Consumer medicine information

Champix

Varenicline

BRAND INFORMATION

Brand name

Champix

Active ingredient

Varenicline

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Champix.

SUMMARY CMI

CHAMPIX®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using CHAMPIX?

CHAMPIX contains the active ingredient varenicline tartrate. CHAMPIX is used to help adults stop smoking.
For more information, see Section 1. Why am I using CHAMPIX? in the full CMI.

2. What should I know before I use CHAMPIX?

Do not use if you have ever had an allergic reaction to varenicline tartrate or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use CHAMPIX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CHAMPIX and affect how it works. Furthermore, the effects of changes in your body resulting from stopping smoking, with or without CHAMPIX, may alter the way some medicines work.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use CHAMPIX?

Your doctor will decide with you on how to use CHAMPIX to quit smoking. There are 3 ways to quit smoking with CHAMPIX.

To take CHAMPIX, you start with the white 0.5 mg tablet and then increase the dose up to the light blue 1 mg tablet.

More instructions can be found in Section 4. How do I use CHAMPIX? in the full CMI.

5. What should I know while using CHAMPIX?

Things you should do
  • Make sure you try to stop smoking on your quit date. If you slip up and smoke, try again.
  • Stop taking CHAMPIX and call your doctor straight away if you or those around you notice changes in behaviour, thinking, or mood that are not typical for you, or you develop suicidal thoughts or actions.
  • Call your doctor straight away if you have existing heart or blood vessel problems and notice any changes in symptoms while taking CHAMPIX; or become pregnant while taking CHAMPIX.
  • Remind any doctor, dentist or pharmacist you visit that you are using CHAMPIX.
Things you should not do
  • Do not take CHAMPIX to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they are also trying to stop smoking.
Driving or using machines
  • You should not drive, operate complex machinery or do anything else that could be dangerous until you know whether this medicine affects your ability to perform these activities.
Drinking alcohol
  • Drinking alcohol while taking CHAMPIX may increase your risk of experiencing changes to your behaviour, thinking or mood that are not typical for you.
Looking after your medicine
  • Keep your tablets in a cool dry place where the temperature stays below 30°C.
  • Keep your tablets in the pack until it is time to take them.

For more information, see Section 5. What should I know while using CHAMPIX? in the full CMI.

6. Are there any side effects?

Common side effects of CHAMPIX include: stomach or bowel problems (e.g. nausea), dry mouth, toothache, headache, dizziness, sleep problems, signs and symptoms of a cold, change in appetite, weight gain, changes in taste, muscle or joint pain. Other serious side effects have also been reported: convulsions, vision problems or pain in eyes, blood in stools or vomit, stomach pain, excessive thirst, dry mouth and skin, passing large amounts of urine, changes in behaviour, thinking or mood, severe skin issues, allergic reactions, heart related issues.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

CHAMPIX® (tshamp-iks)

Active ingredient(s): varenicline tartrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using CHAMPIX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using CHAMPIX.

Where to find information in this leaflet:

1. Why am I using CHAMPIX?
2. What should I know before I use CHAMPIX?
3. What if I am taking other medicines?
4. How do I use CHAMPIX?
5. What should I know while using CHAMPIX?
6. Are there any side effects?
7. Product details

1. Why am I using CHAMPIX?

CHAMPIX contains the active ingredient varenicline tartrate.

CHAMPIX is used to help adults stop smoking. It can help to reduce craving and withdrawal symptoms that may happen while you stop smoking.

People giving up smoking are often affected by nicotine withdrawal. Symptoms of nicotine withdrawal can include craving for tobacco, irritability, frustration, feeling angry, sleep problems, depressed mood, feeling anxious, difficulty concentrating, restlessness, decreased heart rate, increased appetite or weight gain. Not everybody is affected by symptoms of nicotine withdrawal.

Although it is not recommended that you smoke after your quit date, CHAMPIX will reduce your enjoyment of cigarettes if you do smoke while on treatment.

How CHAMPIX works

CHAMPIX works by blocking the effects of nicotine in your body. There are receptors for nicotine in the brain. When cigarette smoke is inhaled, nicotine attaches to these receptors. This sends a message to a different part of the brain to release a chemical called dopamine. Dopamine gives a feeling of pleasure which only lasts for a short time. The body wants to repeat this feeling reinforcing the need to keep smoking. It is believed that CHAMPIX works by activating these receptors and blocking nicotine from attaching to them. CHAMPIX does not contain nicotine and it is not addictive.

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.

Deciding to stop smoking

CHAMPIX helps you give up smoking. Other things you need include:

  • willpower
  • a quit plan
  • support from your family, friends or carers
  • counselling, advice or additional support
  • changes in your behaviour, so you avoid situations where you are likely to smoke.

Most people are unable to quit smoking without support. Your doctor and pharmacist can give you advice, support and sources of information to help you stop smoking. You can also get free advice and support from Quitline by calling 13 7848 (13 QUIT) or online at www.icanquit.com.au

2. What should I know before I use CHAMPIX?

Warnings

Do not use CHAMPIX if:

  1. you are allergic to varenicline tartrate, or 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.
Always check the ingredients to make sure you can use this medicine.
  1. the expiry date printed on the pack has passed.
  2. the packaging is torn or shows signs of tampering.
If it has expired or is damaged, return it to your pharmacist for disposal.

Talk to your doctor if you are not sure whether you should take this medicine.

Check with your doctor if you:

  • have or have had feelings of low mood, anxiety, disturbances in thinking, emotional reactions or behaviour that has interfered or interferes with your everyday life.
For some people, stopping smoking, with or without treatment, has been associated with changes in behaviour, thinking or mood that are not typical for them e.g. developing suicidal thoughts or actions, anxiety, panic, aggression, anger, mania, abnormal sensations, hallucinations, paranoia or confusion.
Some people had these symptoms when they began taking CHAMPIX, and others developed them after several weeks of treatment or after stopping CHAMPIX.
Your family, friends or carers should be asked to monitor any changes in your behaviour, thinking or mood that are not typical for you e.g. if you develop suicidal thoughts or actions, anxiety, panic, aggression, anger, mania, abnormal sensations, hallucinations, paranoia or confusion.
Discuss with your doctor the benefits and risks of taking CHAMPIX to decide if it is right for you.
  • have or have had any other medical conditions, especially:
    - mental health conditions such as depression, thoughts of suicide or self-harm
    - kidney problems
    - repeated fits or convulsions (epilepsy)
    Some people have reported convulsions or fits while taking CHAMPIX.
    - heart and blood vessel problems such as heart attack, chest pain or stroke.
  • take any medicines for any other condition
  • have allergies to any other medicines, foods, preservatives or dyes.

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

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

It is not recommended that you take CHAMPIX while you are pregnant or breast-feeding.

Check with your doctor if you are pregnant or intend to become pregnant.

If you plan to become pregnant, your treatment should be timed so that you have completed the course before becoming pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Use in children

Available information does not support the use of this medicine in children and adolescents under the age of 19 years.

3. What if I am taking other medicines?

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

This includes other medicines to help you stop smoking such as:

  • nicotine replacement therapy (NRT), which includes patches, gum, lozenges, sublingual tablets and inhalers (such as Nicorette, Nicabate, QuitX)
  • bupropion (e.g. Zyban).

Taking CHAMPIX in combination with other smoking cessation therapies is not recommended.

The safety and benefits of taking CHAMPIX in combination with other medicines to stop smoking have not been studied.

The effects of changes in your body resulting from stopping smoking, with or without CHAMPIX, may alter the way some medicines work.

These medicines include:

  • insulin
  • theophylline, a medicine used to treat asthma
  • warfarin, a medicine used to thin the blood.

In some cases, an adjustment of dose may be necessary.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect CHAMPIX.

4. How do I use CHAMPIX?

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information in this leaflet.

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

How to start CHAMPIX

There are 3 ways to quit smoking with CHAMPIX:

Option 1

  • Choose a quit date when you will stop smoking.
  • Make a note of this date. You can write this date on the carton of the Initiation Pack as a reminder.
  • Start taking CHAMPIX 1 to 2 weeks (7 to 14 days) before your quit date.
  • You can keep smoking during this time.
  • Make sure that you try to stop smoking on your quit date. If you slip-up and smoke, try again.

Option 2

  • Start taking CHAMPIX.
  • Choose a quit date when you will stop smoking between days 8 and 35 of starting CHAMPIX.
  • Make a note of this date. You can write this date on the carton of the Initiation Pack as a reminder.
  • Make sure that you try to stop smoking on your quit date. If you slip-up and smoke, try again.

