Consumer medicine information

Strattera

Atomoxetine

BRAND INFORMATION

Brand name

Strattera

Active ingredient

Atomoxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Strattera.

What is in this leaflet

This leaflet answers some common questions about STRATTERA. It does not contain all the 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 risks of you taking STRATTERA against the benefits it may have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

What STRATTERA is used for

STRATTERA is used to treat Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years and older, adolescents and adults. ADHD is a behavioural disorder that causes lack of focus and/or hyperactivity that is much more frequent or severe than others who are close in age or development.

STRATTERA works by acting on brain chemicals called amines which are involved in controlling behaviour.

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

Available evidence suggests that STRATTERA does not have a significant potential for abuse.

This medicine is available only with a doctor's prescription.

Before you take STRATTERA

When you must not take it

Do not take STRATTERA if you have an allergy to:

  • any medicine containing atomoxetine hydrochloride (the active ingredient in STRATTERA)
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take STRATTERA if you have any of the following conditions:

  • certain heart diseases such as moderate to severe raised blood pressure (hypertension), abnormal or dangerously fast heart beat, thickening and hardening of the walls of the arteries due to cholesterol deposits
  • an uncontrolled overactive thyroid gland which causes increased appetite, weight loss, intolerance to heat, increased sweating, tremors, and rapid heart rate
  • a tumour of the adrenal gland, which sits near the kidney. The symptoms are bouts of anxiety and headaches, palpitations, dizziness, a feeling of weakness, nausea, vomiting, diarrhoea, dilated pupils and blurring vision, stomach pains, and raised blood pressure.

Do not take STRATTERA if you are taking medicine called a monoamine oxidase inhibitor (MAOI) for the treatment of depression or have been taking a MAOI within the last 14 days. Check with your doctor or pharmacist if you are unsure as to whether or not you are taking a MAOI.

If you do take STRATTERA while you are taking a MAOI, you may experience elevated body temperature, muscle stiffness, involuntary muscle jerking, fluctuations of vital signs (blood pressure, heart rate, breathing rate) and mental state from extreme agitation progressing to confusion and coma (a condition resembling neuroleptic malignant syndrome).

Do not take STRATTERA if you have high pressure in the eye (glaucoma), or have a family history of glaucoma.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • high blood pressure
  • low blood pressure
  • fast heart beat
  • heart disease
  • conditions affecting blood flow in the brain, such as stroke
  • liver disease
  • kidney disease
  • an overactive thyroid gland
  • enlargement or disease of the prostate
  • difficulty passing urine
  • seizures, fits or convulsions
  • any psychiatric disorder, including depression or bipolar disorder.

Tell your doctor if you or your child have or have had:

  • thoughts or talk of death or suicide
  • thoughts or talk of self-harm or harm to others
  • any recent attempts at self-harm.

You may wish to see a paediatric psychiatrist for further assessment and supervision of your child.

Tell your doctor if you:

  • are involved in strenuous exercise or activities
  • are using a group of medicines called stimulants
  • have a family history of sudden/cardiac death.

STRATTERA generally should not be used in children, adolescents or adults with known structural heart abnormalities due to increased risks of sudden death/stroke.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

Safety and effectiveness in elderly patients older than 65 years and children younger than 6 years have not been established.

If you have not told your doctor about any of the above, tell him/her before you start taking STRATTERA.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by STRATTERA or may affect how it works. You may need different amounts of your medicines or you may need to take different medicines.

These include:

  • monoamine oxidase inhibitors (MAOIs), medicines used to treat some types of depression.
    You should stop taking MAOIs at least two weeks before starting STRATTERA
  • certain medicines used to treat depression such as fluoxetine, paroxetine, desipramine, imipramine, venlafaxine and mirtazapine
  • certain medicines used to treat irregular heart beat such as quinidine
  • medicines used to treat low blood pressure or to raise blood pressure (anti-hypertensive medicines and pressor agents)
  • medicines containing the decongestants pseudoephedrine or phenylephrine
  • asthma reliever medicines such as salbutamol, when taken orally as a syrup or as an injection
  • certain medicines taken for anxiety such as diazepam or to treat epilepsy such as phenytoin.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking STRATTERA.

How to take STRATTERA

Carefully follow all directions given to you by your doctor or pharmacist. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

For children and adolescents up to 70 kg body weight, the usual starting dose is approximately 0.5 mg/kg once a day.

After a minimum of 3 days, if necessary, the dose may be increased to approximately 1.2 mg/kg once daily in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, if necessary, the dose may be increased to a maximum of 1.4 mg/kg once daily or 100 mg.

For children and adolescents greater than 70 kg body weight and adults, the usual starting dose is 40 mg once a day.

After a minimum of 3 days, if necessary, the dose may be increased to approximately 80 mg once daily in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg.

If therapy is interrupted for more than 1 week, treatment should be started at the lowest recommended dose.

Your doctor will tell you how much STRATTERA you need to take each day.

Your doctor may increase or decrease your dose depending on your condition and any other illness that you may have.

How to take it

Swallow the capsules whole with a full glass of water.

STRATTERA can be taken with or without food.

When to take it

STRATTERA is usually taken one or two times a day (early morning and late afternoon/early evening).

If you find that you are sleepy during the day or have trouble sleeping at night, talk to your doctor about the best time to take your medicine.

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take it

Continue taking your medicine for as long as your doctor tells you. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally. Do not take more than your total daily dose in a 24-hour period.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

If you think that you or anyone else may have taken too much STRATTERA, immediately telephone your doctor or the Poisons Information Centre (telephone Australia: 13 11 26, NZ: 0800 POISON or 0800 764 766) for advice, or go to Emergency Department at the nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you have taken too much STRATTERA, the most common signs are sleepiness, dizziness, tremor, agitation, hyperactivity, unusual behaviour and an upset stomach. In some cases of overdose, seizures and changes to the way that the heart beats (a condition called QT prolongation) have been reported.

While you are taking STRATTERA

Things you must do

Contact your doctor or a paediatric psychiatrist straight away or go to the nearest hospital for treatment if you notice any sudden change in your child's behaviour, if your child is demonstrating any of the following warning signs, if you notice any of the following or if they seem worse.

Signs to watch for:

  • thoughts or talk of death or suicide
  • thoughts or talk of self-harm or harm to others
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling very agitated or restless
  • panic attacks
  • difficulty sleeping (insomnia)
  • new or worse irritability
  • acting on dangerous impulses
  • an extreme increase in activity and talking
  • appearance or worsening of aggressive behaviour or hostility
  • other unusual changes in behaviour.

Preventing suicidal thoughts or action:

To try and prevent suicidal thoughts or actions in your child, talk with and listen to your child about his or her thoughts and feelings and pay close attention to changes in his or her moods or action, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g. brothers and sisters, teachers, caregivers and other important people). Pay close attention to your child whenever STRATTERA is started or its dose is changed (see Side Effects).

If you notice an increase in aggression or hostility since taking this medication, you should call your doctor as soon as possible.

Tell your doctor if you experience a seizure, fit or convulsion. If you already suffer from seizures, fits or convulsions, tell your doctor if they seem to increase in frequency.

Tell your doctor if you notice changes in your sexual function while you are taking this medicine.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking STRATTERA.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some tests (blood pressure and heart rate) from time to time while on therapy. After starting STRATTERA children may have a reduced rate of growth so your doctor may also monitor your height and weight from time to time when on long term therapy.

Things you must not do

Do not take STRATTERA to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not open your STRATERRA capsules as the content is an eye irritant. In the event of capsule content coming in contact with the eye, flush the affected eye immediately with water and seek medical advice. Hands and any potentially contaminated surfaces should be washed as soon as possible.

