duration in the double-blind randomised withdrawal phase was 42.0 and 39.1 days, respectively. For
subjects receiving placebo, the median and mean duration in the double-blind randomised
withdrawal phase was 13.0 and 18.2 days, respectively. The difference in duration between the two
treatment groups was because the majority of treatment failures occurred in the first 14 days after
subjects were switched from open-label SPD489 treatment to placebo.
5.2 Pharmacokinetic properties
Pharmacokinetic studies of dexamphetamine after oral administration of lisdexamfetamine
dimesilate have been conducted in healthy adult subjects and paediatric (6-12 years) patients with
ADHD.
Absorption
After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract,
thought to be mediated by the high capacity PEPT1 transporter.
In 18 paediatric patients (6-12 years) with ADHD, the Tmax of dexamphetamine was approximately
3.5 hours following single-dose oral administration of lisdexamfetamine dimesilate either 30 mg, 50
mg, or 70 mg after an 8-hour overnight fast. The Tmax of lisdexamfetamine dimesilate was
approximately 1 hour. Linear pharmacokinetics of dexamphetamine after single-dose oral
administration of lisdexamfetamine dimesilate was established over the dose range of 30 mg to 70
mg in children aged 6 to 12 years and over the dose range of 50 mg to 250 mg in adults.
Dexamphetamine pharmacokinetic parameters following administration of lisdexamfetamine in
adults exhibited low inter-subject (<25%) and intra-subject (<8%) variability. Safety and efficacy have
not been studied above the maximum recommended dose of 70 mg.
Food (a high fat meal or soft food such as yogurt) or orange juice does not affect the observed AUC
and Cmax of dexamphetamine in healthy adults after single-dose oral administration of 70 mg of
VYVANSE capsules. Food prolongs Tmax by approximately 1 hour (from 3.8 h at fasted state to 4.7 h
after a high fat meal or to 4.2 h after soft food such as yogurt).
After an 8-hour fast, the AUC for dexamphetamine following oral administration of
lisdexamfetamine dimesilate in solution and as intact capsules were equivalent.
Weight/Doses normalised AUC and Cmax for dexamphetamine 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 normalised AUC and Cmax values were the same in girls and boys following single doses
of 30-70 mg.
Distribution
There is no accumulation of dexamphetamine AUC at steady state in healthy adults and no
accumulation of lisdexamfetamine dimesilate after once-daily dosing for 7 consecutive days.
Metabolism
Lisdexamfetamine is converted to dexamphetamine and L-lysine, not by cytochrome P450 enzymes
metabolism, but by metabolism in blood primarily due to the hydrolytic activity of red blood cells.
Red blood cells have a high capacity for metabolism of lisdexamfetamine as in vitro data
demonstrated substantial hydrolysis occurs even at low haematocrit levels.
Amphetamine is reported to be oxidised 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 oxidised to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes

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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.
Excretion
Following the oral administration of a 70 mg dose of radiolabelled lisdexamfetamine dimesilate to 6
healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the urine and
only 0.3% recovered in the faeces 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% to intact
lisdexamfetamine. Plasma concentrations of unconverted lisdexamfetamine 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
dimesilate in volunteers.
Special populations
Age
The pharmacokinetics of dexamphetamine is similar in paediatric (aged 6 to 12) and adolescent
(aged 13 to 17) ADHD patients, and healthy adult volunteers. Any differences in kinetics seen after
oral administration are a result of differences in mg/kg dosing. Following administration of
lisdexamfetamine dimesilate in a study of 47 subjects aged 55 years of age or older, amphetamine
clearance was approximately 0.7 L/h/kg for subjects 55-74 years of age and 0.55 L/h/kg for subjects
≥75 years of age. This is slightly reduced compared to younger adults (approximately 1 L/h/kg for
subjects 18-45 years of age).
Sex
Following administration of lisdexamfetamine dimesilate, systemic exposure to dexamphetamine is
similar for men and women given the same mg/kg dose.
Race
Formal pharmacokinetic studies for race have not been conducted.
Renal disease
In a pharmacokinetic study of lisdexamfetamine in subjects with normal and impaired renal function,
dexamphetamine clearance was reduced from 0.7 L/h/kg in normal subjects to 0.4 L/h/kg in subjects
with severe renal impairment (GFR 15 to <30 mL/min/1.73m2). [See section 4.4 Special warnings and
precautions for use – Renal impairment]
In subjects with ESRD requiring dialysis, mean dexamphetamine clearance was reduced to 0.3 L/h/kg
both pre- and post-dialysis. Dialysis did not significantly affect the clearance of dexamphetamine.
5.3 Preclinical safety data
Carcinogenicity
Carcinogenicity studies of lisdexamfetamine dimesilate have not been performed.
No evidence of carcinogenicity was found in studies in which d-, l-amphetamine sulphate
(enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to
30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats.
Genotoxicity
Lisdexamfetamine dimesilate was negative (not clastogenic) in the mouse micronucleus test in vivo
and was negative in the bacterial reverse mutation test and the L5178Y/TK+/- mouse lymphoma

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assay in vitro.

6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
VYVANSE capsules contain the following inactive ingredients: microcrystalline cellulose,
croscarmellose sodium, and magnesium stearate. The capsule shells contain gelatin, titanium
dioxide (all strengths), erythrosine (30mg and 70 mg), brilliant blue FCF (40 mg, 50 mg, 60 mg and 70
mg), iron oxide yellow (20 mg and 40 mg), iron oxide black (40 mg) and TekPrint SW-9008 (all
strengths). Refer to Section 2 – QUALITATIVE AND QUANTITATIVE COMPOSITION.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years. The expiry date can be found on the packaging.
6.4 Special precautions for storage
Store below 25°C.
6.5 Nature and contents of container
VYVANSE capsules are packed in high density polyethylene (HDPE) bottles with polypropylene child
resistant (PP CR) cap containing 30 capsules, inside a cardboard carton.
6.6 Special precautions for disposal <and other handling>
No special requirements.

7 MEDICINE SCHEDULE
Controlled Drug – B2

8 SPONSOR
Takeda New Zealand Limited
Level 10, 21 Queen Street
Auckland 1010
Auckland Central
Auckland
New Zealand
Telephone: 0508 169 077
www.takeda.com/en-au

9 DATE OF FIRST APPROVAL

29 March 2021

10 DATE OF REVISION OF THE TEXT

22 August 2024
VYVANSE® and the VYVANSE Logo® are registered trademarks of Takeda Pharmaceuticals
U.S.A., Inc.

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SUMMARY TABLE OF CHANGES

Section changed Summary of new information
1, 2, 4.2 and 6 Addition of information relating to new 20mg, 40mg and 60mg strengths.

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