Option 3

  • Start taking CHAMPIX.
  • Reduce the number of cigarettes you smoke by half during the first 4 weeks (weeks 1-4)
  • Reduce by half again the number of cigarettes you smoke in the next 4 weeks (weeks 5-8)
  • Aim to have stopped smoking on the last day of the 12 week treatment period - this is your quit date
  • Continue taking CHAMPIX 1 mg tablets for a further 12 weeks.

How much to take

Start with the white 0.5 mg tablet and then increase the dose up to the light blue 1 mg tablet.

Starting with a low dose helps your body get used to CHAMPIX.

If you have severe kidney disease your doctor may prescribe a different dose.

The usual dosage instructions are listed below.

  • Days 1-3: Take one white 0.5 mg tablet once a day.
  • Days 4-7: Take one white 0.5 mg tablet in the morning and one in the evening.
  • Weeks 2-4: Take one light blue 1 mg tablet in the morning and one in the evening.
  • Weeks 5-12: Take one light blue 1 mg tablet in the morning and one in the evening.
  • Weeks 13-24: Take one light blue 1 mg tablet in the morning and one in the evening.

Follow the instructions provided and use CHAMPIX until your doctor tells you to stop.

How to take CHAMPIX

Swallow the tablets whole with a full glass of water.

When to take CHAMPIX

Take your medicine at about the same time each day.

This will have the best effect and help you remember when to take it.

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

Some people find it helpful to take CHAMPIX with food.

How long to take CHAMPIX

  • If options 1 or 2 are the selected way to quit smoking, take CHAMPIX for 12 weeks.
    - Your first pack of CHAMPIX will cover your first four weeks of treatment.
    - Visit your doctor before the end of the fourth week that you take CHAMPIX for a check-up and for a new prescription.
    - At this appointment, your doctor will check your progress and give you a new prescription for the tablets you need to complete your treatment.
    - Visit your doctor before the end of the eleventh week for a check-up.
    - Your doctor may advise you to take CHAMPIX for an additional 12 weeks. This may increase your chances of stopping smoking in the long term.
  • If option 3 is the selected way to quit smoking, take CHAMPIX for 12 weeks.
    - Your first pack of CHAMPIX will cover your first four weeks of treatment.
    - Visit your doctor before the end of the fourth week that you take CHAMPIX for a check-up and for a new prescription.
    - At this appointment, your doctor will check your progress and give you a new prescription for the tablets to continue your treatment.
    - Visit your doctor before the end of the eleventh week for a check-up and for a new prescription.
    - You must then take CHAMPIX for an additional 12 weeks (24 weeks in total).

If you do not stop smoking during the first 12 weeks of treatment or if you start smoking again after treatment, you can make another attempt to stop smoking.

However, before you make another attempt, you should try to understand the reasons why your attempt to stop smoking failed, so that your next attempt has a better chance of success.

If you forget to use CHAMPIX

CHAMPIX should be used regularly at the same time each day.

If it is almost time for your next dose (less than 6 hours before 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 a double dose to make up for the dose you missed.

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 use too much CHAMPIX

If you think that you have used too much CHAMPIX, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Take your tablets with you to hospital.

5. What should I know while using CHAMPIX?

Things you should do

Make sure you try to stop smoking on your quit date.

If you slip up and smoke, try again.

Stop taking CHAMPIX and call your doctor straight away if:

  • you or your family, friends or carers notice agitation, hostility, depression or changes in behaviour, thinking, or mood that are not typical for you, or you develop suicidal thoughts or actions, anxiety, panic, aggression, anger, mania, abnormal sensations, hallucinations, paranoia or confusion.
    - All mentions of suicide or violence must be taken seriously. These are very serious side effects. You may need urgent medical attention or hospitalisation.
    - It is not known whether these changes are related to CHAMPIX as it is known that mood changes can also be due to the effects of stopping smoking.

Call your doctor straight away if you:

  • have existing heart or blood vessel problems and you notice any changes in symptoms while taking CHAMPIX.
    - Your doctor may check your blood pressure and blood glucose levels from time to time to make sure you have not developed any unwanted side effects.
    - It is important to keep all of your doctor's appointments so that your progress can be checked.
  • become pregnant while taking this medicine

Remind any doctor, dentist or pharmacist you visit that you are using CHAMPIX.

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

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.

Things you should not do

  • Do not take CHAMPIX to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they are also trying to stop smoking.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how CHAMPIX affects you.

CHAMPIX may cause dizziness, sleepiness, blackouts, seizures or difficulty concentrating in some people. You should not drive, operate complex machinery or do anything else that could be dangerous until you know whether this medicine affects your ability to perform these activities.

Drinking alcohol

Tell your doctor if you drink alcohol.

Be careful if drinking alcohol while you are taking this medicine.

There have been reports of increased feelings of being drunk while taking CHAMPIX. Drinking alcohol while taking CHAMPIX may also increase your risk of experiencing changes to your behaviour, thinking or mood that are not typical for you e.g. developing suicidal thoughts or actions, anxiety, panic, aggression, anger, mania, abnormal sensations, hallucinations, paranoia or confusion.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of the pack they may not keep well.

Store it in a cool dry place (where the temperature stays below 30°C) away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date or when your doctor tells you to stop taking CHAMPIX.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are you are taking CHAMPIX.

Giving up smoking with or without treatment can cause various symptoms. These could include changes of mood, sleeplessness, difficulty concentrating, decreased heart rate, increased appetite or weight gain. This medicine helps many people give up smoking, but it may have unwanted side effects in some people.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Do not be alarmed by the following lists of side effects.

You may not experience any of them.

Stop taking CHAMPIX and tell your doctor immediately if you or your family, friends or carers notice agitation, hostility, depression or changes in behaviour, thinking, or mood that are not typical for you, or you develop suicidal thoughts or actions, anxiety, panic, aggression, anger, mania, abnormal sensations, hallucinations, paranoia or confusion.

Some people have had changes in behaviour, thinking or mood that are not typical for them when they start taking CHAMPIX. These may include suicidal thoughts or actions, anxiety, panic, aggression, anger, mania, abnormal sensations, hallucinations, paranoia or confusion.

These symptoms have occurred in people with previous mental health problems, as well as those with no previous history.

Tell your doctor or pharmacist if you have nausea (feel sick) while taking CHAMPIX and it worries you.

Around 3 in 10 people experience nausea, usually starting in the first week. Most people who have nausea are able to keep taking the medicine. Some people find it helpful to take CHAMPIX with food.

Common side effects

Common side effectsWhat to do
  • stomach or bowel problems
    - constipation
    - diarrhoea
    - feeling bloated
    - indigestion
    - wind
    - nausea, vomiting
    - stomach discomfort
  • dry mouth, toothache
  • headache
  • dizziness
  • sleep problems
    - difficulty sleeping
    - sleepiness
    - abnormal dreams
    - sleep walking
  • feeling tired, fatigue
  • signs and symptoms of a cold
  • change in appetite, weight gain
  • changes in taste
  • muscle or joint pain
Speak to your doctor if you have any of these common side effects and they worry you.
They are usually mild.

Serious side effects

Serious side effectsWhat to do
  • trembling, fits or convulsions
  • problems with your vision or pain in your eyes
  • red blood in stools
  • stomach pain
  • excessive thirst, having a dry mouth and skin, passing large amounts of urine.
Call your doctor straight away if you notice any of these serious side effects.
You may require medical attention.

Very serious side effects

Very serious side effectsWhat to do
Changes in behaviour, thinking or mood
  • self-harm or thoughts of self-harm
  • changes in behaviour, thinking or mood that are not typical for you e.g. if you develop suicidal thoughts or actions, anxiety, panic, aggression, anger, mania, abnormal sensations, hallucinations, paranoia or confusion
Skin issues
  • severe painful red blisters on the skin with chills, fever, aching muscles and generally feeling unwell
Allergic reactions
  • rash or sudden severe itchy swellings on the skin
  • breathing problems
    - wheezing
    - difficulty breathing
    - shortness of breath
  • swelling of the face, lips, mouth, tongue, throat, hands or feet
    Some people have reported swelling of parts of their face and body after taking CHAMPIX.
Heart related issues
  • chest pain, which may spread to the neck and shoulders, numbness or weakness of the arms or legs, headache, dizziness and confusion, visual disturbance, difficulty swallowing, slurred speech or loss of speech, collapse
  • abnormal or fast heartbeat
Other
  • blood in vomit.
Stop taking CHAMPIX and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects.
You may need urgent medical attention or hospitalisation.
Very serious side effects are rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people. Some of these side effects (for example, changes in blood pressure or blood sugar levels) can only be found when your doctor does tests to check your progress.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What CHAMPIX contains

Active ingredient
(main ingredient)		varenicline tartrate
Other ingredients
(inactive ingredients)

microcrystalline cellulose

calcium hydrogen phosphate

croscarmellose sodium

colloidal anhydrous silica

magnesium stearate

Opadry Blue (1 mg tablet), Opadry White (0.5 mg tablet) and Opadry Clear.