Things to be careful of

Be careful driving or operating machinery until you know how STRATTERA affects you. This medicine may cause dizziness, tiredness or drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

If your doctor advises you to stop taking STRATTERA, do not take monoamine oxidase inhibitors (MAOIs) within the first two weeks after stopping STRATTERA.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking STRATTERA. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You 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 notice any of the following:

Children, adolescents and Adults

  • constipation
  • upset or sore stomach, nausea, vomiting
  • diarrhoea
  • decreased appetite
  • weight loss
  • decreased growth (weight and height)
  • headache
  • drowsiness
  • dizziness
  • constant flu like symptoms such as chills, fever, irritated watery eyes, sore throat
  • feeling cold
  • dilated pupils
  • blurred vision
  • Eye redness
  • mood swings
  • skin rash, redness, itching
  • early morning waking, tiredness
  • unusual weakness
  • lacking energy, feeling tired
  • cough, sore throat, blocked or runny nose, which may be associated with a respiratory infection

Adults

  • dry mouth
  • thirst
  • flatulence
  • difficulty urinating, abnormal, painful and/or frequent urination
  • sexual disturbances including reduced sex drive, erectile dysfunction, abnormal orgasm
  • testicular or genital pain in males
  • painful or irregular menstrual periods
  • hot flushes
  • increased sweating
  • tickling, tingling, burning, pricking, or numbness of skin
  • feeling jittery, tremors
  • persistent abnormal taste

Tell your doctor immediately or go to the Emergency Department of your nearest hospital if you notice any of the following in you/your child while taking STRATTERA:

  • fast or irregular heart beat
  • fainting
  • numbness, tingling and colour change (white, blue then red) in fingers and toes when exposed to cold
  • seizures, fits or convulsions
  • signs of liver injury such as dark urine, yellowing of the skin or eyes, severe cramps of the stomach, or unexplained nausea, fatigue, lethargy, itching or flu-like symptoms
  • episodes of overactivity, restlessness, elation or irritability, hostility or aggressiveness
  • anxiety, agitation, impulsive behaviour and other changes in behaviour
  • difficulty in sleeping
  • panic attacks
  • chest pain
  • depression
  • confusion or hallucinations (seeing or feeling things that are not really there)
  • thoughts of suicide or attempts to harm yourself. (also see Things You Must Do if you notice this behaviour in children or adolescents)

These are serious side effects, which may require medical attention. Serious side effects are rare or very rare. Other side effects not listed above may also occur in some people.

Other changes you may not be aware of:

  • increased blood pressure
  • heart rhythm changes

Tell your doctor or pharmacist if you notice any other effects.

After taking STRATTERA

Storage

Keep your capsules in the pack until it is time to take them. If you take the capsules out of the pack they may not keep as well.

Keep your capsules in a cool dry place where the temperature stays below 25°C.

Do not store STRATTERA or any other medicine in the bathroom or near a sink. Do not leave it on a windowsill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

STRATTERA 10 mg capsules are coloured opaque white and are marked with "Lilly", "3227" and "10 mg".

STRATTERA 18 mg capsules are coloured gold and opaque white and are marked with "Lilly", "3238" and "18 mg".

STRATTERA 25 mg capsules are coloured opaque blue and opaque white and are marked with "Lilly", "3228" and "25 mg".

STRATTERA 40 mg capsules are coloured opaque blue and are marked with "Lilly", "3229" and "40 mg".

STRATTERA 60 mg capsules are coloured opaque blue and gold and are marked with "Lilly", "3239" and "60 mg".

STRATTERA 80 mg capsules are coloured opaque brown and opaque white and are marked with "Lilly", "3250" and "80 mg".

STRATTERA 100 mg capsules are coloured opaque brown and are marked with "Lilly", "3251" and "100 mg".

Ingredients

STRATTERA contains 10, 18, 25, 40, 60, 80 or 100 mg of atomoxetine hydrochloride as the active ingredient. It also contains:

  • starch (pregelatinised maize)
  • dimeticone 350
  • gelatin
  • sodium lauryl sulfate
  • edible black ink
  • one or more of the following:
    - indigo carmine CI73015
    - iron oxide yellow CI77492
    - iron oxide red CI77491
    - titanium dioxide

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Supplied in Australia by:

Eli Lilly Australia Pty Ltd
Level 9, 60 Margaret Street,
Sydney, NSW 2000
Australia

Supplied in NZ by:

Eli Lilly and Company (NZ) Ltd.
PO Box 109 197, Newmarket,
AUCKLAND
New Zealand

Australian Registration Number:

STRATTERA 10 mg capsules -
AUST R 90592

STRATTERA 18 mg capsules -
AUST R 90593

STRATTERA 25 mg capsules -
AUST R 90594

STRATTERA 40 mg capsules -
AUST R 90595

STRATTERA 60 mg capsules -
AUST R 90596

STRATTERA 80 mg capsules -
AUST R 146333

STRATTERA 100 mg capsules -
AUST R 146413

This leaflet was revised in January 2024.

® = Registered Trademark

vA8

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Strattera

Active ingredient

Atomoxetine

Schedule

S4

 

1 Name of Medicine

Strattera (atomoxetine hydrochloride) tablets.

2 Qualitative and Quantitative Composition

Capsules containing 5, 10, 18, 25, 40, 60, 80 and 100 mg of atomoxetine hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Strattera is available as capsules for oral administration.
Each capsule contains 10, 18, 25, 40, 60, 80 or 100 mg of atomoxetine (as the hydrochloride).
The capsule colours and markings are as follows:

*5 mg capsules.

Gold and marked with "Lilly 3226" and "5 mg".

10 mg capsules.

Opaque white and marked with "Lilly 3227" and "10 mg".

18 mg capsules.

Gold and opaque white and marked with "Lilly 3238" and "18 mg".

25 mg capsules.

Opaque blue and opaque white and marked with "Lilly 3228" and "25 mg".

40 mg capsules.

Opaque blue and marked with "Lilly 3229" and "40 mg".

60 mg capsules.

Opaque blue and gold and marked with "Lilly 3239" and "60 mg".

80 mg capsules.

Opaque brown and opaque white and marked with "Lilly 3250" and "80 mg".

100 mg capsules.

Opaque brown and marked with "Lilly 3251" and "100 mg".
* Not currently available.

4 Clinical Particulars

4.1 Therapeutic Indications

Strattera is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as defined by DSM-IV criteria in children 6 years of age and older, adolescents and adults.

4.2 Dose and Method of Administration

Instructions for use/handling.

Strattera capsules are not intended to be opened. Atomoxetine is an ocular irritant. In the event of capsule content coming in contact with the eye, the affected eye should be flushed immediately with water, and medical advice obtained. Hands and any potentially contaminated surfaces should be washed as soon as possible.

Initial treatment.

Dosing of children and adolescents up to 70 kg bodyweight.

Strattera should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the total daily dose may be increased to a maximum of 1.4 mg/kg in patients who have not achieved an optimal response (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The maximum recommended total daily dose in children and adolescents is 1.4 mg/kg or 100 mg, whichever is less.

Dosing of children and adolescents over 70 kg bodyweight and adults.

Strattera should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response (see Section 5.1 Pharmacodynamic Properties, Clinical trials). There are no data supporting increased effectiveness at higher doses.
The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg.

Interrupted treatment.

If therapy is interrupted for more than 1 week, treatment should be started at the recommended starting dose (see Section 4.2 Dose and Method of Administration, Initial treatment.)

Maintenance/extended treatment.

There is no evidence available from controlled trials to indicate how long the patient with ADHD should be treated with Strattera. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use Strattera for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

General dosing information.

Strattera may be taken with or without food.
The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated.
For those ADHD patients who have endstage renal disease, cautious titration of Strattera to the desired clinical response is recommended (see Section 5.2 Pharmacokinetic Properties, Special populations). Atomoxetine may exacerbate hypertension in patients with endstage renal disease.
Strattera may be discontinued without tapering the dose.

Hepatic impairment dosage adjustment.

Atomoxetine clearance may be reduced in patients with hepatic impairment. For those ADHD patients who have hepatic impairment, dosage adjustment is recommended as follows: For patients with moderate hepatic impairment (Child-Pugh class B), initial and target doses should be reduced to 50% of the normal dose. For patients with severe hepatic impairment (Child-Pugh class C), initial dose and target doses should be reduced to 25% of the normal dose.

Dosing adjustment for use with a strong CYP2D6 inhibitor.

In children and adolescents up to 70 kg bodyweight administered strong CYP2D6 inhibitors, e.g. paroxetine, fluoxetine and quinidine, Strattera should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.
In children and adolescents over 70 kg bodyweight and adults administered strong CYP2D6 inhibitors, e.g. paroxetine, fluoxetine and quinidine, Strattera should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.

4.3 Contraindications

Strattera is contraindicated in patients with:
Known hypersensitivity to atomoxetine or any excipients in this product.

Symptomatic cardiovascular disease.

Moderate to severe hypertension, atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation, or ventricular flutter, advanced arteriosclerosis (see Section 4.4 Special Warnings and Precautions for Use).

Severe cardiovascular disorders.

Atomoxetine should not be used in patients with severe cardiovascular disorders whose condition would be expected to deteriorate if they experienced increases in blood pressure or in heart rate (for example, 15 to 20 mmHg in blood pressure or 20 beats per minute in heart rate) (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular effects.)

Uncontrolled hyperthyroidism.


Phaeochromocytoma.

Strattera should not be used in patients with pheochromocytoma or a history of pheochromocytoma (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular effects).

Monoamine oxidase inhibitors.

Strattera should not be taken with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuing MAOIs. Treatment with MAOIs should not be initiated within 2 weeks after discontinuing Strattera.
With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal, reactions when taken in combination with MAOIs. These reactions include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs and mental status changes that include extreme agitation progressing to delirium and coma; some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity.

Narrow angle glaucoma.

In clinical studies, the use of Strattera was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma.

4.4 Special Warnings and Precautions for Use

Suicidal ideation and behaviour.

Pooled analyses of short-term (6 to 18 weeks) placebo controlled trials of Strattera in children and adolescents showed a greater risk of suicidal ideation during treatment in those receiving Strattera. There were a total of 12 trials (11 in ADHD and 1 in enuresis) involving over 2200 patients. The average risk of suicidal ideation in patients treated with Strattera was 0.4% (5/1357) compared with 0% (0/851) in patients treated with placebo. There was 1 suicide attempt in patients treated with Strattera and none in patients treated with placebo. No suicides occurred in these trials. All events of suicidal ideation and behaviour associated with Strattera occurred in children 12 years of age and younger. It is unknown whether the risk of suicidality in children extends to longer-term use of Strattera. A similar meta-analysis in adult patients treated with Strattera for either ADHD or major depressive disorder (MDD) did not reveal an increased risk of suicidal ideation or behaviour in association with the use of Strattera.
All children being treated with Strattera should be monitored closely for suicidality, clinical worsening and unusual changes of behaviour, especially during the first few months of treatment or at times of dose change. The following symptoms have been reported with Strattera: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania. Although a causal link between the emergence of such symptoms and the emergence of suicidal ideation and behaviour has not been established, there is a concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including discontinuing Strattera, in patients who are experiencing emergent suicidality or symptoms that might be precursors to emerging suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patients' presenting symptoms. These patients should be referred to a paediatric psychiatrist for assessment and supervision.
Families and caregivers of children and adolescents being treated with Strattera should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behaviour, and the other symptoms described above, as well as the emergence of suicidality and to report such symptoms immediately to healthcare providers.
Based on clinical trials conducted in children and adolescents (< 18 years of age) to establish the efficacy of the drug over placebo for the treatment of ADHD, the number needed to treat calculations suggest that a clinician should expect to treat 2 to 3 patients to see one patient respond and 4 to 5 patients to see one patient respond that wouldn't have with placebo treatment. This is balanced against suicidal ideation occurring in 1 out of about every 271-272 patients treated.

Aggressive behaviour or hostility.

Hostility (predominantly aggression, oppositional behaviour and anger) and emotional lability are often observed in patients with ADHD and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no conclusive evidence that atomoxetine causes aggressive behaviour or hostility, aggressive behaviour or hostility was more frequently observed in clinical trials among children, adolescents and adults treated with atomoxetine compared to placebo (not statistically significant). Patients beginning treatment for ADHD should be monitored for the appearance or worsening of aggressive behaviour or hostility. Referral of patients to a psychiatrist for regular assessment and supervision during treatment should also be considered.

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 a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. In a pooled analysis of multiple short-term, placebo controlled studies, such symptoms occurred in about 0.2% (4 patients with reactions out of 1939 exposed to atomoxetine for several weeks at usual doses) of atomoxetine treated patients compared to 0 out of 1056 placebo treated patients.

Screening patients for bipolar disorder.

In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with Strattera, 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.

Possible allergic events.

Although uncommon, allergic reactions, including anaphylactic reactions, rash, angioneurotic oedema and urticaria, have been reported in patients taking Strattera.

Seizures.

The preclinical and clinical trial data for Strattera do not suggest that Strattera is proconvulsive. However, seizures have been very rarely reported in postmarketing spontaneous reports. Strattera should be used with caution in patients with a history of seizures. Discontinuation of Strattera should be considered in any patient developing seizures or if there is an increase in seizure frequency where no other cause is identified.

Cardiovascular effects.

Patients should be screened for pre-existing or underlying cardiovascular or cerebrovascular conditions before initiation of treatment with atomoxetine and monitored during the course of treatment.
Strattera can affect heart rate and blood pressure. It is recommended that heart rate and blood pressure should be measured at baseline, following Strattera dose increases, and periodically while on therapy to detect possible clinically important increases.
Most patients taking Strattera experience a modest increase in heart rate (mean < 10 bpm) and/or increase in blood pressure (< 5 mmHg) that are not clinically important. In children and adolescents, pulse increased an average of 6-8 bpm in EMs (90-95% of patients) or 10-14 bpm in PMs (5-10% of patients) and systolic or diastolic blood pressure increased an average of 2 mmHg in EMs (90-95% of patients) or 4 mmHg in PMs (5-10% of patients). Adult patients experienced a mean pulse increase of 5 bpm and/or mean increases in systolic (3 mmHg) or diastolic (1 mmHg) blood pressures (see Section 4.8 Adverse Effects (Undesirable Effects)). However, data from ADHD clinical trials show that some patients do experience clinically important changes in heart rate or blood pressure.

Paediatric.

Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 39% of paediatric patients experienced clinically relevant changes (≥ 20 beats per min) in heart rate during the study, and paediatric patients experiencing clinically relevant changes in heart rate at study endpoint were 12%; 33% of paediatric patients experienced clinically relevant changes (≥ 15 mmHg) in diastolic and 23% in systolic (≥ 20 mmHg) blood pressure during the study, and paediatric patients experiencing clinically relevant changes in diastolic and systolic blood pressure (≥ 15 and ≥ 20 mmHg) at study endpoint were 11% and 8%, respectively.

Adult.

Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 26% of adult patients experienced clinically relevant changes (≥ 20 beats per min) in heart rate during the study, and adult patients experiencing clinically relevant changes in heart rate at study endpoint were approximately 10%; 16% of adult patients experienced clinically relevant changes (≥ 15 mmHg) in diastolic and 14% in systolic (≥ 20 mmHg) blood pressure during the study, and adult patients experiencing clinically relevant changes in diastolic and systolic blood pressure (≥ 15 and ≥ 20 mmHg) at study endpoint were 7% and 6%, respectively.
Strattera should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate, such as patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease.
Strattera should not be used in patients with severe cardiovascular disorders whose condition would be expected to deteriorate if they experienced increases in blood pressure or heart rate that could be clinically important (see Section 4.3 Contraindications).
In addition, Strattera should be used with caution in patients with congenital QT prolongation, acquired QT prolongation (for example, due to concomitant use of a drug that prolongs the QT), or with a family history of QT prolongation.
A thorough QT/QTc study, conducted in healthy adult CYP2D6 poor metabolizer (PM) subjects dosed up to 60 mg of atomoxetine BID, demonstrated that at maximum expected concentrations the effect of atomoxetine on QTc interval was not significantly different from placebo. There was an increase in QTc interval with increased atomoxetine concentration (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Because orthostatic hypotension has also been reported, Strattera should be used with caution in any condition that may predispose patients to orthostatic hypotension, or conditions associated with abrupt heart rate or blood pressure changes (see Section 4.3 Contraindications).
Strattera should be used with caution in patients with a history of hyperthyroidism.

Sudden death and pre-existing structural cardiac abnormalities or other serious heart problems.

A pharmacological potential exists for all ADHD drugs to increase the risk of sudden/cardiac death. Although confirmation of an incremental risk for adverse cardiac events arising from treatment with ADHD medications is lacking, prescribers should consider this potential risk.
All drugs with sympathomimetic effects prescribed in the management of ADHD should be used with caution in patients who: a) are involved in strenuous exercise or activities, b) use stimulants, or c) have a family history of sudden/cardiac death. Strattera is a drug with peripheral sympathomimetic effects and should not generally be used in children, adolescents or adults with known structural cardiac abnormalities. Prior to the initiation of treatment, a personal and family cardiac and psychiatric history should be obtained. In patients with relevant risk factors and based on the clinician's judgment, further evaluation by a specialist should be considered.

Paediatric.

Sudden death has been reported in association with atomoxetine treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, Strattera 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 noradrenergic effects of atomoxetine.

Adults.

Sudden deaths, stroke, and myocardial infarction have been reported in adults taking atomoxetine at usual doses for ADHD. Although the role of atomoxetine 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. Consideration should be given to not treating adults with clinically significant cardiac abnormalities.

Effects on urine outflow from the bladder.

In adult ADHD controlled trials, the rates of urinary retention (3%, 7/269) and urinary hesitation (3%, 7/269) were increased among Strattera subjects compared with placebo subjects (0%, 0/263). A complaint of urinary retention or urinary hesitancy should be considered potentially related to Strattera. Use with caution in patients with enlarged prostates or other conditions predisposing to urinary retention.

Effects on growth (height and weight).

Data from longer-term trials (≥ 2 years) suggest that any effect of Strattera on growth is minimal and is most strongly associated with initiation of treatment. At 24 months, patients displayed a marked absolute mean weight gain (approximately 10.7 kg), which corresponded to a slight decrease relative to baseline normative weights (-2.8 percentiles). The decrease at endpoint from the weight that would have been reached had the baseline normative weight been maintained was 0.9 kg. At 24 months, there was also marked absolute mean height gain (approximately 13.1 cm), which corresponded to a slight decrease relative to baseline normative heights (-2.2 percentiles). The decrease at endpoint from the height predicted by baseline normative height and the mean observed height was approximately 0.5 cm.
In the placebo controlled study LYAF, a statistically significant effect was seen for both height and weight corresponding to decreases relative to baseline normative heights (-2.68 percentiles for atomoxetine group versus 0.76 for placebo group) and normative weights (-3.93 percentiles for atomoxetine group versus 5.44 percentiles for placebo group). A similar response was seen in the open label study LYAB with weight and height increases lower than normative rates (-2.0 percentile for height and -3 percentiles for weight). Analysis of effects by baseline weight and height shows that patients in the lowest quartile for weight and height are the least affected by Strattera. The potential effect of treatment with Strattera on final adult stature is unknown. Periodic monitoring of height and weight is recommended for patients requiring long-term therapy.

Effects on comorbid chronic tics or Tourette's disorder.

A randomised, double blind study of atomoxetine and placebo in paediatric outpatients with ADHD and comorbid tic disorders, showed that Strattera did not worsen tics in patients with ADHD and comorbid chronic motor tics or Tourette's disorder (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
There have been very rare postmarketing reports of tics with Strattera treatment (see Section 4.8 Adverse Effects (Undesirable Effects), Adverse events based on postmarketing reports).

Effects on comorbid anxiety.

Two randomised, double blind, placebo controlled studies of Strattera, one in children and adolescents with ADHD and comorbid anxiety and one in adults with comorbid social anxiety disorder, showed that Strattera did not worsen anxiety in patients with ADHD and comorbid anxiety (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
There have been rare postmarketing reports of anxiety with Strattera treatment (see Section 4.8 Adverse Effects (Undesirable Effects), Adverse events based on postmarketing reports).

Hepatic effects.

Postmarketing reports indicate that Strattera can cause severe liver injury in rare cases, including acute liver failure. Very rarely, spontaneous reports of liver injury, manifested by elevated hepatic enzymes and bilirubin with jaundice, have been reported. More than 2 million patients have received Strattera during the first two years of global postmarketing experience. During such time, there have been two reported cases of markedly elevated hepatic enzymes and bilirubin, in the absence of other obvious explanatory factors. In one of these cases, liver injury recurred upon rechallenge, and was followed by recovery upon drug discontinuation. The patients described above recovered from their liver injury. Such reactions may occur several months after therapy is started, but laboratory abnormalities may continue to worsen for several weeks after drug is stopped.
As with other medications which can cause severe drug related liver injury, it is possible that a small percentage of patients may progress to acute liver failure resulting in death or the need for a liver transplant.
Strattera should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be conducted on the first symptom or sign of liver dysfunction (e.g. pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained flu-like symptoms).

Use in the elderly.

The safety and efficacy of Strattera in elderly patients (over 65) have not been established.

Paediatric use.

The safety and efficacy of Strattera in paediatric patients less than 6 years of age have not been established. The safety and efficacy of Strattera has been established in acute studies (up to 9 weeks) and long-term studies (up to 2 years). When considering treatment with Strattera for extended periods, physicians should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Section 4.2 Dose and Method of Administration, Maintenance/extended treatment).
Young rats were treated with atomoxetine to evaluate effects on growth and neurobehavioural and sexual development. Rats were treated with 1, 10 and 50 mg/kg/day atomoxetine (0.1, 1 and 6 times, respectively, the maximum paediatric dose on a mg/m2 basis) by gavage from the early postnatal period (day 10 of age) through adulthood (day 85 of age). Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg) and a slight decrease in corpora lutea (50 mg/kg) were noted, but there were no effects on fertility or reproductive performance. A slight delay in onset of incisor eruption was seen at 50 mg/kg. A slight increase in motor activity was seen on day 15 (males given 10 and 50 mg/kg) and on day 30 (females at 50 mg/kg) but not on day 60 of age. There were no effects on learning and memory tests. The significance of these findings in humans is unknown.

Effects on laboratory tests.

No information is available on the effect of Strattera on laboratory tests.

Male and female sexual dysfunction.

Atomoxetine appears to inhibit sexual function in some patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them.

Drug abuse and dependence.

Physical and psychological dependence.

A randomised, double blind, placebo controlled, abuse potential study was conducted in recreational drug users (n = 16) of the ages 18 to 36 who did not meet DSM-IV criteria for substance abuse. Atomoxetine was administered in single doses. The study results suggest that Strattera does not have a significant potential for abuse.
Clinical study data in over 3000 children, adolescents and adults with ADHD and over 1200 adults with depression did not demonstrate any pattern of drug diversion or inappropriate self administration associated with Strattera. There was no evidence of symptom rebound or adverse events suggesting a drug discontinuation or withdrawal syndrome.

Study LYBO.

A randomised, double blind, placebo and comparator controlled study compared the subjective, euphoriant effects of Strattera at doses of 45 mg, 90 mg and 180 mg with placebo, methylphenidate (90 mg), phentermine (60 mg free base), and desipramine (100, 200 mg) in 40 drug abusing adults with the extensive metaboliser (EM) genotype for cytochrome P450 2D6 (CYP2D6) substrates. This patient group did not report euphoriant effects from use of Strattera.

Animal experience.

Drug discrimination studies in rats and monkeys showed inconsistent stimulus generalisation between atomoxetine and cocaine. Atomoxetine substituted for the discriminative stimulus effect of cocaine in some monkeys (0.6-5.6 mg/kg, 0.1-0.8 times the maximum adult dose on a mg/m2 basis) and rats (at 5-50 mg/kg, 0.4-3.8 times the maximum adult dose on a mg/m2 basis). The main 4-hydroxyatomoxetine metabolite has moderate affinity (Ki 95-422 nanoM) for opioid receptors.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6 and CYP2C9. Using in vitro preparations, atomoxetine and N-desmethylatomoxetine are predicted to inhibit the activities of cytochrome P450 enzymes CYP2D6, CYP3A and CYP2C9 (predicted inhibition is 65%, 73% and 16% at maximum dose, respectively). However, in clinical studies evaluating the coadministration of atomoxetine with desipramine, a model compound for CYP2D6 metabolised drugs, or midazolam, a model compound for CYP3A4 metabolised drugs, atomoxetine did not significantly alter the pharmacokinetics of these model compounds. Atomoxetine is principally metabolised by the CYP2D6 pathway. In CYP2D6 extensive metabolisers, inhibitors of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in CYP2D6 poor metabolisers. In extensive metabolisers, selective inhibitors of CYP2D6 increased atomoxetine steady-state plasma concentrations to exposures less than or similar to those observed in poor metaboliser subjects. This pharmacokinetic interaction did not result in an increased sensitivity to Strattera.
In vitro studies suggest that several CYP isoforms are involved in the formation of 4-hydroxyatomoxetine in CYP2D6 poor metabolisers (including CYP2B6, CYP2C19 and CYP2E1) and, therefore, coadministration of cytochrome P450 inhibitors may not markedly increase the circulating plasma concentration of atomoxetine.

Fluoxetine, paroxetine or quinidine.

Administration of Strattera to patients taking fluoxetine, paroxetine or quinidine, known inhibitors of CYP2D6, resulted in a higher plasma exposure to atomoxetine. In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css,max is about 3- to 4-fold greater than atomoxetine alone.
A thorough QT/QTc study, conducted in healthy adult CYP2D6 poor metabolizer (PM) subjects dosed up to 60 mg of atomoxetine BID, demonstrated that at maximum expected concentrations the effect of atomoxetine on QTc interval was not significantly different from placebo. There was an increase in QTc interval with increased atomoxetine concentration (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use, Cardiovascular effects).
In postmarketing reports, QT prolongation has been very rarely reported amongst patients taking Strattera in overdose, and in conjunction with CYP2D6 inhibitors such as fluoxetine, paroxetine or quinidine. Concomitant administration of Strattera with drugs that prolong QT interval, drugs that cause electrolyte disturbance and drugs that inhibit CYP2D6 is cautioned. Dosage adjustment of Strattera may be necessary in those patients who are also taking CYP2D6 inhibitor drugs (see Section 4.2 Dose and Method of Administration, Dosing adjustment for use with a strong CYP2D6 inhibitor).

Methylphenidate.

Coadministration of methylphenidate with Strattera did not increase cardiovascular effects beyond those seen with methylphenidate administration alone.

Midazolam.

Coadministration of Strattera with midazolam resulted in small increases in midazolam plasma concentrations. These changes were smaller than those caused by weak inhibitors of CYP3A and, therefore, no dose adjustment is recommended for drugs metabolised by CYP3A.

Monoamine oxidase inhibitors.

See Section 4.3 Contraindications.

Antihypertensive drugs and pressor agents.

Because of possible effects on blood pressure, Strattera should be used cautiously with antihypertensive drugs and pressor agents or other drugs that increase blood pressure.

Drugs that affect noradrenaline.

Drugs that affect noradrenaline such as α1-agonists or those that inhibit the reuptake of noradrenaline should be used cautiously when coadministered with Strattera because of the potential for additive or synergistic pharmacological effects.

Beta-adrenergic receptor agonists.

Strattera should be administered with caution to patients being treated with systemically administered (oral or intravenous) salbutamol (or other beta2-agonists) because the action of salbutamol on the cardiovascular system can be potentiated.

Tricyclic antidepressants.

Strattera can increase the adverse cardiovascular effects of tricyclic antidepressants if coadministered.
Desipramine (a tricyclic antidepressant) pharmacokinetics, which are dependent on CYP2D6 metabolism, were not altered by steady-state atomoxetine concentrations. However, these drugs should not be used in combination because one of desipramine's effects is to block noradrenaline reuptake.

Drugs highly bound to plasma protein.

In vitro drug displacement studies were conducted with atomoxetine and other highly bound drugs at therapeutic concentrations. Atomoxetine did not affect plasma protein binding of acetylsalicylic acid, desipramine or warfarin to human plasma proteins. However, atomoxetine increased the fraction of unbound diazepam (by 60%), paroxetine (by 19%) and phenytoin (by 11%). Desipramine, diazepam, paroxetine, phenytoin, midazolam and warfarin did not change the fraction of atomoxetine bound to plasma proteins. High concentrations of acetylsalicylic acid (≥ 300 microgram/mL) caused up to a 3-fold increase in the unbound fraction of atomoxetine.

Drugs that affect gastric pH.

Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on Strattera bioavailability.

Alcohol.

Consumption of ethanol with Strattera did not change the intoxicating effects of ethanol.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Atomoxetine hydrochloride did not impair fertility when administered to rats from 10 days of age through adulthood at oral doses up to 50 mg/kg/day (up to 7 times the maximum recommended daily oral dose in children and 4 times the maximum recommended daily oral dose in adults, on a mg/m2 basis). In addition, there was no evidence of impaired fertility in two studies in adult rats given atomoxetine in the diet at time weighted average doses up to 57 mg/kg/day in males and 46 mg/kg/day in females (up to 6-8 times the maximum recommended daily oral dose in children and 4 times the maximum recommended daily oral dose in adults, on a mg/m2 basis).
(Category B3)
Pregnant rabbits were treated orally with up to 100 mg/kg/day atomoxetine throughout the period of organogenesis. At this dose, a decrease in live fetuses and/or an increase in early resorptions were observed, along with evidence of slight maternal toxicity. Slight increases in the incidences of major blood vessel variations were observed in 1 of 3 studies; the no effect dose for the cardiovascular findings was 30 mg/kg/day. The 100 mg/kg/day dose is 14 times the maximum human dose on a mg/m2 basis; exposure (plasma AUC) to active moiety (atomoxetine + 4-hydroxyatomoxetine) at this dose is estimated to be less than that in extensive metabolisers or poor metabolisers receiving the maximum human adult dose.
Rats were treated with up to 57 (males) and 46 (females) mg/kg/day of atomoxetine (4 times the maximum human adult dose on a mg/m2 basis) in the diet from 2 (females) or 10 (males) weeks prior to mating through the periods of organogenesis and lactation. In one study, decreases in fetal and pup bodyweight and fetal skeletal anomalies were seen at 41-98 mg/kg/day (3-7 times the maximum tolerated human adult dose on a mg/m2 basis) along with maternal toxicity and incisor overgrowth/teeth clipped was seen at 7 mg/kg/day or greater. In a second study, decreases in pup weight were seen at 46-70 mg/kg/day (4-5 times the maximum human adult dose on a mg/m2 basis) and reduced pup survival at 23-39 mg/kg/day (2-3 times the maximum adult dose on a mg/m2 basis) along with maternal toxicity. No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (11 times the maximum human dose on a mg/m2 basis) by gavage during the period of organogenesis only.
No adequate and well controlled studies have been conducted in pregnant women. Strattera should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.

Labour and delivery.

Parturition (gestational length or live birth indices) in rats was not affected by atomoxetine. The effect of Strattera on labour and delivery in humans is unknown.
Atomoxetine and/or its metabolites are excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Treatment of rats with atomoxetine prior to mating through the periods of organogenesis and lactation was associated with adverse effects on pups (see Use in pregnancy). Caution should be exercised if Strattera is administered to a nursing woman.

4.7 Effects on Ability to Drive and Use Machines

Patients should be advised to use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by Strattera.

4.8 Adverse Effects (Undesirable Effects)

Adverse events identified from clinical trials.

Strattera was administered to over 3000 children or adolescent patients with ADHD and over 470 adults with ADHD in clinical studies. During the ADHD clinical trials, 1236 children or adolescent patients and 173 adult patients were treated for longer than 1 year, 1704 children or adolescent patients and 236 adult patients were treated for over 6 months.
Adverse events associated with discontinuation of treatment. In acute child and adolescent placebo controlled trials, 3.5% (15/427) of atomoxetine subjects and 1.4% (4/294) placebo subjects discontinued for adverse events. For all studies, (including open label and long-term studies), 5% of extensive metaboliser (EM) patients and 7% of poor metaboliser (PM) patients discontinued because of an adverse event. Among Strattera treated patients, aggression (0.5%, N = 2), irritability (0.5%, N = 2), somnolence (0.5%, N = 2) and vomiting (0.5%, N = 2) were the reasons for discontinuation reported by more than 1 patient.
In the acute adult placebo controlled trials, 8.5% (23/270) atomoxetine subjects and 3.4% (9/266) placebo subjects discontinued for adverse events. Among Strattera treated patients, insomnia (1.1%, N = 3), chest pain (0.7%, N = 2), palpitations (0.7%, N = 2) and urinary retention (0.7%, N = 2) were the reasons for discontinuation reported by more than 1 patient.
Child and adolescent clinical trials. The most commonly observed adverse events associated with the use of Strattera (incidence of 2% or greater) and not observed at an equivalent incidence among placebo treated patients (Strattera incidence at least twice placebo) are listed in Table 1.
The following events did not meet this criteria but were reported by more atomoxetine treated patients than placebo treated patients and are possibly related to atomoxetine treatment.
Very common (≥ 10%): abdominal pain (includes abdominal pain upper, stomach discomfort, abdominal discomfort, and epigastric discomfort), vomiting, nausea, blood pressure increased, heart rate increased (heart rate and blood pressure are based on measured vital signs from clinical trials), somnolence (including sedation).
Common (≥ 1% and < 10%): anorexia, insomnia (also includes initial insomnia, middle insomnia, and terminal insomnia), irritability, mydriasis, pruritus, rash, weight decreased, depression (also includes major depression, depressive symptoms, depressed mood, and dysphoria).
Uncommon (≥ 0.1% and < 1%): flushing, palpitations, sinus tachycardia, conjunctivitis, syncope (also includes syncope vasovagal), tremor.
In a post hoc meta-analysis of the placebo controlled paediatric clinical trial database, suicidal ideation (suicidal thoughts) was statistically more frequently observed among children and adolescents treated with Strattera (5/1357; 0.4%) compared to those treated with placebo (0/851; 0%). There was one report of suicidal behaviour in a patient in this age group treated with Strattera compared with no reports in patients treated with placebo (see Section 4.4 Special Warnings and Precautions for Use, Suicidal ideation and behaviour).
Adverse events that occurred after acute treatment were assessed in study LYAF. Table 2 presents new or worsened adverse events in patients who after an initial 3 month period continued on Strattera for 9 months or who were switched to placebo.
The following events did not meet this criterion but were reported by more atomoxetine treated patients than placebo treated patients and are possibly related to atomoxetine treatment.
Very common (≥ 10%): headache, nausea.
Common (≥ 1% and < 10%): constipation, fatigue, pyrexia, irritability, rash.
Uncommon (≥ 0.1% and < 1%): palpitations, sinus tachycardia, tachycardia, asthenia, pruritus.
The following adverse events occurred in at least 2% of child and adolescent CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared with CYP2D6 extensive metaboliser (EM) patients: weight decreased (7.3% of PMs, 4.4% of EMs), constipation (6.8% of PMs, 4.3% of EMs), insomnia (11% of PMs, 6.1% of EMs), depression (6.5% of PMs, 4.1% of EMs), tremor (4.5% of PMs, 0.9% of EMs); middle insomnia (2.8% of PMs, 1.3% of EMs); syncope (2.5% of PMs, 0.7% of EMs); conjunctivitis (2.5% of PMs, 1.2% of EMs); early morning awakening (2.3% of PMs, 0.8% of EMs); mydriasis (2.0% of PMs, 0.6% of EMs); sedation (3.9% of PMs, 2.1% of EMs).

Growth.

Paediatric patients treated with atomoxetine in ADHD clinical trials had a mean initial decrease in weight and height gain. Subsequently, over the long-term period, patients recovered to the mean weight and height predicted by group baseline data.
Adult clinical trials. The most commonly observed adverse events associated with the use of Strattera (incidence of 2% or greater) and not observed at an equivalent incidence among placebo treated patients (Strattera incidence at least twice placebo) are listed in Table 3.
The following events did not meet this criterion but were reported by more atomoxetine treated patients than placebo treated patients and are possibly related to atomoxetine treatment.
Very common (≥ 10%): blood pressure increased, heart rate increased (heart rate and blood pressure are based on measured vital signs from clinical trials).
Common (≥ 1% and < 10%): abdominal pain (includes abdominal pain upper, stomach discomfort, abdominal discomfort, and epigastric discomfort), rash, dyspepsia, terminal insomnia, ejaculation disorder, ejaculation failure, fatigue, lethargy, tachycardia, paraesthesia, chills, vomiting, asthenia, feeling jittery, irritability, thirst, dysgeusia, somnolence (including sedation), tremor, agitation, pollakiuria, testicular pain1, flushing, urine flow decreased.
Uncommon (≥ 0.1% and < 1%): peripheral coldness, feeling cold, muscle spasms, restlessness, micturition urgency, pruritus, urticaria, blurred vision.
The following adverse events occurred in at least 2% of adult CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metaboliser (EM) patients: vision blurred (3.9% of PMs, 1.3% of EMs); dry mouth (34.5% of PMs, 17.4% of EMs); constipation (11.3% of PMs, 6.7% of EMs); feeling jittery (4.9% of PMs, 1.9% of EMs), decreased appetite (23.2% of PMs, 14.7% of EMs); tremor (5.4% of PMs, 1.2% of EMs); insomnia (19.2% of PMs, 11.3% of EMs); sleep disorder (6.9% of PMs, 3.4% of EMs); middle insomnia (5.4% of PMs, 2.7% of EMs); terminal insomnia (3.0% of PMs, 0.9% of EMs); urinary retention (5.9% of PMs, 1.2% of EMs); erectile dysfunction (20.9% of PMs, 8.9% of EMs); ejaculation disorder (6.1% of PMs, 2.2% of EMs); hyperhidrosis (14.8% of PMs, 6.8% of EMs); peripheral coldness (3.0% of PMs, 0.5% of EMs).

Adverse events based on postmarketing reports.

The following list of undesirable effects (adverse drug effects) is based on postmarketing spontaneous reports and corresponding reporting rates have been provided.

General disorders and administration site conditions.

Very rare (< 0.01%): lethargy.

Psychiatric.

Rare (> 0.01% to < 0.1%): completed suicide, suicide attempt, suicidal ideation, aggression/hostility, psychosis/mania, anxiety, depression and depressed mood. Very rare (< 0.01%): sensory disturbances including hallucinations.
As of October 2005, the reporting rate of suicidal and self injurious behaviours was 0.0126% (or about 1/8000) from a cumulative exposure of approximately 3.4 million patients.

Vascular disorders.

Very rare (< 0.01%): peripheral vascular instability and/or Raynaud's phenomenon, potential to exacerbate pre-existing Raynaud's phenomenon.

Urogenital system.

Very rare (< 0.01%): painful or prolonged erection, male genital pain, urinary hesitation in children and adolescents, urinary retention in children and adolescents.

Cardiovascular system.

Very rare (< 0.01%): QT prolongation, syncope. Rare (> 0.01% to < 0.1%): blood pressure increased.

Nervous system.

Very rare (< 0.01%): seizures, paraesthesia in children and adolescents, hypoaesthesia, tics.

Skin and subcutaneous tissue disorders.

Very rare (< 0.01%): hyperhydrosis.

Reporting suspected adverse effects.

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

During postmarketing overseas, there have been no fatalities involving overdose with Strattera alone, including intentional overdoses at amounts up to or exceeding 1500 mg. The most commonly reported symptoms accompanying acute and chronic overdoses were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behaviour. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g. tachycardia, blood pressure increased, mydriasis, dry mouth) were also observed. Most events were mild to moderate. In some cases of overdose involving Strattera, seizures and QT prolongation have been reported. There have also been reports of fatal, acute overdoses involving mixed ingestion of Strattera and at least one other drug. There is limited clinical trial experience with Strattera overdose.
No specific information is available on the treatment of overdose with Strattera. Patients who overdose with atomoxetine should be monitored carefully and receive supportive care. Activated charcoal may be useful in limiting absorption. Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Dialysis is not likely to be useful in the treatment of overdose because Strattera is highly protein bound.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Strattera is a treatment for attention deficit hyperactivity disorder (ADHD). ADHD was formerly known as attention deficit disorder (ADD) with or without hyperactivity. Atomoxetine is a relatively potent inhibitor of the presynaptic noradrenaline transporter (Ki 4.5 nanoM), a moderate inhibitor of 5HT uptake (Ki 152 nanoM) and a weak inhibitor of dopamine uptake (Ki 658 nanoM), with minimal affinity for the other noradrenergic receptors. Atomoxetine has moderate affinity for 5HT2 and GABAA receptors but poor affinity for most other receptors. The main hydroxyatomoxetine metabolite is equipotent to the parent compound at the noradrenaline transporter (Ki 3.0 nanoM), and a more potent inhibitor of the 5HT transporter (Ki 43 nanoM) than the parent compound.
A thorough QT/QTc study, conducted in healthy adult CYP2D6 poor metabolizer (PM) subjects dosed up to 60 mg of atomoxetine BID, demonstrated that at maximum expected concentrations the effect of atomoxetine on QTc interval was not significantly different from placebo. There was an increase in QTc interval with increased atomoxetine concentration (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use, Cardiovascular effects; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Clinical trials.

The efficacy of Strattera for the treatment of ADHD in children and adolescents (age 6 to 17 years) meeting the Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria was satisfactorily established in four short-term (6-9 weeks), randomised, double blind, placebo controlled studies; one long-term (9 months), randomised, double blind, placebo controlled study; and one long-term (2 years), open label study. The efficacy of Strattera for the treatment of ADHD in adults (18 years of age and older) meeting DSM-IV criteria and with a childhood history of ADHD was established in two short-term (10 weeks), randomised, double blind, placebo controlled studies; and one long-term (up to 2 years), open label study. There are no long-term, randomised, double blind, placebo controlled studies in adults.
Children and adolescents. The efficacy of Strattera in the treatment of ADHD was established in four acute, randomised, double blind, placebo controlled studies of paediatric patients (ages 6 to 17) who met DSM-IV criteria for ADHD (studies LYAC, LYAT, HFBD, HFBK). Approximately one-third of the patients met DSM-IV criteria for inattentive subtype and two-thirds met criteria for both inattentive and hyperactive/impulsive subtypes.
Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for Strattera treated and placebo treated patients using an intent to treat analysis. The primary outcome measure was the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS) total score including hyperactive/impulsive and inattentive subscales. Each item on the ADHDRS maps directly to one symptom criterion for ADHD in the DSM-IV.

Study LYAC.

An 8 week randomised, double blind, placebo controlled acute treatment study of children and adolescents aged 8 to 18 (N = 297), patients received either a fixed dose of Strattera (0.5 mg/kg/day, 1.2 mg/kg/day or 1.8 mg/kg/day) or placebo. Strattera was administered as a divided dose in the early morning and late afternoon/early evening. Treatment with Strattera showed an overall improvement in the reductions from baseline in mean ADHDRS total score. The average score decreased by 25% on Strattera 0.5 mg/kg/day, 35% on 1.2 mg/kg/day and 34% on 1.8 mg/kg/day, compared to 15% with placebo. At the two higher doses, improvements in ADHD symptoms were superior and statistically significant (p < 0.001 vs placebo) in Strattera treated patients compared with placebo treated patients as measured on the ADHDRS scale. The results of study LYAC are summarised in Figure 1.

Study LYAT.

A 6 week randomised, double blind, placebo controlled acute treatment study of children and adolescents aged 6 to 16 (N = 171), patients received either Strattera or placebo. Strattera was administered as a single dose in the early morning and titrated on a weight adjusted basis according to clinical response. The maximum Strattera dose was 1.5 mg/kg/day. The mean final dose of Strattera was approximately 1.3 mg/kg/day. Treatment with Strattera showed an overall improvement in the reductions from baseline in mean ADHDRS total score. The average score decreased by 34% on Strattera, compared to 13% with placebo (p < 0.001 vs placebo). Improvements in ADHD symptoms were superior and statistically significant in Strattera treated patients compared with placebo treated patients as measured on the ADHDRS scale beginning at one week and through the end of the study. This study demonstrates that Strattera is effective when administered once daily in the morning. The results of study LYAT are summarized in Figure 2.

Studies HFBD and HFBK.

In two identical, 9 week, acute, randomised, double blind, placebo controlled studies of children aged 7 to 13 (study HFBD, N = 147; study HFBK, N = 144), Strattera or methylphenidate was compared with placebo. Methylphenidate was only used to show that the study design was valid (i.e. by its separation from placebo). These studies were not statistically powered to provide a comparative analysis between Strattera and methylphenidate (patient numbers per treatment, study HFBD, Strattera N = 65, methylphenidate N = 20, placebo N = 62; study HFBK, Strattera N = 64, methylphenidate N = 18, placebo N = 62). The primary comparison of interest in both studies was Strattera versus placebo. Strattera was administered as a divided dose in the early morning and late afternoon (after school) and titrated on a weight adjusted basis according to clinical response. The maximum recommended Strattera dose was 2.0 mg/kg/day. The mean final dose of Strattera for both studies was approximately 1.6 mg/kg/day. Treatment with Strattera showed an overall improvement from baseline in mean ADHDRS total score. The average score decreased by 38% on Strattera, compared to 13% with placebo (p < 0.0001 vs placebo) in study HFBD and 38% on Strattera, compared to 16% with placebo (p < 0.0003 vs placebo) in study HFBK.

Study LYAF.

Study LYAF was a two stage relapse prevention study in children and adolescents who met DSM-IV criteria for ADHD. In this study, patients were treated for 12 weeks with Strattera and responders were randomised to a further 40 weeks of treatment discontinuation phase (Strattera N = 292, placebo N = 124). At endpoint (1 year), Strattera was superior to placebo in maintaining clinical response (see Kaplan-Meier plot provided as Figure 3). The relapse rate was 18.7% on Strattera versus 31.4% on placebo (p = 0.021 all qualified patients).

Study LYAB.

Study LYAB was a multicentre open label safety and efficacy study in children and adolescents who met DSM-IV criteria for ADHD. In this study patients were treated for 10 weeks with Strattera (study period II) and responders were eligible to enter a long-term treatment phase of up to 2 years (study period III) (N = 301 completing long-term treatment). On average, symptoms of ADHD in Strattera treated patients decreased by 48.5% as measured by the ADHD rating scale total score for study periods II and III. Strattera was well tolerated in this long-term safety study and adverse events did not increase over time. The adverse event profile for poor metaboliser patients was similar to that for extensive metaboliser patients with a similar tolerability profile as described in the short-term studies.
Examination of population subsets (gender, age or prior stimulant treatment) did not reveal any differential responsiveness on the basis of these subgroupings.

Study LYBP.

A randomised, double blind, placebo controlled study to assess the efficacy of Strattera compared with placebo in children and adolescents with ADHD and comorbid anxiety. Patients enrolled in the trial met the DSM-IV criteria for ADHD and also had at least one of the following anxiety disorders: separation anxiety disorder, generalised anxiety disorder, or social phobia. The study confirmed the efficacy of Strattera in treating the core symptoms of ADHD as evidenced by the statistically significant improvement in the prespecified coprimary measure for ADHD (ADHDRS) (see Section 4.4 Special Warnings and Precautions for Use, Effects on comorbid anxiety).

Study LYAS.

A randomised, double blind, placebo controlled study of Strattera in children and adolescents with ADHD and comorbid Tourette's disorder or chronic motor tics. Patients were aged 7 to 17 years 6 months and met the DSM-IV criteria for ADHD with comorbid Tourette's disorder or chronic motor tics. Consistent with other studies, Strattera produced a significant improvement in ADHD symptoms as measured by the ADHDRS and CGI-ADHD-S (see Section 4.4 Special Warnings and Precautions for Use, Effects on comorbid chronic tics or Tourette's disorder).
Adults. The efficacy of Strattera in the treatment of ADHD was established in two randomised, double blind, placebo controlled clinical studies of adult patients age 18 and older who met DSM-IV criteria for ADHD.
Signs and symptoms of ADHD were evaluated using the investigator administered Conners Adult ADHD Rating Scale Screening Version (CAARS), a 30 item scale. The primary efficacy measure was the 18 item Total ADHD Symptom score (the sum of the inattentive and hyperactivity/impulsivity subscales) evaluated by a comparison of mean change from baseline to endpoint using an intent to treat analysis.

Studies LYAA and LYAO.

In two identical, 10 week, randomised, double blind, placebo controlled acute treatment studies (study LYAA, N = 280; study LYAO, N = 256), patients received either Strattera or placebo. Strattera was administered as a divided dose in the early morning and late afternoon/early evening and titrated according to clinical response. The maximum Strattera dose was 120 mg/day. The mean final dose of Strattera for both studies was approximately 95 mg/day. Treatment with Strattera showed an overall improvement from baseline in mean CAARS total score. The average score decreased by 28% on Strattera, compared to 18% with placebo (p < 0.001 vs placebo) in study LYAA and 30% on Strattera, compared to 20% with placebo (p < 0.001 vs placebo) in study LYAO. In both studies, improvements in ADHD symptoms were superior and statistically significant in Strattera treated patients compared with placebo treated patients as measured on the CAARS scale.

Study LYAR.

Study LYAR was an open label, multicentre investigation of the long-term safety and tolerability of Strattera in patients aged 18 years or older who meet the DSM-IV criteria for ADHD. This was an open label extension of the LYAA and LYAO studies. Average symptom severity decreased by 30.6% (p < 0.001) as measured by the CAARS investigator rated scale for 18 item total ADHD symptoms. The adverse event profile was similar to that observed in short-term studies with most treatment emergent adverse events reported to be of mild or moderate severity.
Examination of population subsets (gender, age, prior stimulant treatment or CYP2D6 metabolic status) did not reveal any differential responsiveness on the basis of these subgroupings.

Study LYDQ.

Study LYDQ was a randomised, double blind, placebo controlled study of Strattera in adults (18-65 years) with ADHD and comorbid social anxiety disorder. Patients enrolled in the trial met the DSM-IV criteria for ADHD and social anxiety disorder. Patients showed statistically significant mean change improvements over placebo treated patients from baseline to endpoint on the CAARS investigator rated scale. See Section 4.4 Special Warnings and Precautions for Use, Effects on comorbid anxiety.

Cardiac electrophysiology.

The effect of atomoxetine on QTc prolongation was evaluated in a randomised, double blinded, positive (moxifloxacin 400 mg) and placebo controlled, crossover study in healthy male CYP2D6 poor metabolizers. A total of 120 healthy subjects were administered atomoxetine (20 mg and 60 mg) twice daily for 7 days. Although a statistically significant increase in QTc was associated with increasing plasma concentrations, atomoxetine was not associated with a clinically significant change in QTc (see Section 5.1 Pharmacodynamic Properties; Section 4.4 Special Warnings and Precautions for Use, Cardiovascular effects; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

5.2 Pharmacokinetic Properties

Single dose and steady-state individual pharmacokinetic data were obtained in children, adolescents and adults. After administration of the same mg/kg dose to children, adolescents and adults, similar half-life, Cmax and AUC values were observed. Clearance and volume of distribution after adjustment for bodyweight were also similar.

Absorption.

Atomoxetine is rapidly and almost completely absorbed after oral dosing reaching mean maximal observed plasma concentration (Cmax) approximately 1 to 2 hours after dosing. The Cmax observed after a single 1 mg/kg dose of atomoxetine is 568 nanogram/mL (range of 92 to 1544 nanogram/mL).
Strattera can be administered with or without food. In clinical trials with children and adolescents, administration of Strattera with food resulted in a 9% lower Cmax. Administration of Strattera with a standard high fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption resulting in a 37% lower Cmax. After a high fat meal, the Tmax was approximately 4 hours after dosing (range of 0.5-16 hours for high fat; 0.5-6 hours for fasting).
Following oral administration of Strattera, a lower absolute bioavailability (63%) after modest first-pass metabolism was observed in extensive CYP2D6 metabolisers, while a higher absolute bioavailability (94%) was observed in poor CYP2D6 metabolisers.

Distribution.

The steady-state volume of distribution after intravenous administration was approximately 0.85 L/kg indicating atomoxetine distributes primarily into total body water. In children and adolescents, volume of distribution increased nearly proportionally to increases in bodyweight. Volume of distribution was similar across the patient weight range after normalising for bodyweight.
At therapeutic concentrations, 98.5% of atomoxetine in plasma is bound to protein, primarily albumin.

Metabolism.

Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. There are two major phenotypes associated with CYP2D6: extensive metabolisers (93% of Caucasians and 98% of African Americans) and poor metabolisers (7% of Caucasians and 2% of African Americans). The major oxidative metabolite formed, regardless of CY2D6 status, is 4-hydroxyatomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine at inhibiting noradrenaline uptake and is slightly more potent at inhibiting 5HT uptake than the parent compound. This metabolite circulates in plasma at much lower concentrations but it is also less plasma protein bound (66%) than the parent compound (98.5%), so that in extensive metabolisers the exposure to unbound 4-hydroxyatomoxetine exceeds exposure to unbound atomoxetine. Although 4-hydroxyatomoxetine is primarily formed by CYP2D6, in individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine can be formed by several other cytochrome P450 enzymes, but at a slower rate. N-desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has a much less pharmacological activity than atomoxetine and plasma concentrations are lower (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs).
People with reduced activity in the CYP2D6 pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine and quinidine also cause increases in exposure. Atomoxetine does not inhibit or induce the CYP2D6 pathway.
Coadministration of Strattera with known inhibitors of CYP2D6 does not result in an increased sensitivity to Strattera, although it may result in higher atomoxetine plasma exposure.
Adjustment of dosing regimens based on metabolism through the CYP2D6 pathway is not necessary.

Excretion.

The mean elimination half-life of atomoxetine after oral administration is 3.6 hours in extensive metabolisers and 21 hours in poor metabolisers. Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine.
Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. The elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours).
Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the faeces (less than 17% of the dose). Only a small fraction of the Strattera dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation.

Special populations.

Hepatic impairment.

Single doses of Strattera were administered to subjects with moderate to severe hepatic impairment (Child-Pugh class B and C) resulting in reduced atomoxetine clearance, increased atomoxetine exposure (AUC) (2-fold increase for Child-Pugh class B and 4-fold increase for Child-Pugh class C) and prolonged half-life of parent drug compared with healthy subjects. However, the maximum exposure observed in subjects with hepatic impairment did not exceed that observed in the population of healthy CYP2D6 poor metabolisers. Dosage adjustment is recommended for patients with moderate or severe hepatic impairment (see Section 4.2 Dose and Method of Administration, Hepatic impairment dosage adjustment).

Renal impairment.

Single doses of Strattera were administered to subjects with endstage renal disease, resulting in higher atomoxetine exposure (AUC) than in healthy subjects (about a 65% increase). However, the maximum exposure observed in subjects with endstage renal disease did not exceed that observed in the population of healthy CYP2D6 poor metabolisers. Strattera may exacerbate hypertension in patients with endstage renal disease. For those ADHD patients who have endstage renal disease, cautious titration of Strattera to the desired clinical response is recommended, with particular attention to those with hypertension who may experience deterioration in the control of their blood pressure.

Elderly.

The pharmacokinetics of atomoxetine have not been evaluated in the elderly population (over 65).

Paediatric.

The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine have not been evaluated in children under 6 years of age.

Gender.

Gender did not influence atomoxetine disposition.

Ethnic origin.

Ethnic origin did not influence atomoxetine disposition (except that PMs are more common in Caucasians than in African Americans).

5.3 Preclinical Safety Data

Genotoxicity.

Atomoxetine hydrochloride was not genotoxic in a battery of tests including bacterial reverse mutation assays, a mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, in vivo micronucleus test in mice, unscheduled DNA synthesis test in rat hepatocytes and in vivo sister chromatid exchange test in bone marrow of Chinese hamsters. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration). The metabolite N-desmethylatomoxetine hydrochloride was negative in the Ames test, mouse lymphoma assay and unscheduled DNA synthesis test.

Carcinogenicity.

Atomoxetine hydrochloride was not carcinogenic in rats and mice when given in the diet for 2 years. The time-weighted average doses of up to 47 and 458 mg/kg/day were approximately 6 (rat) and 30 (mouse) times the maximum recommended daily oral dose in children and approximately 4 (rat) and 17 (mouse) times the maximum recommended daily oral dose in adults, on a mg/m2 basis. Systemic exposure (plasma AUC) to active moiety (atomoxetine + 4-hydroxyatomoxetine) in rats was estimated to be less than that in extensive or poor metabolisers receiving the maximum dose, and exposure in mice was estimated to be 1 to 3 times that in extensive metabolisers but less than that in poor metabolisers.

6 Pharmaceutical Particulars

6.1 List of Excipients

Pregelatinised maize starch, dimethicone 350, gelatin, sodium lauryl sulfate, titanium dioxide, edible black ink (TekPrint SW-9008 or SW-9010), indigo carmine CI73015 (25 mg, 40 mg and 60 mg only), yellow iron oxide CI77492 (5 mg, 18 mg, 60 mg, 80 and 100 mg only), red iron oxide CI77491 (80 and 100 mg only).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

The recommended storage condition for the capsules is in a cool dry place where the temperature stays below 25°C.

6.5 Nature and Contents of Container

Capsules containing 5 mg*, 10 mg, 18 mg, 25 mg, 40 mg, and 60 mg atomoxetine (as hydrochloride) in packs of 7.
Capsules containing 5 mg*, 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg and 100 mg atomoxetine (as hydrochloride) in packs of 28.
* Not currently available.

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

Chemical structure.

The active ingredient in Strattera capsules is atomoxetine hydrochloride.
Atomoxetine hydrochloride is a white to practically white solid which has a solubility of 27.8 mg/mL in water.
Chemically, Strattera is (R)-(-)-N-methyl-γ-(2-methylphenoxy)-benzenepropanamine hydrochloride. The empirical formula is C17H21NO.HCl which corresponds to a molecular weight of 291.82 daltons.
The chemical structure is:

CAS number.

The CAS number for atomoxetine hydrochloride is 82248-59-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes