Consumer medicine information

Vyvanse Capsules

Lisdexamfetamine dimesilate

BRAND INFORMATION

Brand name

Vyvanse Capsules

Active ingredient

Lisdexamfetamine dimesilate

Schedule

S8: Care must be taken to comply with provisions of State/ Territory law

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Vyvanse Capsules.

What is in this leaflet

Please read this leaflet before you/your child start taking VYVANSE.

This leaflet answers some common questions about VYVANSE.

It does not contain all available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risk of you or your child taking VYVANSE against the benefit it is expected to have.

If you have any concerns about taking VYVANSE, talk to your doctor or pharmacist.

Keep this leaflet with the medicine. You may want to read it again.

What VYVANSE is used for

VYVANSE is a central nervous system stimulant used to treat:

  • Attention Deficit Hyperactivity Disorder (ADHD). VYVANSE increases attention and decreases impulsiveness and hyperactivity in patients with ADHD.
  • Binge Eating Disorder (BED). VYVANSE may help to reduce the number of binge eating days in patients with moderate to severe BED.

VYVANSE is not for weight loss.

It is not to be taken by children with ADHD under 6 years of age or in patients with BED under 18 years of age. VYVANSE should be used as part of a comprehensive treatment program which usually includes psychological, educational and social therapy. For BED, VYVANSE should only be prescribed by a psychiatrist as part of a comprehensive treatment program.

The main ingredient in VYVANSE is lisdexamfetamine dimesilate which itself is not active (such medicines are sometimes called a pro-drug). After VYVANSE is taken, it is converted in the blood to dexamphetamine which is the active medicine.

Your doctor may have prescribed VYVANSE for another reason. Ask your doctor if you have any questions about why this medicine has been prescribed for you/your child.

VYVANSE can be abused or lead to dependence. VYVANSE is a controlled substance and should be handled responsibly. It is illegal for anyone prescribed VYVANSE to sell or give it to other people.

Keep VYVANSE in a safe place to prevent misuse and abuse. Also, return any unused capsules to your pharmacy to safeguard against them being taken by anyone else (see Disposal section).

Before you take VYVANSE

VYVANSE capsules are not suitable for everyone.

When you must not take it

Do not take VYVANSE if you/your child:

  • have a disease of the arteries due to cholesterol deposits e.g. atherosclerosis
  • are allergic (hypersensitive) to amphetamines or any of the other ingredients of VYVANSE listed in "Other ingredients" section of this leaflet
  • have heart disease such as angina or myocardial infarction (heart attack)
  • have moderate to severe high blood pressure
  • have hyperthyroidism (hyperactive thyroid)
  • have an eye condition called glaucoma
  • have a tumour of the adrenal gland tissue (phaeochromocytoma)
  • have tics (muscle twitching usually in the face and shoulders)
  • have Tourette's syndrome
  • have severe depression, suicidal ideation or behaviour, thoughts or acts of self-harm or mental illness
  • have periods of severe anxiety, tension or agitation
  • suffer with drug dependence or abuse alcohol
  • are taking or have taken an antidepressant called a monoamine oxidase inhibitor or MAOI within the past 14 days.

Do not use VYVANSE if the bottle shows signs of tampering.

Do not use VYVANSE beyond the expiry date (month and year) printed on the bottle.

If you/your child takes VYVANSE after the expiry date has passed, it may have no effect, or worse, there may be an entirely unexpected effect.

Do not give it to children unless your doctor has prescribed it. VYVANSE is not recommended for use in children with ADHD under 6 years of age or in patients with BED under 18 years of age.

If you are not sure whether you/your child should start using VYVANSE, contact your doctor.

Before you take it

Tell your doctor or pharmacist if you or your child:

  • are allergic to any other medicines, or any foods, dyes or preservatives
  • are pregnant or planning to become pregnant
  • are breastfeeding or wish to breastfeed
  • have any other medical conditions or heart problems, including ischemic heart disease (such as angina or myocardial infarction), suspicion or presence of any cardiac or heart -related abnormalities, irregular heartbeats or rate, family history of sudden/cardiac death
  • suffer from blood pressure and/or taking medications to treat blood pressure
  • disorders of the blood vessels of the brain e.g. stroke
  • suffer from depression, bipolar illness, or schizophrenia or other mental illness
  • have liver or kidney disease. Your doctor may lower the dose if you have kidney disease.
  • have epilepsy or other seizures or have had an abnormal brain wave test (EEG)
  • have circulation problems in fingers and toes

If you have not told your doctor or pharmacist about any of the above, tell them before you/your child take any VYVANSE.

Taking other medicines

Tell your doctor or pharmacist about all the medicine you/your child are taking or have recently taken, including prescription and non-prescription medicines, vitamins and herbal supplements. VYVANSE can affect the way other medicines work, and other medicines may affect how VYVANSE works. Using VYVANSE with other medicines can cause serious side effects.

It is especially important to tell your doctor or pharmacist if you or your child is taking medicines to treat any of the following conditions:

  • depression including MAOIs
  • anxiety, mania or bipolar disorder
  • high blood pressure
  • schizophrenia or schizophrenia-like illness
  • strong pain

In addition, the following medicines may also interact with VYVANSE:

  • Urinary acidifying agents eg. ascorbic acid (Vitamin C), ammonium chloride, sodium acid phosphate
  • Urinary alkalinising agents eg. sodium bicarbonate, acetazolamide, some thiazides

Tell your doctor or pharmacist if you/your child are taking or have recently taken other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Do not start any new medicine while taking VYVANSE without talking to your doctor first.

How to take VYVANSE

Follow all directions given to you by your pharmacist or doctor carefully as this may differ from the information contained in this leaflet.

Your doctor may do regular checks of the blood, heart, and blood pressure while taking VYVANSE. Children should have their height and weight checked often while taking VYVANSE. VYVANSE treatment may be stopped if a problem is found during these check-ups.

If you do not understand the instructions in this leaflet, ask your doctor or pharmacist for help.

How much to take

The usual starting dose for children, adolescents and adults is 30 mg once a day. Your doctor may increase the dose until it is right for you or your child. For treatment of BED your psychiatrist will assess the response to VYVANSE after 12 weeks.

How to take it

  • Take VYVANSE exactly as prescribed. VYVANSE comes in 6 different strength of capsules.
  • Take VYVANSE once a day in the morning.
  • VYVANSE can be taken with or without food.
  • If you have trouble swallowing capsules, you may open your VYVANSE capsule and pour all of the powder into a soft food such as yogurt, water or orange juice.
  • Use all of the VYVANSE powder from the capsule so you get all of the medicine.
  • Using a spoon, break apart any powder that is stuck together. Stir the VYVANSE powder and yogurt, water or orange juice until they are completely mixed together.
  • Consume all of the yogurt, water or orange juice right away after it has been mixed. Do not store the yogurt, water or orange juice after it has been mixed with VYVANSE.
  • Do not worry if there is a film or residue left in the glass or container afterwards - this is not the active ingredient.
  • From time to time, your doctor may stop VYVANSE treatment for a while to check your/your child's ADHD or your BED symptoms.

If you forget to take it

If you/your child forget to take capsules then take them as usual the next morning. Do not take a double dose to make up for a forgotten capsule.

Avoid taking VYVANSE in the afternoon or evening as it can cause an inability to sleep.

A Dosage Chart is provided on the VYVANSE carton to help track the capsules are taken properly. Cross off a symbol each time a capsule is taken.

If you take too much

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you/your child or anyone else may have used too much VYVANSE. Do this even if there are no signs of discomfort or poisoning.

If too much VYVANSE is taken, following symptoms may be experienced: confusion, restlessness, tremor, irregular heart beat, nausea, vomiting, diarrhoea, stomach aches, seizures and coma.

While you are taking VYVANSE

Things you must do

  • VYVANSE should be taken in the morning
  • Make sure that all of your doctors, dentists, ophthalmologists, psychologists and pharmacists know you/your child are taking VYVANSE. Remind them if any new medicines are about to be started.
  • Like all stimulants, VYVANSE may become habit-forming and can be abused by some people. If it is taken correctly as instructed by your doctor, this should not happen, either now or later in life.
  • Be sure to keep all doctors' appointments so that you/your child's progress can be checked.
  • Your doctor will want to check your/your child's blood pressure and pulse
  • Tell your doctor immediately if you/your child become pregnant while on VYVANSE.

Things you must not do

  • Do not stop treatment or change the dosage without checking with your doctor
  • Do not give VYVANSE to anyone else, even if they have the same condition as you/your child. It may not be safe for another person to take VYVANSE
  • Do not take VYVANSE to treat any other complaints unless your doctor tells you to. It may not be safe to use VYVANSE for another complaint.
  • Do not take VYVANSE for a longer time than your doctor has prescribed

Things to be careful of

Do not drive or operate machinery until you know how VYVANSE affects you

VYVANSE may cause dizziness, drowsiness and blurry or double vision. This is uncommon; but if affected, you/your child should avoid driving or using heavy machinery. Check with your doctor if driving is advisable for you/your child while you/your child are taking VYVANSE.

Be careful when drinking alcohol while taking VYVANSE

If you/your child drink alcohol, it could make some of the unwanted side effects of VYVANSE worse. Your doctor may suggest that you/ your child avoid alcohol completely or reduce the amount you drink while you are taking VYVANSE.

Side effects

Tell your doctor or pharmacist as soon as possible if you/your child feel unwell while you/your child are taking VYVANSE.

Like all medicines, VYVANSE can cause some side effects. Sometimes they are serious, most of the time they are mild and temporary.

Do not be alarmed by this list of possible side effects. You/your child may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you/your child notice any of the following and they worry you:

  • decreased or loss of appetite
  • trouble sleeping
  • headache
  • dry mouth
  • weight loss
  • upper belly pain
  • agitation, anxiety, aggression, affect lability, irritability, feeling jittery, feeling tired, feeling sleepy
  • dizziness, restlessness, excessive motor activity with or without feelings of restlessness, tic, tremor
  • rapid heart beat (tachycardia), palpitations, increased blood pressure
  • nausea, vomiting, diarrhoea
  • involuntary clenching or grinding of the teeth
  • rash, fever, shortness of breath
  • excessive sweating
  • excessive widening of the pupil
  • decreased sex drive, erectile dysfunction
  • circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud's phenomenon): Fingers or toes may feel numb, cool, painful; change colour or have sensitivity to temperature

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you/your child develop:

  • allergic reaction which may result in a rash or more rarely to a sharp drop in blood pressure, difficulty breathing, and hives/itching (anaphylactic reaction)
  • chest pain or tightness in the chest
  • shortness of breath
  • irregular heart beat
  • seizures (fits)
  • vision problems
  • mood changes such as depression or irritability
  • new or worsening aggressive behaviour
  • excitement, overactivity and uninhibited behaviour
  • confusion, delusion or hallucinations (seeing or feeling things that are not really there)
  • abnormal thinking (psychosis)

These may be serious side effects. You/your child may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you/your child notice anything that is making you/your child feel unwell.

Other side effects not listed above may also occur in some people.

After taking VYVANSE

Storage

  • Keep the capsules in the bottle until it is time to take them.
  • Keep medicines where children cannot see or reach them.
    A locked cupboard at least one-and-a-half metres (1.5m) above the floor is a good place to store medicines.
  • Store VYVANSE in a cool dry place where the temperature is below 25°C. Keep the container tightly closed.
    Do not store VYVANSE or any other medicines in the bathroom or near a sink. Do not leave medicines in the car or on windowsills. Heat and dampness can destroy medicines.

Disposal

Return any unused or out of date medicine to your pharmacist. Do not keep unused or expired VYVANSE as it can be abused or taken by someone else. Do not throw out with your household waste.

For more information about proper disposal of medicines, please contact the RUM Project (Return Unwanted Medicines):
Telephone 1300 650 835
Website: www.returnmed.com.au

It is illegal for anyone prescribed VYVANSE to sell or give it to other people.

Product description

What VYVANSE looks like

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 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.

VYVANSE is supplied in bottles of 30 capsules, inside a cardboard box.

Ingredients

Active ingredient
The active ingredient is lisdexamfetamine dimesilate

Other ingredients
The inactive ingredients are: microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The capsule shells contain gelatin, titanium dioxide (E171) (all strengths) erythrosine (E127) (30 mg and 70 mg), brilliant blue (E133) (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).

Sponsor

Shire Australia Pty Ltd
Level 39, 225 George Street
Sydney NSW 2000
Australia
Phone: 1800 012 612

This leaflet was prepared in January 2018.

Australian Registration Number:

VYVANSE 20 mg AUST R 284019

VYVANSE 30 mg AUST R 199227

VYVANSE 40 mg AUST R 284020

VYVANSE 50 mg AUST R 199226

VYVANSE 60 mg AUST R 284021

VYVANSE 70 mg AUST R 199228

VYVANSE® is a registered trademark of Shire LLC.

BRAND INFORMATION

Brand name

Vyvanse Capsules

Active ingredient

Lisdexamfetamine dimesilate

Schedule

S8: Care must be taken to comply with provisions of State/ Territory law

 

1 Name of Medicine

Lisdexamfetamine dimesilate.

2 Qualitative and Quantitative Composition

Vyvanse capsules contain 20 mg, 30 mg, 40 mg, 50 mg, 60 mg or 70 mg of lisdexamfetamine dimesilate as the active ingredient.
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.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsules.

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 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

Attention deficit hyperactivity disorder (ADHD).

Vyvanse is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Treatment should be commenced by a specialist.
A diagnosis of Attention Deficit Hyperactivity Disorder (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.

Binge eating disorder (BED).

Vyvanse is indicated for the treatment of moderate to severe BED in adults when non-pharmacological treatment is unsuccessful or unavailable. Treatment should be commenced and managed by a psychiatrist.

Need for comprehensive treatment programme.

Vyvanse is indicated as part of a total treatment program for BED that optimally includes other measures (nutritional, psychological, and medical) for patients with this disorder. When remedial measures including psychotherapy 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.

Limitation of use.

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. The safety and effectiveness of Vyvanse for the treatment of obesity have not been established.
Prescribers should consider that serious cardiovascular events have been reported with this class of sympathomimetic drugs. The BED clinical trials were not designed to assess cardiovascular safety. While there is an accumulation of safety data with Vyvanse use in the ADHD population, this is of limited relevance regarding cardiovascular risk in the BED population. Given the higher cardiovascular risk associated with obesity, the BED population may be at a higher risk. See Section 4.4 Special Warnings and Precautions for Use, Cardiovascular disease; Section 4.2 Dose and Method of Administration.

Long term use.

For BED the initial treatment period is 12 weeks. Patients should then be observed to assess whether further treatment with Vyvanse is required. Periodic re-evaluation of the usefulness of Vyvanse for the individual patient should be undertaken. See Section 5.1 Pharmacodynamic Properties, Clinical trials.

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.
The maximum recommended dose is 70 mg/day; doses greater than 70 mg/day of Vyvanse have not been studied. 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/1.73 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; Section 4.4 Special Warnings and Precautions for Use.
Lisdexamfetamine and dexamphetamine are not dialysable.

Treatment of ADHD.

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 the starting dose, daily dosage may be adjusted in increments of 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. Vyvanse has not been studied in children under 6 years of age.

Treatment of BED.

Vyvanse should be commenced and managed by a psychiatrist as part of a comprehensive treatment programme for BED.
The recommended starting titration dose is 30 mg/day to be adjusted in increments of 20 mg at approximately weekly intervals to achieve the recommended target dose of 50 or 70 mg/day. Dose titration should be guided by clinical outcome to an optimal dose, with a maximum dose of 70 mg/day.
Vyvanse should be prescribed for the shortest duration that is clinically indicated. The initial treatment period is 12 weeks. Patients should then be observed to assess whether further treatment with Vyvanse is required. Periodic re-evaluation of the usefulness of Vyvanse for the individual patient should be undertaken.

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).
Pheochromocytoma.
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 liability for abuse, drugs of the amphetamine type are subject to special restrictions on their availability. Prescriptions of this substance may require validation by State or Territory Health Departments or Commissions.
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.
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.

Serious cardiovascular events have been reported with the use of sympathomimetic drugs, including Vyvanse, in the ADHD population (see below). Given the higher cardiovascular risk associated with obesity, the BED population may be at a higher risk. Prescribers should consider this potential risk when treating BED. See Section 4.1 Therapeutic Indications; Section 4.2 Dose and Method of Administration.
Limited cardiovascular safety information is provided by the BED clinical trials, given the exclusion of higher risk patients (e.g. those with diabetes, moderate to severe hypertension and cardiovascular disease, and older than 55 years of age) combined with limited patient numbers and limited treatment duration.

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.

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. Therefore, clinical evaluation for tics and Tourette's syndrome in children and their families should precede use of stimulant medications.

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.

Peripheral vasculopathy, including Raynaud's phenomenon.

Stimulants, including Vyvanse, used to treat ADHD 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, have been observed in postmarketing 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 ADHD stimulants. Further clinical evaluation (e.g. rheumatology referral) may be appropriate for certain patients.

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.
For BED the initial treatment period is 12 weeks. Patients should then be observed to assess whether further treatment with Vyvanse is required. Periodic re-evaluation of the usefulness of Vyvanse for the individual patient should be undertaken.

Paediatric use.

ADHD.

Vyvanse should not be used in children under the age of 6 years. Safety and efficacy in this age group has not been established.

BED.

Safety and effectiveness have not been established in children and adolescents under the age of 18 years. Clinical studies on the use of Vyvanse in this age group with BED have not been conducted.

Adult patients aged over 55 years.

Safety and efficacy has not been established in adult patients over the age of 55 years.

Use in hepatic impairment.

No studies have been conducted in patients with hepatic impairment.

Use in renal impairment.

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 Pharmacological Properties, Special populations.
Lisdexamfetamine and dexamphetamine are not dialysable.

Effects on laboratory tests.

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 Interactions with Other Medicines and Other Forms of Interactions

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 impacted 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 co-administration 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 (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.
(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.
Amphetamines are excreted in human milk. Mothers taking Vyvanse should be advised to refrain from breast feeding.
Oral administration of amphetamine sulfate to rats from early gestation through to weaning was associated with adverse effects on offspring, see Section 4.6 Fertility, Pregnancy and Lactation, 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 Adverse Effects (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 meeting DSM criteria for ADHD who received Vyvanse. Table 4 presents common ADRs reported in long-term, open-label clinical trials in children, adolescents and adults meeting DSM criteria for ADHD who received Vyvanse. Table 5 presents common ADRs reported in two parallel-group, placebo-controlled dose-optimisation clinical trials of adults meeting DSM criteria for BED who received Vyvanse. Table 6 presents common ADRs reported in long-term, open-label clinical trials in adults meeting DSM criteria for BED who received Vyvanse.

Adverse reactions associated with discontinuation of treatment in ADHD clinical trials.

In the controlled trial in patients aged 6 to 12 years, 8% (18/218) of Vyvanse-treated patients discontinued due to adverse reactions compared to 0% (0/72) of placebo-treated patients. The most frequently reported adverse reactions 1% or more and twice rate of placebo were ECG voltage criteria for ventricular hypertrophy, tic, vomiting, psychomotor hyperactivity, insomnia, decreased appetite and rash [2 instances for each adverse reaction, i.e. 2/218 (1%)]. Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included abdominal pain upper, dry mouth, weight decreased, dizziness, somnolence, logorrhea, chest pain, anger and hypertension.
In the controlled trial in patients aged 13 to 17 years, 3% (7/233) of Vyvanse-treated patients discontinued due to adverse reactions compared to 1% (1/77) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were decreased appetite (2/233; 1%), and insomnia (2/233; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included irritability, dermatillomania, mood swings, and dyspnea.
In the controlled adult trial, 6% (21/358) of Vyvanse-treated patients discontinued due to adverse reactions compared to 2% (1/62) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate 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 dyspnoea (3/358; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included palpitations, diarrhea, nausea, decreased appetite, dizziness, agitation, depression, paranoia and restlessness.

Adverse reactions associated with discontinuation of treatment in BED clinical trials.

In controlled trials of patients aged 18 to 55 years, 5.1% (19/373) of Vyvanse treated patients discontinued due to adverse reactions compared to 2.4% (9/372) of placebo-treated patients. No single adverse reaction led to discontinuation in 1% or more of Vyvanse-treated patients. The most common adverse reactions (incidence ≥ 5% and at a rate at least twice placebo) reported in adults were dry mouth, insomnia, decreased appetite, increased heart rate, constipation, feeling jittery, and anxiety. Less commonly reported adverse reactions (less than 1% or less than twice rate of placebo) included increased heart rate, headache, abdominal pain upper, dyspnea, rash, insomnia, irritability, feeling jittery and anxiety.
The following definitions apply to the frequency terminology used:
Incidence categories: very common (≥ 10%); common (≥ 1% and < 10%); uncommon (≥ 0.1% and < 1%); rare (≥ 0.01% and < 0.1%); very rare (< 0.01%); incidence not known (cannot be estimated from the available data). See Table 7.

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 -1.12 kg, 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 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).
In children and adolescents (aged 6-17) who received Vyvanse over two years, careful monitoring of weight suggested that consistent medication (i.e. treatment for 7 days per week throughout the two years) resulted in a slowing of growth as measured by body weight. In children and adolescents, the average weight percentiles and standard deviations (SD) at baseline (N = 314) and 24 months (week 104, N = 189), were 65.4 (SD 27.11) and 48.2 (SD 29.94), respectively. The age- and sex-normalized mean change from baseline in percentile over 2 years was -16.9 (SD 17.33).

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.

Weight changes in adults with BED.

In the two phase 3 controlled adult trials after treatment with 50 and 70 mg of Vyvanse, mean weight loss after 12 weeks was 5.8 kilograms for patients receiving Vyvanse (baseline mean BMI 33.8 kg/m2, baseline mean weight of 94.5 kilograms), compared to a mean weight change of 0.0 kilograms for patients receiving placebo (baseline mean BMI 33.2 kg/m2, baseline mean weight of 92.9 kilograms); no subject on active treatment shifted to a BMI category of underweight (less than 18.5 kg/m2). Weight data from long term controlled studies (greater than 12 weeks) with Vyvanse are not available.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre telephone: 131126 (Australia).
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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

General.

Lisdexamfetamine is a pharmacologically inactive prodrug of dexamphetamine, which is a central nervous system stimulant.

Mechanism of action.

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 Attention Deficit Hyperactivity Disorder (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 with ADHD.

A double-blind, randomised, placebo-controlled, parallel-group study was conducted in children aged 6 to 12 (N = 290) who met American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) 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 Table 8.
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 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 with ADHD.

A double-blind, randomised, placebo-controlled, parallel-group study was conducted in adolescents aged 13 to 17 (N = 314) who met DSM 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 Table 9.
Vyvanse was studied in two double-blind, parallel-group, active-controlled (OROS-methylphenidate [MPH]) studies conducted in adolescents aged 13-17 years with ADHD. Both studies also included a placebo reference arm. The primary objective of these studies was to evaluate the efficacy of Vyvanse compared with OROS-MPH as assessed by the ADHD-RS-IV total score.
The 8-week dose-optimisation study (SPD489-405) had a 5-week dose-optimisation period and a 3-week dose-maintenance period. During the dose-optimisation period, subjects were titrated once weekly based on TEAEs and clinical response to an optimal dose of 30, 50, or 70 mg/day (for Vyvanse subjects) or 18, 36, 54, or 72 mg/day (for OROS-MPH subjects), which was maintained throughout a 3-week dose-maintenance period. The mean doses at endpoint were 57.9 mg and 55.8 mg for Vyvanse and OROS-MPH, respectively. In this study, neither Vyvanse nor OROS-MPH was found to be statistically superior to the other product at Week 8. The between group difference in the LS mean change from baseline to week 8 was -2.1 (95% CI of -4.3, 0.2) (p = 0.0717). The 6-week fixed-dose study (SPD489-406) had a 4-week forced-dose titration period and a 2-week dose-maintenance period. At the highest doses of Vyvanse (70 mg/day) and OROS-MPH (72 mg/day), Vyvanse treatment was found to be superior to OROS-MPH as measured by the primary efficacy analysis (change from baseline at Week 6 on the ADHD-RS Total score). The between group difference in the LS mean change from baseline to week 6 was -3.4 (95% CI of--5.4, -1.3) (p = 0.0013).

Children and adolescents aged from 6 to 17 years with ADHD.

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 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 (OROS-MPH) (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 Table 10.
The long-acting methylphenidate formulation (OROS-MPH) 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 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 with ADHD.

A double-blind, randomised, placebo-controlled, parallel-group study was conducted in adults (N = 420) who met DSM 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 Table 11.
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 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 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 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.

Adults with binge eating disorder (BED).

The efficacy of Vyvanse in the treatment of BED was demonstrated in two 12 week randomised, double-blind, multicentre, parallel-group, placebo-controlled, dose-optimisation studies in adults aged 18-55 years with moderate to severe BED (SPD489-343: N = 374 and SPD489-344: N = 350). A diagnosis of BED was confirmed using DSM criteria for BED. Severity of BED was determined based on having at least 3 binge days per week for 2 weeks prior to the Baseline Visit and on having a CGI-S score of ≥ 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.
Both 12-week studies consisted of a 4-week Dose-optimisation Period and an 8-week Dose-maintenance Period. During dose-optimisation, subjects assigned to Vyvanse began treatment at the titration dose of 30 mg/day and, after 1 week of treatment, were subsequently up-titrated to 50 mg/day. Additional increases to 70 mg/day were made as tolerated and clinically indicated. Following the Dose-optimisation Period, subjects continued on their optimised dose for the duration of the Dose-maintenance Period.
The primary efficacy endpoint for the two studies was defined as the change from baseline at Weeks 11/12 in the number of binge days per week. Baseline was defined as the weekly average of the number of binge days per week for the 14 days prior to the Baseline Visit.
Subjects from both studies on Vyvanse had a statistically significantly (p < 0.001) greater reduction from baseline in mean number of binge days per week at Weeks 11/12. In addition, subjects on Vyvanse showed greater improvement as compared to placebo across key secondary outcomes with higher proportion of subjects rated improved on the CGI-I rating scale, higher proportion of subjects with 4-week binge cessation, and greater reduction in the Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) total score in both studies. See Table 12.

Maintenance of efficacy study.

A double-blind, placebo controlled, randomised 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 (N = 267) with moderate to severe BED. In this longer-term study patients who had responded to Vyvanse in the preceding 12-week open-label treatment phase were randomised 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 randomised-withdrawal baseline. Maintenance of efficacy for patients who had an initial response during the open-label period and then continued on Vyvanse during the 26-week double-blind randomised-withdrawal phase was demonstrated with Vyvanse being superior over placebo as measured by time to relapse. Additionally, 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%). See Figure 1.

5.2 Pharmacokinetic Properties

Pharmacokinetic studies of dexamphetamine after oral administration of lisdexamfetamine dimesilate have been conducted in healthy adult 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 h 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 h. 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/Dose 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 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 1 hour in studies of lisdexamfetamine dimesilate in volunteers.

Special populations.

Age.

The pharmacokinetics of dexamphetamine, as evaluated by clearance, is similar in paediatric (aged 6 to 12) and adolescent (aged 13 to 17) ADHD patients, and healthy adult volunteers after correcting for body weight. 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/hr/kg in subjects with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m2). See Section 4.4 Special Warnings and Precautions for Use.
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

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 assay in vitro.

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.

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 (30 mg 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). See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For interactions, please see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

20 mg, 40 mg, 60 mg: 36 months from date of manufacture.
30 mg, 50 mg, 70 mg: 30 months from date of manufacture.

6.4 Special Precautions for Storage

Vyvanse should be stored below 25°C.

6.5 Nature and Contents of Container

Container type.

Vyvanse capsules are packed in high density polyethylene (HDPE) bottles with polypropylene child resistant (PP CR) cap, inside a cardboard carton.

Pack size.

30 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Formula.

C17H33N3O7S2.

Chemical structure.


CAS numbers.

Lisdexamfetamine: 608137-32-2.
Lisdexamfetamine dimesilate: 608137-33-3.

Molecular weight.

455.59.

7 Medicine Schedule (Poisons Standard)

Controlled Drug (S8).

Summary Table of Changes