Do not take this medicine if you are allergic to any of these ingredients.

CHAMPIX is gluten free.

What CHAMPIX looks like

CHAMPIX is available in 2 strengths:

  • CHAMPIX 0.5 mg tablets are white, film-coated, modified capsular shaped tablets marked "Pfizer" on one side and "CHX 0.5" on the other.
  • CHAMPIX 1 mg tablets are light blue, film-coated, modified capsular shaped tablets, marked "Pfizer" on one side and "CHX 1.0" on the other.

The following packs are available:

  • Initiation pack to start treatment, contains 11 x 0.5 mg tablets and 42 x 1 mg tablets. (AUST R 124940)
  • Continuation pack containing 56 x 1 mg tablets to continue treatment. (AUST R 124941)

Who distributes CHAMPIX

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedinfo.com.au

This leaflet was prepared in November 2021.

® Registered Trademark

© Pfizer Australia Pty Ltd 2021.

Published by MIMS February 2022

BRAND INFORMATION

Brand name

Champix

Active ingredient

Varenicline

Schedule

S4

 

1 Name of Medicine

Varenicline (as tartrate).

2 Qualitative and Quantitative Composition

Each Champix 0.5 mg film-coated tablet contains 0.5 mg varenicline (as tartrate).
Each Champix 1 mg film-coated tablet contains 1 mg varenicline (as tartrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.
Champix is supplied for oral administration in two strengths:
0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with "Pfizer" on one side and "CHX 0.5" on the other side.
1 mg capsular biconvex, light blue film-coated tablet debossed with "Pfizer" on one side and "CHX 1.0" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Champix is indicated as an aid to smoking cessation in adults over the age of 18 years.

4.2 Dose and Method of Administration

Use in adults.

Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided with additional advice and support.
The recommended dose of Champix is 1 mg twice daily following a 1 week titration (see Table 1).
The patient should set a date to stop smoking. Champix dosing should start 1-2 weeks before this date. Alternatively, a flexible approach to quitting smoking may be adopted. Patients can begin varenicline dosing and then quit smoking between days 8 and 35 of treatment (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Flexible quit date study).
Patients should be treated with Champix for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with Champix at 1 mg twice daily is recommended to further increase the likelihood of long-term abstinence.
A gradual approach to quitting smoking with varenicline should be considered for patients who are not able or willing to quit abruptly. Patients should reduce smoking by 50% from baseline within the first four weeks, by an additional 50% in the next four weeks, and continue reducing with the goal of reaching complete abstinence by 12 weeks. Patients should then continue taking varenicline for an additional 12 weeks for a total of 24 weeks of treatment (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Gradual approach to quitting smoking study).
Patients who are motivated to quit and who do not succeed in stopping smoking during prior varenicline therapy, or who relapse after treatment, should be encouraged to make another attempt once factors contributing to the failed attempt have been identified and addressed (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Retreatment with varenicline study).
Champix tablets should be swallowed whole with water. Champix can be taken with or without food.
Dose tapering of Champix is not required at the end of treatment.

Use in renal impairment.

No dosage adjustment is necessary for patients with mild to moderate renal impairment.
For patients with severe renal impairment, the recommended dose of Champix is 1 mg once daily. Dosing should begin at 0.5 mg once daily for the first 3 days then increase to 1 mg once daily (see Section 5.2 Pharmacokinetic Properties).
Based on insufficient clinical experience with Champix in patients with endstage renal disease, treatment is not recommended in this patient population (see Section 5.2 Pharmacokinetic Properties, Special populations).

Use in hepatic impairment.

No dosage adjustment is necessary for patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

No dosage adjustment is necessary for elderly patients (see Section 5.2 Pharmacokinetic Properties). Because elderly patients are more likely to have decreased renal function, prescribers should consider the renal status of an elderly patient.

Use in paediatric and adolescent patients.

Champix is not recommended for use in paediatric and adolescent patients because its efficacy in this population was not demonstrated (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Paediatric and adolescent population; Section 5.2 Pharmacokinetic Properties, Use in paediatric and adolescent patients).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Effects of smoking cessation.

Physiological changes resulting from smoking cessation, with or without treatment with Champix, may alter pharmacokinetics or pharmacodynamics of some drugs, for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking induces CYP1A2, smoking cessation may result in an increase of plasma levels of CYP1A2 substrates.
Smoking cessation, with or without pharmacotherapy, has been associated with the exacerbation of underlying psychiatric illness (e.g. depression). Care should be taken with patients with a history of psychiatric illness and patients should be advised accordingly.
At the end of treatment, discontinuation of Champix was associated with an increase in irritability, urge to smoke, depression, and/or insomnia in up to 3% of patients. The prescriber should inform the patient accordingly.

Psychiatric symptoms.

Serious neuropsychiatric symptoms have occurred in patients being treated with Champix. Patients and their families, friends or carers should be advised that the patient should stop taking Champix and contact a healthcare professional immediately if changes in behaviour or thinking, agitation or depressed mood that are not typical for the patient are observed, or if patient develops suicidal ideation or suicidal behaviour.
Doctors should discuss the efficacy and safety profile of Champix with patients attempting to quit smoking with Champix and advise them of the possible emergence of neuropsychiatric symptoms. Patients and their families, friends or carers should be alerted to the need to monitor for neuropsychiatric symptoms including changes in behaviour or thinking, anxiety, psychosis, mood swings, agitation, aggression, depressed mood, suicidal ideation and suicidal behaviour. Patients should be advised that alcohol intake may increase the risk of experiencing neuropsychiatric events during treatment with Champix.
Patients and their families, friends or carers should be encouraged to report any history of psychiatric illness prior to initiating treatment. There have been postmarketing reports of neuropsychiatric symptoms, some serious, as well as worsening of pre-existing psychiatric illness. A causal association between Champix and these symptoms has not been established although association cannot be excluded. Some cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking; however, some of these symptoms have occurred in patients who continued to smoke. In many postmarketing cases, resolution of symptoms after discontinuation of Champix was reported, although in some cases the symptoms persisted; therefore, ongoing follow-up should be provided until symptoms resolve. Doctors and other healthcare professionals should continue to monitor patients for the development of neuropsychiatric symptoms.

Neuropsychiatric study.

See Section 5.1 Pharmacodynamic Properties, Clinical trials, Neuropsychiatric safety study in patients with and without a history of psychiatric disorder; Section 4.8 Adverse Effects (Undesirable Effects), Special populations.

Meta-analysis.

A meta-analysis of 5 randomised, double blind, placebo controlled trials, including 1907 patients (1130 varenicline, 777 placebo), was conducted to assess suicidal ideation and behaviour as reported on the Columbia Suicide Severity Rating Scale (C-SSRS). This meta-analysis included one trial (N = 127) in patients with a history of schizophrenia or schizoaffective disorder and another trial (N = 525) in patients with a history of depression. The results showed no increase in the incidence of suicidal ideation and/or behaviour in patients treated with varenicline compared to patients treated with placebo, with a risk ratio (RR) of 0.79 (95% confidence interval [CI]: 0.46, 1.36), as shown in Table 2. Forty eight (48) of the 55 patients who reported suicidal ideation or behaviour (24 varenicline, 24 placebo) were from the two trials that enrolled patients with a history of schizophrenia, schizoaffective disorder, or depression. The majority of patients in both the varenicline and placebo groups who reported suicidal ideation and/or behaviour on the C-SSRS during treatment period had a pre-dosing C-SSRS positive history (23 [82%]) and (17 [63%]) respectively. Few patients reported these events in the other three trials (4 varenicline, 3 placebo), which generally excluded individuals with a known psychiatric history.
A meta-analysis of 18 double blind, randomised, placebo controlled clinical trials assessed the neuropsychiatric safety of varenicline. These trials included the 5 trials described above that used the C-SSRS, and a total of 8521 patients (5072 varenicline, 3449 placebo). Sixteen of the 18 trials generally excluded individuals with a history of neuropsychiatric disease. The results showed a similar incidence of combined neuropsychiatric adverse events, other than sleep disorders, in patients treated with varenicline compared to patients treated with placebo, with a risk ratio (RR) of 1.01 (95% CI: 0.88, 1.15). Pooled data from these 18 trials showed a similar incidence rate of individual categories of psychiatric events in patients treated with varenicline compared to patients treated with placebo. Table 3 describes the most frequently (≥ 1%) reported categories of adverse events related to psychiatric safety other than sleep disorders and disturbances.

Observational studies.

Four observational studies, each including 10,000 to 30,000 users of varenicline in the adjusted analyses, compared the risk of serious neuropsychiatric events, including neuropsychiatric hospitalisations and fatal and nonfatal self harm, in patients treated with varenicline versus patients prescribed NRT or bupropion. One study looked at rates of suicide, self harm and treated depression and the other three looked at neuropsychiatric events requiring hospitalisation or emergency room visit. All studies were retrospective cohort studies and included patients with and without a psychiatric history. All studies used statistical methods to control for confounding factors, including preferential prescribing of varenicline to healthier patients, although there is the possibility of residual confounding.
Two of the studies found no difference in risk of neuropsychiatric hospitalisations between varenicline users and NRT patch users (hazard ratio [HR] 1.14; 95% confidence interval [CI]: 0.56-2.34 in the first study, and 0.76; 95% CI: 0.40-1.46 in the second study). However, the power to detect differences in these two studies was limited, especially for rare events. The third study reported no difference in risk of psychiatric adverse events diagnosed during an emergency department visit or inpatient admission between varenicline users and bupropion users (HR 0.85; 95% CI: 0.55-1.30). The fourth study showed no evidence of a higher risk of fatal and nonfatal self harm (HR of 0.88; 95% CI: 0.52-1.49) in patients prescribed varenicline compared to patients prescribed NRT. The occurrence of detected suicide was rare during the three months after patients initiated any drug treatment (two cases in 31,260 varenicline users and six cases in 81,545 NRT users).

Accidental injury, including while driving or operating machinery.

There have been post-marketing reports of traffic accidents, near-miss incidents in traffic, and other accidental injuries in patients taking Champix. In some cases, the patients reported somnolence, dizziness, loss of consciousness (blackouts), seizures or difficulty concentrating.
Therefore, patients should be advised not to engage in potentially hazardous activities, such as driving or operating complex machinery, until they know how Champix may affect them.

Seizures.

In clinical trials and postmarketing experience there have been reports of seizures in patients with or without a history of seizures, treated with varenicline. Varenicline should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Advise patients to discontinue Champix and immediately contact a healthcare provider if they experience a seizure while on treatment.

Hypersensitivity reactions.

There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with Champix. Clinical signs included swelling of the face, mouth (tongue, lips and gums), neck (throat and larynx) and extremities. There were rare reports of life threatening angioedema requiring urgent medical attention due to respiratory compromise. Patients experiencing these symptoms should discontinue treatment with Champix and contact a health care provider immediately (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).

Skin reactions.

There have also been postmarketing reports of rare but severe cutaneous reactions, including Stevens-Johnson syndrome and erythema multiforme in patients using Champix. As these skin reactions can be life threatening, patients should discontinue treatment at the first sign of rash or skin reaction and contact a healthcare provider immediately (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).

Cardiovascular events.

In a post-marketing randomised, controlled study of 703 patients with stable cardiovascular (CV) disease, deaths and serious CV events occurring over the 52 weeks of the study (treatment-emergent and non-treatment-emergent) were adjudicated by a blinded, independent committee. The following adjudicated treatment-emergent events (on treatment or up to 30 days after treatment) occurred with a frequency ≥ 1% in either treatment group: nonfatal myocardial infarction (1.1% vs. 0.3% for varenicline and placebo, respectively), and hospitalisation for angina pectoris (0.6% vs. 1.1%). During non-treatment follow up to 52 weeks, adjudicated events with a frequency ≥ 1% included need for coronary revascularisation (2.0% vs. 0.6%), hospitalisation for angina pectoris (1.7% vs. 1.1%), and new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring coronary revascularisation underwent the procedure as part of management of nonfatal MI and hospitalisation for angina. Cardiovascular death occurred in 0.3% of patients in the varenicline arm and 0.6% of patients in the placebo arm over the course of the 52 week study.
In the above smoking cessation study in patients with stable CV disease and in a meta-analysis of 15 clinical trials, which included the smoking cessation trial of patients with stable CV disease, some CV events were reported more frequently in patients treated with varenicline compared to placebo. These events occurred primarily in patients with known CV disease. No causal relationship between these events and varenicline has been established. In a large smoking cessation trial that assessed CV safety in patients with and without a history of psychiatric disorder, major CV events (CV death, non-fatal MI, non fatal stroke) were reported less frequently in patients treated with varenicline compared to placebo. In these studies, major CV events were infrequent overall and all-cause and CV mortality was lower in patients treated with varenicline compared to patients treated with placebo.
Smoking is an independent and major risk factor for cardiovascular disease. Patients should be advised to seek medical attention in the event of new or worsening cardiovascular symptoms or if they experience signs and symptoms of myocardial infarction or stroke. Patients with known cardiovascular disease require ongoing assessment and management of other risk factors for cardiovascular disease (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Cardiovascular disease study).

Somnambulism.

Cases of somnambulism have been reported in patients taking Champix. Some cases described harmful behaviour to self, others, or property. Instruct patients to discontinue Champix and notify their healthcare provider if they experience somnambulism.

Use in the elderly.

No dosage adjustment is necessary for elderly patients (see Section 5.2 Pharmacokinetic Properties). Because elderly patients are more likely to have decreased renal function, prescribers should consider the renal status of an elderly patient.

Use in paediatric and adolescent patients.

Champix is not recommended for use in patients < 19 years of age because its efficacy in this population was not demonstrated (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Paediatric and adolescent population; Section 5.2 Pharmacokinetic Properties, Use in paediatric and adolescent patients).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Based on varenicline characteristics and clinical experience to date, varenicline has no known clinically meaningful drug interactions. No dosage adjustment of varenicline or coadministered drugs listed below is recommended.
In vitro studies demonstrate that varenicline tartrate does not inhibit cytochrome P450 enzymes (IC50 > 6,400 nanogram/mL). The P450 enzymes tested for inhibition were: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4/5. Also, in human hepatocytes in vitro, varenicline was shown not to induce the activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline tartrate is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.
In vitro studies demonstrate that varenicline tartrate does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (e.g. metformin (see below)) are unlikely to be affected by varenicline tartrate.
In vitro studies demonstrate that active renal secretion of varenicline tartrate is mediated by the human organic cation transporter, OCT2. Coadministration with inhibitors of OCT2 does not require a dose adjustment of Champix as the increase in systemic exposure to varenicline tartrate is not expected to be clinically meaningful (see cimetidine interaction below). Furthermore since metabolism of varenicline tartrate contributes to less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of varenicline tartrate (see Section 5.2 Pharmacokinetic Properties) and therefore, a dose adjustment of Champix would not be required.

Metformin.

Varenicline tartrate (1 mg twice daily) did not affect the pharmacokinetics of metformin (500 mg twice daily), which is a substrate of OCT2. Metformin had no effect on varenicline pharmacokinetics.

Cimetidine.

Coadministration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with varenicline (2 mg single dose) increased the systemic exposure of varenicline by 29% due to a reduction in varenicline renal clearance. No dosage adjustment is recommended based on concomitant cimetidine administration in subjects with normal renal function or in patients with mild to moderate renal impairment. In patients with severe renal impairment, the concomitant use of cimetidine and varenicline should be avoided.

Digoxin.

Varenicline tartrate (1 mg twice daily) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose.

Warfarin.

Varenicline tartrate (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R,S)-warfarin. Prothrombin time (INR) was not affected by varenicline tartrate. Smoking cessation itself may result in changes to warfarin pharmacokinetics (see Section 4.4 Special Warnings and Precautions for Use).

Alcohol.

There is limited clinical data on any potential interaction between alcohol and varenicline. There have been postmarketing reports of increased intoxicating effects of alcohol in patients treated with varenicline. Drinking alcohol may increase the risk of experiencing neuropsychiatric events during treatment with Champix.

Use with other therapies for smoking cessation.

Bupropion.

Varenicline tartrate (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily).

Nicotine replacement therapy (NRT).

When varenicline (1 mg twice daily) and nicotine replacement therapy (transdermal 21 mg/day) were coadministered to smokers (N = 24) for 12 days, there was a statistically significant decrease in average systolic blood pressure (mean 2.6 mmHg) measured on the final day of the study. In this study, the incidence of nausea, headache, vomiting, dyspepsia, fatigue and dizziness was greater for the combination than for NRT alone.
Safety and efficacy of Champix in combination with other smoking cessation therapies have not been studied.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

It is not expected that varenicline tartrate would impair fertility. Varenicline did not impair fertility in rats at oral doses producing plasma concentrations up to 40 times the human plasma Cmax at the maximal recommended dose of 1 mg twice daily. Offspring of treated rats have shown decreased fertility (see Use in pregnancy).
(Category B3)
A moderate amount of data on pregnant women indicated no malformative or fetal/neonatal toxicity of varenicline (see Section 5.1 Pharmacodynamic Properties). The use of Champix in pregnant women is not recommended.
A population-based cohort study compared infants exposed to varenicline in utero (N=335) with infants born to mothers who smoked during pregnancy (N=78,412) and infants born to non-smoking mothers (N=806,438). In this study, infants exposed to varenicline in utero were no more likely to have major congenital malformations (3.6%) than infants born to mothers who smoked during pregnancy (4.3%) or to non-smoking mothers (4.2%). Similarly, infants exposed to varenicline in utero, as compared to infants of smoking and non-smoking mothers, were not at increased risk of stillbirth (0.3%, 0.5%, 0.3%, respectively), small for gestational age (12.5%, 17.1%, 9.1%), preterm birth (7.5%, 7.9%, 5.8%), or premature rupture of membrane (3.6%, 5.4%, 3.8%).
There was no evidence of teratogenicity following oral administration of varenicline to rats and rabbits during organogenesis with systemic exposure (plasma AUC) up to 36 times the human plasma AUC at the maximal recommended dose of 1 mg twice daily.
In animal reproduction studies, varenicline has been shown to have adverse effects on the fetus and offspring. Oral administration of varenicline to pregnant rabbits during organogenesis resulted in reduced fetal weights at systemic exposure (plasma AUC) 50 times the human plasma AUC at the maximal recommended dose; the no-effect exposure was 23 times the clinical exposure. Oral administration of varenicline to pregnant rats from early gestation until weaning resulted in reduced fertility, increased auditory startle response and decreased rearing in offspring at maternal plasma concentrations 40 times the human plasma Cmax at the maximal recommended dose; the no-effect exposure was 17 times clinical exposure.

Women of child bearing potential.

Where drug therapy is initiated, treatment should be timed such that the course is completed before conception.
It is not known whether varenicline is excreted in human milk. Because many drugs are excreted in human milk and because the potential for adverse effects in nursing infants from Champix is unknown, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Varenicline is excreted in the milk of lactating rats. Oral administration of varenicline to pregnant rats from early gestation until weaning was associated with adverse effects in offspring (see Use in pregnancy). The clinical significance of this finding is unknown.

4.7 Effects on Ability to Drive and Use Machines

Champix may cause dizziness, sleepiness and loss of consciousness and therefore may influence the ability to drive or use machines. Patients are advised not to drive, operate complex machinery, or engage in other potentially hazardous activities until it is know whether this medicine affects their ability to perform these activities.

4.8 Adverse Effects (Undesirable Effects)

Smoking cessation with or without treatment is associated with various symptoms. For example, dysphoric or depressed mood; insomnia, irritability, frustration or anger; anxiety; difficulty concentrating; restlessness; decreased heart rate; increased appetite or weight gain have been reported in patients attempting to stop smoking. No attempt has been made in either the design or the analysis of the Champix studies to distinguish between adverse effects associated with study drug treatment or those possibly associated with nicotine withdrawal.
Premarketing development trials included approximately 4,000 patients treated with Champix for up to 1 year (average exposure 84 days). In general, where adverse events occurred, onset was in the first week of therapy; severity was generally mild to moderate and there were no differences by age, race or gender with regard to the incidence of adverse effects.
The treatment discontinuation rate was 11.4% for varenicline compared with 9.7% for placebo. In this group, the discontinuation rates for the most common adverse events in varenicline treated patients were as follows: nausea (2.7% vs. 0.6% placebo), headache (0.6% vs. 1.0% for placebo), insomnia (1.3% vs. 1.2% for placebo) and abnormal dreams (0.2% vs. 0.2% for placebo).
Table 4 includes the most frequently occurring adverse events based on evaluation of data from premarketing phase 2-3 studies and updated based on pooled data from 19 placebo controlled premarketing and postmarketing studies, including approximately 5,800 patients treated with varenicline.
In the listing below, all adverse reactions which occurred at a rate < 1% are listed by system organ class and frequency (uncommon (≥ 1/1,000, < 1/100) and rare (≥ 1/10,000 to < 1/1,000)). This listing is based on treatment emergent (during treatment and 30 days after last dose) all-causality AEs from the 19 placebo-controlled studies and takes into account the following factors: event rates related to placebo rates; plausibility of a causal relationship based on pharmacokinetic/ pharmacodynamics properties; specificity of the event such that it is informative; and whether clusters of two or more similar events were best combined under a single term.

System organ class.

Blood and lymphatic system disorders.

Rare: platelet count decreased.

Metabolism and nutrition disorders.

Rare: polydipsia.

Psychiatric disorders.

Uncommon: thinking abnormal, mood swings, restlessness, libido decreased.
Rare: bradyphrenia, dysphoria.

Nervous system disorders.

Uncommon: tremor, hypoaesthesia, lethargy, hypogeusia.
Rare: circadian rhythm sleep disorder, dysarthria, coordination abnormal, visual field defect.

Eye disorders.

Uncommon: conjunctivitis, eye pain.
Rare: photophobia.

Ear and labyrinth disorders.

Uncommon: tinnitus.

Cardiac disorders.

Uncommon: palpitations, angina pectoris, tachycardia, heart rate increased.
Rare: electrocardiogram T wave amplitude decreased, atrial fibrillation, electrocardiogram ST segment depression.

Vascular disorders.

Uncommon: hot flush, blood pressure increased.

Respiratory, thoracic and mediastinal disorders.

Uncommon: throat irritation, respiratory tract congestion, sinus congestion, upper airway cough syndrome, rhinorrhoea, rhinitis allergic, upper respiratory tract inflammation, dysphonia.
Rare: snoring.

Gastrointestinal disorders.

Uncommon: haematochezia, gastritis, eructation, aphthous stomatitis, gingival pain.
Rare: haematemesis.

Skin and subcutaneous tissue disorders.

Uncommon: erythema, acne, hyperhidrosis.

Musculoskeletal, connective tissue and bone disorders.

Uncommon: muscle spasms.
Rare: joint stiffness.

Renal and urinary disorders.

Uncommon: pollakiuria, nocturia, polyuria.
Rare: glycosuria.

Reproductive system and breast disorders.

Uncommon: menorrhagia.
Rare: sexual dysfunction.

General disorders and administration site conditions.

Uncommon: chest discomfort, pyrexia, asthenia, malaise, influenza-like illness.

Investigations.

Uncommon: liver function test abnormal.

Special populations.

Studies have been conducted on patients with and without a history of psychiatric disorder, with cardiovascular disease (CV), chronic obstructive pulmonary disease (COPD), major depressive disorder (MDD) and stable schizophrenia or schizoaffective disorder. Safety analyses included all subjects who received at least one dose of the study drug (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use, Psychiatric symptoms, Cardiovascular events).

Patients with and without a history of psychiatric disorder.

Adverse events from the neuropsychiatric (NPS) safety study are presented in Tables 5, 6 and 7. There were more events reported in patients in the psychiatric cohort in each treatment group compared with the nonpsychiatric cohort.
Table 5 shows the rates of the composite NPS adverse event primary end point by treatment group and the risk differences (RDs) (95% CI) vs placebo in the nonpsychiatric and psychiatric cohorts.
In the non-psychiatric cohort, the composite endpoint risk differences (RDs (95% Confidence Interval [CI])) vs placebo were -1.28% (-2.40, -0.15) for varenicline, -0.08% (-1.37, 1.21) for bupropion and -0.21% (-1.54, 1.12) for NRT patch.
In the psychiatric cohort, the composite endpoint RDs (95% CI) vs placebo were 1.59% (-0.42, 3.59) for varenicline, 1.78% (-0.24, 3.81) for bupropion and 0.37% (-1.53, 2.26) for NRT patch.
The use of varenicline, bupropion and NRT patch in the non-psychiatric or psychiatric cohort was not associated with an increased risk of NPS adverse events in the composite primary endpoint compared with placebo (95% CIs were lower than, or included, zero). Similarly, the use of varenicline was not associated with an increased risk of NPS adverse events in the composite primary endpoint compared with bupropion or NRT patch in the nonpsychiatric or psychiatric cohort.
Based on the generalised linear regression model, the rate of the primary NPS AE endpoint was significantly higher in the psychiatric cohort compared to the nonpsychiatric cohort (p < 0.0001) for effect of the cohort in all treatment arms.
The most commonly reported adverse events in subjects treated with varenicline in this study were similar to those observed in premarketing studies. Adverse events reported in ≥ 10% of subjects treated with varenicline in the entire study population were nausea (25.3% vs 6.8% on placebo) and headache (12.2% vs 9.9% on placebo).
A cardiovascular safety assessment of this study (N=8,058) showed no statically significant difference in the primary cardiovascular endpoint of time to major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke between treatment groups during the treatment phase. The total number of MACE events reported during this study and through a 28-week observational extension of this study (N=4,595) in which no subjects received study treatment, was low with 3 (0.15%) subjects given varenicline reporting such events, 9 (0.45%) subjects given bupropion, 6 (0.3%) subjects given nicotine replacement therapy and 8 (0.4%) subjects given placebo. Due to the relatively low number of MACE events overall, an association between varenicline and increased risk of cardiovascular outcomes cannot be entirely excluded. Of all treated subjects, 1,749 (21.7%) had a medium CV risk and 644 (8.0%) had a high CV risk, as defined by Framingham score at baseline.

Postmarketing experience.

The following adverse events have been reported during postapproval use of Champix. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
There have been reports of neuropsychiatric symptoms, some serious, as well as worsening of pre-existing psychiatric illness such as depressed mood, agitation, hallucinations, changes in behaviour or thinking, anxiety, psychosis, mood swings, aggressive behaviour, suicidal ideation and suicide in patients attempting to quit smoking while taking Champix. There are a number of confounding factors which may have contributed, including effects of nicotine withdrawal due to partial or complete smoking discontinuation; concomitant, or history of psychiatric conditions; and the concomitant use of other CNS drugs and/or alcohol. In many postmarketing cases, resolution of symptoms after discontinuation of Champix was reported, although in some cases the symptoms persisted; therefore, ongoing follow up should be provided until symptoms resolve. Smoking cessation with or without treatment is associated with nicotine withdrawal symptoms and the exacerbation of underlying psychiatric illness. Not all patients had known pre-existing psychiatric illness and not all had discontinued smoking. The role of Champix in these reports is not known (see Section 4.4 Special Warnings and Precautions for Use).
There have also been reports of hypersensitivity reactions, such as angioedema and of rare but severe cutaneous reactions, including Stevens-Johnson syndrome and erythema multiforme in patients taking Champix (see Section 4.4 Special Warnings and Precautions for Use).
There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischaemic and haemorrhagic events in patients taking Champix. In the majority of the reported cases, patients had pre-existing cardiovascular disease and/or other risk factors. Although smoking is a risk factor for MI and CVA, based on temporal relationship between medication use and events, a contributory role of varenicline cannot be ruled out.
There have been reports of somnambulism, some resulting in harmful behaviour to self, others, or property, in patients treated with Champix.
There have been post-marketing reports of traffic accidents, near-miss incidents in traffic, and other accidental injuries in patients taking Champix. In some cases, the patients reported somnolence, dizziness, loss of consciousness (blackouts), seizures or difficulty concentrating.
There have also been postmarketing reports of diabetes mellitus, hyperglycaemia and convulsions.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

No cases of overdose were reported in premarketing clinical trials.
In case of overdose, standard supportive measures should be instituted as required.
Varenicline has been shown to be dialysed in patients with endstage renal disease (see Section 5.2 Pharmacokinetic Properties); however, there is no experience in dialysis following overdose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: drugs used in nicotine dependence; ATC code: N07BA.
Varenicline is a partial agonist at α4β2 neuronal nicotinic acetylcholine receptors where it binds with high affinity and selectivity to produce an effect sufficient to alleviate symptoms of craving and withdrawal (agonist activity), while simultaneously resulting in blockade of the rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors (antagonist activity).
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor mediated activity. The maximal activity of varenicline was approximately 30-50% that of nicotine in vitro and ranged from 30-60% that of nicotine in vivo. Varenicline blocks the ability of nicotine to activate the α4β2 receptor and thus to stimulate the central nervous mesolimbic dopamine system, the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds with higher affinity to the α4β2 receptor subtype than to other common nicotinic receptors (> 00-fold α3β4, > 3,500-fold α7, > 20,000-fold α1βγδ) or to non-nicotinic receptors and transporters (> 2,000-fold).

Clinical trials.

The efficacy of Champix in smoking cessation was demonstrated in three premarketing clinical trials in which a total of 2,619 chronic cigarette smokers (≥ 10 cigarettes per day) received varenicline. Two of these studies were double blind comparisons between varenicline, bupropion and placebo, assessing critical aspects of smoking cessation, including end of treatment and long-term abstinence rates after 12 weeks of treatment. In addition, the effects on reducing craving and withdrawal that can occur during smoking cessation and the reinforcing effects that can perpetuate smoking behaviour were studied. The third study assessed the effect of an additional 12 weeks of treatment on maintaining long-term abstinence.

Comparative clinical studies.

Two identical double blind clinical trials prospectively compared the efficacy of Champix (1 mg twice daily), sustained release bupropion (150 mg twice daily) and placebo in smoking cessation. Patients were treated for 12 weeks and then were followed up for a total study duration of 52 weeks. The Champix dosage of 1 mg twice daily was achieved using a titration of 0.5 mg once daily for the initial 3 days followed by 0.5 mg twice daily for the next 4 days. The bupropion dosage of 150 mg twice daily was achieved using a 3 day titration of 150 mg once daily. Patients set a date to stop smoking (target quit date, TQD) with dosing starting 1-2 weeks before this date.
The primary endpoint of the two studies was the carbon monoxide (CO) confirmed, 4 week continuous quit rate (4W-CQR) from week 9 through week 12. The quit rates are the proportions of all patients treated (i.e. intent to treat analysis) who abstained from smoking. The primary endpoint for Champix demonstrated statistical superiority to bupropion and placebo. Key secondary endpoints for both studies were continuous abstinence (CA) from weeks 9-52 and the long-term quit rate (LTQR) at week 52. CA was defined as the proportion of all subjects who did not smoke (not even a puff of a cigarette) from week 9 through week 52 and had an exhaled CO measurement of ≤ 10 ppm. LTQR was defined as the proportion of all subjects treated who were responders for the primary endpoint in the treatment phase and had no more than 6 days of cigarette smoking during the nontreatment phase.
In both studies the CO confirmed 4 week CQR for week 9 through week 12 was superior (p < 0.0001) for patients given Champix compared with the placebo and bupropion groups. Based on this endpoint, the odds of stopping on Champix were 3.91 (95% CI: 2.74, 5.59) and 3.85 (2.69, 5.50) times those of stopping on placebo in studies 1 and 2, respectively; the odds of stopping on Champix were 1.96 (1.42, 2.72) to 1.89 (1.37, 2.61) times those of stopping on bupropion.
The 4W-CQR (weeks 9-12), CA (weeks 9-52) and LTQR (week 52) from studies 1 and 2 are included in Table 8.
Based on the key secondary endpoint of carbon monoxide confirmed (not even a puff of a cigarette) continuous abstinence from week 9 through week 52 (CA weeks 9-52), the odds of stopping on Champix were 2.66 (95% CI: 1.72, 4.11) and 3.13 (1.97, 4.97) times those of stopping on placebo in studies 1 and 2, respectively.
For the LTQR at 52 weeks the odds of stopping smoking on Champix were 3.30 (2.13, 5.11) and 2.40 (1.60, 3.60) times those of stopping on placebo in studies 1 and 2, respectively.

Patient reported craving, withdrawal and reinforcing effects of smoking.

In studies 1 and 2, three aspects of smoking cessation were investigated using validated patient reported outcomes questionnaires: craving, measured by brief questionnaire of smoking urges (QSU-Brief) and Minnesota nicotine withdrawal scale (MNWS) urge to smoke item; withdrawal, measured by 4 MNWS subscales; and reinforcing effects of smoking, measured by five modified cigarette evaluation questionnaire (mCEQ) subscales.
Across both studies 1 and 2, craving and withdrawal were significantly reduced in patients randomised to Champix in comparison with placebo. Champix also significantly reduced reinforcing effects of smoking that can perpetuate smoking behaviour in patients who smoke during treatment compared with placebo.

Maintenance of abstinence study.

The third study assessed the benefit of an additional 12 weeks of Champix therapy on the maintenance of abstinence. Patients in this study (n = 1,927) received open label Champix 1 mg twice daily for 12 weeks. Patients who stopped smoking by week 12 were then randomised to receive either Champix (1 mg twice daily) or placebo for an additional 12 weeks for a total study duration of 52 weeks.
The primary study endpoint was the CO confirmed continuous abstinence rate from week 13 through week 24 in the double blind treatment phase. The two key secondary endpoints were the continuous abstinence (CA) rate for week 13 through week 52 and the long-term quit rate (LTQR) at week 52.
The key results are summarised in Table 9.
This study showed the benefit of an additional 12 week treatment with Champix 1 mg twice daily for the maintenance of smoking cessation compared to placebo. The odds of maintained abstinence at week 24, following an additional 12 weeks of treatment with Champix, were 2.47 times those for placebo (95% CI: 1.95, 3.15). Superiority to placebo for continuous abstinence was maintained through week 52 (odds ratio = 1.35, 95% CI: 1.07, 1.70).

Flexible quit date study.

The effect of varenicline 1 mg twice a day in a flexible, patient-selected quit date setting was assessed in a double-blind, placebo-controlled study of 651 patients. Patients were randomised 3:1 to varenicline or placebo for a treatment of 12 weeks and a followed up post-treatment for another 12 weeks. In this study, 486 patients received varenicline and 165 received placebo. Patients were instructed to select a quit date after the initial week of dose titration and before the clinical visit at the end of week 5 of treatment. Patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (53.94%) compared to patients treated with placebo (19.4%) (odds ratio 6.03; 95% CI 3.80, 9.56; p < 0.0001) and from week 9 through 24 (35.2%) compared to patients treated with placebo (12.73%) (odds ratio 4.45; 95% CI 2.62, 7.55; p < 0.0001). Adverse events in this study were quantitatively and qualitatively similar to those observed in premarketing studies.
The key results are summarised in Table 10.

Retreatment with varenicline study.

Varenicline was evaluated in a double-blind, placebo-controlled trial of 494 patients who had made a previous attempt to quit smoking with varenicline, and either did not succeed in quitting or relapsed after treatment. Subjects were randomised 1:1 to varenicline 1 mg twice daily (N=249) or placebo (N=245) for 12 weeks of treatment and followed for up to 40 weeks post-treatment. Patients included in this study had taken varenicline for a smoking-cessation attempt in the past (for a total treatment duration of a minimum of two weeks), at least three months prior to study entry, and had been smoking for at least four weeks.
Patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (45.0%) compared to patients treated with placebo (11.8%) (odds ratio 7.08; 95% CI 4.34, 11.55; p < 0.0001) and from weeks 9 through 52 (20.1%) compared to subjects treated with placebo (3.3%) (odds ratio 9.00; 95% CI 3.97, 20.41; p < 0.0001).
Adverse events in this study were quantitatively and qualitatively similar to those observed in premarketing studies.
The key results are summarised in Table 11.

Cardiovascular disease study.

Varenicline was evaluated in a randomised, double blind, placebo controlled study of 703 patients with stable, documented cardiovascular disease (other than or in addition to hypertension) that had been diagnosed for more than 2 months. Patients aged 35 to 75 years were randomised to varenicline 1 mg twice a day or placebo for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Patients treated with varenicline had a superior rate of CO confirmed abstinence during weeks 9 through 12 (47.3%) compared to patients treated with placebo (14.3%) (odds ratio 6.05; 95% CI 4.13, 8.86; p < 0.0001) and from week 9 through 52 (19.8%) compared to patients treated with placebo (7.4%) (odds ratio 3.19; 95% CI 1.97, 5.18; p < 0.0001).
The key results are summarised in Table 12.

Chronic obstructive pulmonary disease (COPD) study.

Varenicline was evaluated in a randomised, double blind, placebo controlled study of patients aged ≥ 35 years with mild to moderate COPD with postbronchodilator FEV1/FVC < 70% and FEV1 ≥ 50% of predicted normal value. Patients were randomised to varenicline 1 mg twice daily (N = 223) or placebo (N = 237) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Patients treated with varenicline had a superior rate of CO confirmed abstinence during weeks 9 through 12 (41.7%) compared to patients treated with placebo (9.3%) and from week 9 through 52 (19.7%) compared to patients treated with placebo (5.9%).
The key results are summarised in Table 13.

Major depressive disorder (MDD) study.

Varenicline was evaluated in a randomised, double blind, placebo controlled study of 525 subjects with major depressive disorder without psychotic features (DSM-IV TR), on stable antidepressant treatment and/or who experienced a major depressive episode in the past 2 years and were successfully treated. Subjects aged 18 to 75 years were randomised to varenicline 1 mg BID or placebo for a treatment of 12 weeks and then followed for 40 weeks post-treatment. Subjects treated with varenicline had a superior rate of CO confirmed abstinence during weeks 9 through 12 (35.9%) compared to subjects treated with placebo (15.6%) (odds ratio 3.35; 95% CI 2.16, 5.21; p < 0.0001) and from week 9 through 52 (20.3%) compared to subjects treated with placebo (10.4%) (odds ratio 2.36; 95% CI 1.40, 3.98; p = 0.0011).
The most common adverse events (≥ 10%) in subjects taking varenicline were nausea (27.0% vs. 10.4% on placebo), headache (16.8% vs. 11.2%), abnormal dreams (11.3% vs. 8.2%), insomnia (10.9% vs. 4.8%) and irritability (10.9% vs. 8.2%). Additionally, the following psychiatric AEs were reported in ≥ 2% of patients in either treatment group (varenicline or placebo, respectively): anxiety (7.0% vs. 9.3%), agitation (6.6% vs. 4.1%), depression (6.6% vs. 4.8%), tension (3.5% vs. 3.0%), depressed mood (2.7% vs. 3.7%), sleep disorder (2.7% vs. 1.5%), hostility (2.0% vs. 0.4%) and restlessness (2.0% vs. 1.9%). Psychiatric scales showed no differences between the varenicline and placebo groups and no overall worsening of depression during the study in either treatment group.
The percentage of subjects with suicidal ideation and/or behaviour was similar between the varenicline and placebo groups during treatment (6.0% and 7.5%, respectively) and the nontreatment follow-up (6.2% and 5.8%, respectively). There was one event of intentional self injury/ possible suicide attempt during treatment (day 73) in a subject with history of alcohol abuse in the placebo group.
The key efficacy results are summarised in Table 14.

Stable schizophrenia or schizoaffective disorder study.

Varenicline safety and tolerability was assessed in a double blind study of 128 smokers with stable schizophrenia or schizoaffective disorder, on antipsychotic medication, randomised 2:1 to varenicline (1 mg twice daily) or placebo for 12 weeks with 12 week nondrug follow-up.
The most common adverse events in subjects taking varenicline were nausea (23.8% vs. 14.0% on placebo), headache (10.7% vs. 18.6% on placebo) and vomiting (10.7% vs. 9.3% on placebo). Among reported neuropsychiatric adverse events, insomnia was the only event reported in either treatment group in ≥ 5% of subjects at a rate higher in the varenicline group than in placebo (9.5% vs. 4.7%).
Overall, there was no worsening of schizophrenia in either treatment group as measured by psychiatric scales and there were no overall changes in extrapyramidal signs.
In the varenicline group compared to placebo, a higher proportion of subjects reported suicidal ideation or behaviour prior to enrolment (lifetime history) and after the end of active treatment period (on days 33 to 85 after the last dose of drugs). During the active treatment period, the incidence of suicide related events was similar between the varenicline treated and the placebo treated subjects (11 vs. 9.3%, respectively). The percentage of subjects with suicide related events in the active treatment phase compared to post-treatment phase was unchanged in the varenicline group; in the placebo group, this percentage was lower in the post-treatment phase. There were no completed suicides. There was one suicidal attempt in a varenicline treated subject whose lifetime history included several similar attempts. The limited data available from this single smoking cessation study is not sufficient to allow definitive conclusions to be drawn.

Gradual approach to quitting smoking study.

Varenicline was evaluated in a 52-week double-blind placebo-controlled study of 1,510 subjects who were not able or willing to quit smoking within four weeks, but were willing to gradually reduce their smoking over a 12 week period before quitting. Subjects were randomised to either varenicline 1 mg twice daily (n=760) or placebo (n=750) for 24 weeks and followed up post-treatment through week 52. Subjects were instructed to reduce the number of cigarettes smoked by at least 50 percent by the end of the first four weeks of treatment, followed by a further 50 percent reduction from week four to week eight of treatment, with the goal of reaching complete abstinence by 12 weeks. After the initial 12-week reduction phase, subjects continued treatment for another 12 weeks. Subjects treated with varenicline had a significantly higher Continuous Abstinence Rate compared with placebo at weeks 15 through 24 (32.1% vs 6.9%; odds ratio 8.74; 95% CI 6.09, 12.53; p < 0.0001) and weeks 21 through 52 (27.0% vs 9.9%; odds ratio 4.02; 95% CI 2.94, 5.50; p < 0.0001).
The key results are summarised in Table 15.

Neuropsychiatric safety study in patients with and without a history of psychiatric disorder.

Varenicline was evaluated in a randomised, double-blind, active and placebo-controlled study that included subjects with a history of psychiatric disorder (psychiatric cohort, N=4074) and subjects without a history of psychiatric disorder (nonpsychiatric cohort, N=3984). Subjects aged 18-75 years, smoking 10 or more cigarettes per day were randomised 1:1:1:1 to varenicline 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy (NRT) patch 21 mg/day with taper or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment.
The primary safety endpoint was a composite of the following neuropsychiatric (NPS) adverse events: severe events of anxiety, depression, feeling abnormal, or hostility, and moderate or severe events of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behaviour or completed suicide.
The most commonly reported adverse events in subjects treated with varenicline in this study were similar to those observed in premarketing studies.
Adverse events reported in ≥ 10% of subjects treated with varenicline in the entire population of this study were nausea (25.3% vs 6.8% on placebo), headache (12.2% vs 9.9% on placebo) and abnormal dreams (10% vs 4.6% on placebo) (see Section 4.8 Adverse Effects (Undesirable Effects), Special populations).
In both cohorts, subjects treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 and 9 through 24 compared to subjects treated with bupropion, NRT patch and placebo.
The key efficacy results are summarised in Table 16.

Paediatric and adolescent population.

The efficacy and safety of varenicline was evaluated in a randomised, double-blind, placebo controlled study of 312 patients aged 12 to 19 years, who smoked an average of at least 5 cigarettes per day during the 30 days prior to recruitment and had a score of at least 4 on the Fagerstrom test for nicotine dependence. Patients were stratified by age (12 to 16 years of age and 17 to 19 years of age) and by body weight (≤ 55 kg and > 55 kg). Following a two week titration, patients randomised to varenicline with a body weight > 55 kg received 1 mg twice daily (high dose group) or 0.5 mg twice daily (low dose group), while patients with a body weight ≤ 55 kg received 0.5 mg twice daily (high dose group) or 0.5 mg once daily (low dose group). Patients received treatment for 12 weeks, followed by a non treatment period of 40 weeks, along with age-appropriate counseling throughout the study.
Results from this study showed that neither varenicline dose significantly increased continuous abstinence rates at weeks 9 through 12 of treatment compared with placebo in subjects 12 to 19 years of age. The varenicline safety profile in this study was consistent with that shown in adult studies. (See Section 4.2 Dose and Method of Administration, Use in paediatric and adolescent patients; Section 5.2 Pharmacokinetic Properties, Use in paediatric and adolescent patients).

5.2 Pharmacokinetic Properties

Absorption.

Maximum plasma concentrations of varenicline tartrate occur typically within 3-4 hours after oral administration. Mean (SD) Cmax was 9.22 (2.05) nanogram/mL at the recommended dose of 1 mg twice daily. Following administration of multiple oral doses to healthy volunteers, steady-state conditions were reached within 4 days. Varenicline tartrate exhibits linear kinetics when given as single or repeated doses. Absorption is virtually complete after oral administration and systemic availability is high. Oral bioavailability of varenicline tartrate is unaffected by food or time of day dosing.

Distribution.

Plasma protein binding of varenicline tartrate is low (< 20%) and independent of both age and renal function. Apparent volume of distribution averaged 415 litres (% CV = 50) at steady state.

Metabolism.

Varenicline tartrate undergoes minimal metabolism with 92% eliminated unchanged in the urine.

Elimination.

The elimination half-life of varenicline tartrate is approximately 24 hours (individual range 10-58 hr). Renal elimination of varenicline tartrate is primarily through glomerular filtration along with active tubular secretion via the organic cationic transporter, OCT2.

Special populations.

There are no clinically meaningful differences in varenicline tartrate pharmacokinetics due to age, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.

Hepatic impairment.

Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic insufficiency and the potential for clinically meaningful drug interactions between varenicline and metabolic inhibitors/ inducers is low.

Renal impairment.

Varenicline tartrate pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance > 50 mL/min and ≤ 80 mL/min); in patients with moderate renal impairment (estimated creatinine clearance ≥ 30 mL/min and ≤ 50 mL/min), varenicline tartrate exposure increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance > 80 mL/min). In subjects with severe renal impairment (estimated creatinine clearance < 30 mL/min), varenicline tartrate exposure increased 2.1-fold. In subjects with endstage renal disease (ESRD), varenicline tartrate was efficiently removed by haemodialysis. While no dosing adjustment is necessary for patients with mild to moderate renal impairment, a reduced dosing frequency of 1 mg once daily is recommended for patients with severe renal impairment (see Section 4.2 Dose and Method of Administration). Dosing should begin at 0.5 mg once daily for the first 3 days, and then increase to 1 mg once daily.

Elderly (> 65 years).

No dosage adjustment is necessary for elderly patients (see Section 4.2 Dose and Method of Administration).
A combined single and multiple dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline tartrate given once or twice daily to 16 healthy elderly male and female smokers (aged 65-75 years) for 7 consecutive days were similar to that of younger subjects.

Use in paediatric and adolescent patients.

Champix is not recommended for use in patients under 19 years of age because its efficacy in this population was not demonstrated.
Single and multiple dose pharmacokinetics of varenicline have been investigated in paediatric subjects aged 12 to 17 years old (inclusive) and were approximately dose proportional over the 0.5 mg to 2 mg daily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight > 55 kg, as assessed by AUC (0-24), was comparable to that noted for the same doses in the adult population. When a 0.5 mg dose was given twice a day, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤ 55 kg compared to that seen in the adult population (see Section 4.2 Dose and Method of Administration, Use in paediatric and adolescent patients; Section 5.1 Pharmacodynamic Properties, Clinical trials, Paediatric and adolescent population).

5.3 Preclinical Safety Data

Carcinogenicity.

Carcinogenicity studies were performed in mice and rats at respective oral doses of varenicline up to 20 mg/kg/day and 15 mg/kg/day for 2 years, with respective systemic drug exposure (Cmax) up to 130 and 50 times the human plasma Cmax at the maximal recommended dose of 1 mg twice daily. There was no evidence of carcinogenicity in mice or female rats. Male rats showed increased incidences of hibernoma (a rare tumour of brown fat) at systemic exposures of 25 times the human Cmax (incidence 1/65 rats) and 50 times the human Cmax (incidence 2/65 rats); the no effect exposure was 10 times the human Cmax. The clinical relevance of this finding has not been established.

Genotoxicity.

Varenicline had no genotoxic effects, with or without metabolic activation, based on the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenic aberrations in vivo in rat bone marrow and in vitro in human lymphocytes.

6 Pharmaceutical Particulars

6.1 List of Excipients

Cellulose-microcrystalline, Calcium hydrogen phosphate, Croscarmellose sodium, Silica-colloidal anhydrous, Magnesium stearate, Opadry White (for 0.5 mg), Opadry Blue (for 1 mg) and Opadry Clear.

6.2 Incompatibilities

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

6.3 Shelf Life

2 years.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Champix tablets are presented in PVC or Aclar/PVC blisters with aluminium foil backing, or high-density polyethylene (HDPE) bottles with polypropylene child resistant closure and an aluminium foil/polyethylene induction seal, in the following pack sizes (not all presentations marketed):
Initiation pack containing 11 x 0.5 mg film-coated tablets and 42 x 1 mg film-coated tablets in blisters within a secondary heat sealed wallet.
Composite carton containing 11 x 0.5 mg film-coated tablets and 42 x 1 mg film-coated tablets in blisters. This carton contains two heat sealed wallets. The first heat sealed wallet consists of an initial dosing pack containing 11 x 0.5 mg tablets and 14 x 1 mg tablets. The second heat sealed wallet consists of 28 x 1 mg tablets.
Continuation pack containing 56 x 1 mg film-coated tablets in blisters within a carton or secondary heat sealed wallet.
Composite pack containing one blister of 11 x 0.5 mg film-coated tablets and a second blister of 14 x 1 mg film-coated tablets in a carton or a heat sealed wallet.
Blisters containing 28 or 140 x 1 mg film-coated tablets in a carton or secondary heat sealed card packaging.
Bottle containing 56 x 1 mg film-coated tablets.

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

Varenicline tartrate powder is a white to off white to slightly yellow solid. It is highly soluble in water. The pKa (ionisation constant) for varenicline is 9.2. The octanol-water partition coefficient (log D) of varenicline tartrate is -1.23 at pH 5, -0.817 at pH 7 and 0.758 at pH 9.
Chemical name: 7,8,9,10-tetrahydro-6, 10-methano-6H-pyrazino [2,3-h][3]benzazepine, (2R,3R)-2, 3-dihydroxybutanedioate (1:1). Molecular weight: 361.35 Daltons. Molecular formula: C13H13N3.C4H6O6.

Chemical structure.


CAS number.

CAS Registry No: 375815-87-5.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes