Consumer medicine information

Victoza

Liraglutide

BRAND INFORMATION

Brand name

Victoza

Active ingredient

Liraglutide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Victoza.

What is in this leaflet

What is in this leaflet

What Victoza® is used for

Before you use Victoza®

How to use Victoza®

While you are using Victoza®

Things to be careful of

Side effects

After using Victoza®

Product description

Further information

Instructions For Use

This leaflet answers some common questions about Victoza®.

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

All medicines have risks and benefits. Your doctor has weighed the risks of you using Victoza® against the benefits they expect it will have for you.

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

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

What Victoza® is used for

Victoza® contains the active ingredient liraglutide. This belongs to a group of medicines called ‘GLP-1 receptor agonists’. Victoza® is an injection that is used once a day.

Victoza® is used to treat type 2 diabetes mellitus.

Diabetes mellitus is a condition where your pancreas does not produce enough insulin to control your blood sugar (glucose) level.

If you have type 2 diabetes mellitus your body is also not able to use insulin properly.

Victoza® helps your body to produce more insulin when your blood sugar level is high.

Victoza® is used on its own if your blood sugar is not properly controlled by diet and exercise alone and you cannot use metformin (another diabetes medicine). Victoza® is also able to be used with other medicines for diabetes when they are not enough to control your blood sugar levels.

Victoza® is used in addition to standard of care therapy to reduce the risk of a heart disease related event if you are at an increased risk for heart disease and have elevated blood sugar levels.

Victoza® has not been studied in children and should not be used in children or adolescents under 18 years.

Victoza® is not addictive.

Victoza® is available only with a doctor’s prescription.

Ask your doctor, diabetes education nurse or pharmacist if you have any questions about why Victoza® has been prescribed for you.

Before you use Victoza®

When you must not use it

Do not use Victoza® if you are allergic (hypersensitive) to liraglutide or to any of the ingredients listed in the “Ingredients” section at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • redness, swelling, rash and itching at the injection site
  • rash, itching or hives on the skin
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body.

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

Do not use 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.

Before you start to use it

Tell your doctor if:

  • you are also taking medicines for your diabetes that contain sulfonylurea (such as glimepiride or glibenclamide) or insulin. Your doctor may tell you to test your blood sugar levels. This will help your doctor to decide if the dose of the sulfonylurea or insulin needs to be changed to avoid you getting hypoglycaemia (low blood sugar).
  • you have severe heart failure (disease of the heart with shortness of breath and swelling of the feet or legs due to fluid build-up).
  • you have inflammatory bowel disease, such as Crohn's disease.
  • you have diabetic gastroparesis (a condition in which your stomach has difficulty in emptying food properly).
  • you currently have or have had thyroid disease.
  • you have or have had a disease of the pancreas.
  • you have kidney problems.
  • you are on dialysis.

Drink plenty of fluids to avoid dehydration if you experience vomiting or diarrhoea when beginning treatment with Victoza®. Dehydration can lead to kidney problems, particularly in patients who have pre-existing kidney disease.

If you notice your urine changes appearance or you produce urine less frequently, see your doctor. Contact your doctor if you have any questions or concerns.

Victoza® should not be used if you have type 1 diabetes or diabetic ketoacidosis (a complication of diabetes with high blood sugar and an increase in the effort required to breathe). Victoza® is not an insulin.

If you experience symptoms of acute pancreatitis, like persistent, severe stomach ache, you should consult your doctor.

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

Tell your doctor if you are pregnant or plan to become pregnant. Use of this medicine in pregnancy has not been studied. Victoza® should not be used during pregnancy. It is not known if Victoza® may harm your unborn child.

Tell your doctor if you are breast-feeding or plan to breast-feed. It is not known if Victoza® passes into breast milk. Do not use Victoza® if you are breast-feeding.

If you have not told your doctor about any of the above, tell them before you use Victoza®.

Taking other medicines

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

In particular, tell your doctor if you are using medicines containing any of the following active ingredients:

  • A sulfonylurea (such as glimepiride or glibenclamide), and/or insulin for your diabetes. This is because using Victoza® at the same time may cause your blood sugar level to become too low (hypoglycaemia or a “hypo”).
    - When you first start using these medicines together, your doctor may tell you to lower the dose of the sulfonylurea or insulin.
    - If you are also taking a sulfonylurea and/or insulin together with Victoza®, your doctor may ask you to test your blood sugar levels to begin with. This will help your doctor to decide if the dose of the sulfonylurea and/or insulin needs to be changed.
  • Warfarin or other anticoagulants(medicines that thin your blood) called ‘coumarin derivatives’. Your doctor may need to monitor you more closely.

Tell your doctor about any other medicines that you are taking. This is very important. Your doctor will advise you if it is all right to keep taking them or if you should stop taking them.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How to use Victoza®

Your doctor, diabetes education nurse or pharmacist will have given you advice on how to use your medicine.

Carefully follow all the directions. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor, diabetes education nurse or pharmacist for help.

Victoza® is supplied as a pre-filled pen containing liraglutide. The Victoza® pen can give 15 doses of 1.2 mg or 10 doses of 1.8 mg. The Victoza® pen can also give starting doses of 0.6 mg.

How much to use

Your doctor or diabetes education nurse will tell you how much of this medicine you need to use.

  • The usual starting dose is 0.6 mg once a day.
  • Your doctor will tell you how long to keep taking this dose. It will be for at least one week.
  • Your dose may then be increased to 1.2 mg once a day.
  • If your blood sugar level is not controlled with a dose of 1.2 mg, your doctor may increase the dose to 1.8 mg once a day.
  • Do not change your dose unless your doctor has told you to. Any change in dose should be made cautiously and only under medical supervision.

When to use it

You can inject Victoza® at any time of day. It is preferable to inject Victoza® at about the same time each day, at a time that is most convenient for you.

Victoza® does not need to be injected at mealtimes.

How to use it

  • Inject Victoza® under the skin (subcutaneous injection) as shown to you by your doctor or diabetes education nurse. Never inject Victoza® into a vein or muscle.
  • Victoza® may be injected into the front of your waist (abdomen), the front of your thigh, or your upper arm.
  • Change the place within the area where you inject each day to reduce the risk of developing lumps under the skin. See ‘Side effects’.
  • Victoza® pen is designed to be used with NovoFine® needles, up to a length of 8 mm and as thin as 32G. Needles are not included with the pen.
  • Ask your doctor or diabetes education nurse which needle width (gauge) and length is best for you.
  • Use a new needle for each injection and dispose of it after use.

Checking your Victoza® pen:

Victoza® should be clear and colourless, or almost colourless.

Do not use this medicine if it is thickened, coloured, or has solid bits in it.

Victoza® should not be used if it has been frozen.

Read the instructions printed later in this leaflet carefully in order to prepare and handle your Victoza® pen correctly.

How long to use it

Do not stop using Victoza® unless your doctor tells you to.

If you use too much (overdose)

If you use more Victoza® than you should, talk to your doctor straight away. You may need medical treatment. Overdose may cause nausea, vomiting, diarrhoea or low blood sugar (hypoglycaemia). See 'Side effects' for the early warning signs of hypos.

If you forget to use it

If you forget a dose, use Victoza® as soon as you remember.

However, if it is more than 12 hours since you should have used Victoza®, skip the missed dose. Then take your next dose as usual the following day.

Do not take an extra dose or increase the dose on the following day to make up for the missed dose.

If you are not sure what to do, talk to your doctor, diabetes education nurse or pharmacist.

While you are using Victoza®

Things you must do

Make sure all your friends, relatives, workmates or carers know that you have diabetes.

Tell your doctor if you often have hypos (low blood sugar levels). When Victoza® is used with a sulfonylurea or with insulin (other medicines for diabetes), hypos can occur. The dose of your sulfonylurea or insulin may need to be reduced while you take Victoza®.

If you experience any of the symptoms of a hypo, immediately eat some sugary food or have a sugary drink, e.g. lollies, biscuits or fruit juice.

Tell your doctor, diabetes education nurse or pharmacist if you are travelling. Ask them for a letter explaining why you are taking injecting devices with you. Each country you visit will need to see this letter, so you should take several copies.

You may not be able to get Victoza® in the country you are visiting.

Your doctor, diabetes education nurse or pharmacist can provide you with some helpful information.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using Victoza®.

Things you must not do

Do not stop using your medicine unless your doctor tells you to. If you stop using it, your blood sugar levels may increase.

Do not use Victoza® in combination with other medicines that work in the same way (also contain ‘GLP-1 receptor agonists’). Ask your doctor, pharmacist or diabetes education nurse if you are not sure what to do.

Do not use this medicine if you think it has been frozen or exposed to excessive heat. It will not work as well.

Do not use this medicine 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 share your pen or needles with anyone else.

Things to be careful of

While you are driving or using tools or machines, you should avoid getting low blood sugar (hypoglycaemia), because this may reduce your ability to concentrate. Your doctor will tell you how to do this.

Side effects

Tell your doctor, diabetes education nurse or pharmacist as soon as possible if you do not feel well while you are using Victoza®.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment 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, diabetes education nurse or pharmacist to answer any questions you may have.

The most common side effects when using Victoza® are diarrhoea and nausea (feeling sick). These side effects are usually mild and normally decrease with continued use.

Tell your doctor if you notice any of the following and they worry you:

  • low blood sugar (a hypo).

Hypos are more likely to occur if you are also taking a sulfonylurea or insulin for your diabetes. A hypo may come on suddenly. The warning signs of a hypo can include:

  • cold sweat, cool pale skin
  • headache
  • feeling sick
  • feeling very hungry
  • changes in vision
  • feeling sleepy, feeling weak
  • feeling nervous or anxious, shaking (tremor), fast heart beat
  • feeling confused, difficulty concentrating.

Your doctor can provide you with further information about how to treat low blood sugar levels and what to do if you notice these warning signs. If you are already taking a sulfonylurea or insulin, your doctor may reduce the dose of these medicines before you start using Victoza®.

  • anorexia (no appetite)
  • decreased appetite
  • headache
  • vomiting (being sick)
  • indigestion (dyspepsia)
  • burping, wind (flatulence) or constipation
  • heartburn
  • painful or swollen stomach (abdomen)
  • blocked or runny nose, sneezing, cough and/or sore throat (upper respiratory tract infection)
  • injection site reactions (such as bruising, pain, irritation, itching and rash)
  • fast heart beat
  • feeling tired
  • increase of pancreatic enzymes (such as lipase and amylase). This can only be detected with a blood test.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor if you experience:

  • rash or urticaria (a type of skin rash)
  • itching
  • malaise (feeling unwell)
  • dehydration, sometimes with a decrease in kidney function
  • change in how things taste (dysguesia).

When initiating treatment with Victoza®, you may in some cases experience dehydration as a result of vomiting, nausea or diarrhoea. It is important to avoid dehydration by drinking plenty of fluids.

Lumps under the skin may be caused by build-up of a protein called amyloid (cutaneous amyloidosis; how often this occurs is not known). Victoza® may not work very well if you inject into a lumpy area. Change the injection site with each injection to help prevent this skin change.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • severe and persistent pain in the abdomen (stomach area) which might reach through to your back, as well as nausea and vomiting. These can be symptoms of acute inflammation of the pancreas (pancreatitis). Pancreatitis can be a serious, potentially life-threatening medical condition. These can also be symptoms of an inflamed gallbladder or gallstones, which can be serious.
  • a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These can be symptoms of a condition called 'goitre'.
  • a severe allergic reaction. Some symptoms may include:
    - skin rashes over a large part of the body
    - shortness of breath, wheezing
    - swelling of the face, lips or tongue
    - fast pulse
    - sweating.

This list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are uncommon, rare or very rare. Tell your doctor if you notice anything else that is making you feel unwell.

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

Ask your doctor, diabetes education nurse or pharmacist to answer any questions you have.

After using Victoza®

Storage

Before opening:
Keep your unopened Victoza® pens in a refrigerator (2°C to 8°C). Keep away from the cooling element. Do not freeze.

During use:
While you are using your Victoza® pen you can keep it for 1 month either at room temperature (not above 30°C), or in a refrigerator (2°C to 8°C), away from the cooling element. Do not freeze. Store the pen without a needle attached.

Discard the Victoza® pen you are using after 1 month even if there is still some medicine left in it.

The medicine in Victoza® must not be frozen, or exposed to heat or direct sunlight. When you are not using the pen, keep the pen cap on in order to protect from light. Never use Victoza® after the expiry date printed on the pen label and carton. Expiry is the last day of the month.

Never use Victoza® if the solution is not clear and colourless, or almost colourless.

Keep out of the reach of children.

Disposal

Dispose of used needles safely into a yellow plastic sharps container.

If your doctor tells you to stop using 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

Victoza® is supplied as a clear and colourless, or almost colourless solution for injection in a pre-filled pen. One mL solution for injection contains 6 mg liraglutide. One pre-filled pen contains 18 mg liraglutide.

Each pen contains 3 mL of solution, delivering 30 doses of 0.6 mg, 15 doses of 1.2 mg or 10 doses of 1.8 mg.

Victoza® is available in packs containing 1, 2 or 3 pens. Not all pack sizes may be marketed.

Ingredients

Victoza® contains liraglutide (rys) 6 mg/mL as the active ingredient. The abbreviation “rys” indicates the method of genetic engineering used to manufacture liraglutide.

Victoza® also contains the following inactive ingredients:

  • dibasic sodium phosphate dihydrate
  • propylene glycol
  • phenol
  • hydrochloric acid
  • sodium hydroxide
  • water for injections.

Sponsor

Victoza® is supplied in Australia by:

Novo Nordisk Pharmaceuticals Pty. Ltd.
Level 10
118 Mount Street
North Sydney NSW 2060

Australian Registration Number:
AUST R 153980

Victoza® is supplied in New Zealand by:

Novo Nordisk Pharmaceuticals Ltd.
11-19 Customs Street West,
Commercial Bay Tower,
Level 18, Office 1834
Auckland 1010
New Zealand

Victoza® and NovoFine® are trademarks owned by Novo Nordisk A/S.

© 2023
Novo Nordisk A/S

Further information

For further information call Novo Nordisk Customer Care on 1800 668 626 (AU) or 0800 733 737 (NZ).

You can also get more information about diabetes from:

Diabetes Australia
freecall helpline 1300 136 588
www.diabetesaustralia.com.au

Diabetes New Zealand
Freecall helpline 0800 342 238
www.diabetes.org.nz

Always check the following websites to ensure you are reading the most recent version of the Victoza® consumer medicine information:

Australia
www.novonordisk.com.au
https://www.ebs.tga.gov.au/

New Zealand
www.novonordisk.co.nz
www.medsafe.govt.nz/

This leaflet was prepared in May 2023

Instructions For Use

Please read these instructions carefully before using your Victoza® pen.

Your Victoza® pen contains 18 mg of liraglutide. You can select doses of 0.6 mg, 1.2 mg and 1.8 mg.

Victoza® pen is designed to be used with NovoFine® disposable injection needles up to a length of 8 mm and as thin as 32G. Needles are not included in the pack.

Prepare your Victoza® pen

Check the name and coloured label of your pen to make sure that it contains Victoza®. Using the wrong medicine could cause severe harm.

A. Pull off the pen cap.

B. Pull off the paper tab from a new disposable needle. Screw the needle straight and tightly onto your pen.

C. Pull off the outer needle cap and keep it for later.

D. Pull off the inner needle cap and dispose of it.

  • Always use a new needle for each injection. This reduces the risk of contamination, infection, leakage of Victoza®, blocked needles and inaccurate dosing.
  • Be careful not to bend or damage the needle.
  • Never try to put the inner needle cap back on the needle. You may stick yourself with the needle.

Caring for your pen

  • Do not try to repair your pen or pull it apart.
  • Keep your pen away from dust, dirt and all kinds of liquids.
  • Clean the pen with a cloth moistened with a mild detergent.
  • Do not try to wash, soak or lubricate it – this can damage the pen.

Important information

  • Do not share your Victoza® pen or needles with anyone else.
  • Keep your Victoza® pen out of reach of others, especially children.

With each new pen, check the flow

Check the flow before your first injection with each new pen. If your pen is already in use, go to ‘Select your dose’, step H.

E. Turn the dose selector until the flow check symbol lines up with the pointer.

F. Hold the pen with the needle pointing up. Tap the cartridge gently with your finger a few times. This will make any air bubbles collect at the top of the cartridge.

G. Keep the needle pointing up and press the dose button until 0 mg lines up with the pointer.

A drop of Victoza® should appear at the needle tip. If no drop appears, repeat steps E to G up to four times.

If there is still no drop of Victoza®, change the needle and repeat steps E to G once more.

Do not use the pen if a drop of Victoza® still does not appear. This indicates the pen is defective and you must use a new one.

  • If you have dropped your pen against a hard surface or suspect that something is wrong with it, always put on a new disposable needle and check the flow before you inject.

Select your dose

Always check that the pointer lines up with 0 mg.

H. Turn the dose selector until your required dose lines up with the pointer (0.6 mg, 1.2 mg or 1.8 mg).

If you select an incorrect dose by mistake, simply change it by turning the dose selector backwards or forwards until the right dose lines up with the pointer.

Be careful not to press the dose button when turning the dose selector backwards, as Victoza® may come out.

If the dose selector stops before your required dose lines up with the pointer, there is not enough Victoza® left for a full dose. Then you can either:

Divide your dose into two injections:
Turn the dose selector in either direction until 0.6 mg or 1.2 mg lines up with the pointer. Inject the dose. Then prepare a new pen for injection and inject the remaining number of mg to complete your dose.

  • You may only divide your dose between your current pen and a new pen if trained or advised by your doctor or diabetes education nurse. Use a calculator to plan the doses. If you divide the dose incorrectly, you may inject too much or too little Victoza®.

Inject the full dose with a new pen:
If the dose selector stops before 0.6 mg lines up with the pointer, prepare a new pen and inject the full dose with the new pen.

  • Do not try to select doses other than 0.6 mg, 1.2 mg or 1.8 mg. The numbers in the display must line up precisely with the pointer to ensure that you get the correct dose. The dose selector clicks when you turn it. Do not use these clicks to select your dose. Do not use the cartridge scale to measure how much Victoza® to inject – it is not accurate enough.

Inject your dose

Insert the needle into your skin using the injection technique shown by your doctor or diabetes education nurse. Then follow the instructions below:

I. Press the dose button to inject until 0 mg lines up with the pointer.

Be careful to only push the dose button when injecting. Turning the dose selector will not inject Victoza®. Be careful not to touch the display with your other fingers or press the dose selector sideways when you inject. This is because it may block the injection.

Keep the dose button pressed down and leave the needle under the skin for at least 6 seconds. This is to make sure that you get your full dose.

J. Pull out the needle.

After that, you may see a drop of Victoza® at the needle tip. This is normal and does not affect your dose.

K. Guide the needle tip into the outer needle cap without touching the needle or the outer needle cap.

L. When the needle is covered, carefully push the outer needle cap completely on. Then unscrew the needle. Dispose of it carefully and put the pen cap back on.

When the pen is empty, carefully dispose of it without a needle attached. Dispose of pens and needles into a yellow plastic sharps container.

  • Always remove the needle after each injection, and store your Victoza® pen without a needle attached.
  • This reduces the risk of contamination, infection, leakage of Victoza®, blocked needles and inaccurate dosing.
  • Healthcare professionals, relatives and other carers should follow general precautionary measures for removal and disposal of needles, to prevent needle injury and cross-infection.

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Victoza

Active ingredient

Liraglutide

Schedule

S4

 

1 Name of Medicine

Liraglutide (rys).

2 Qualitative and Quantitative Composition

Victoza contains liraglutide, a human glucagon-like peptide-1 (GLP-1) analogue that binds to and activates the GLP-1 receptor (GLP-1R). Liraglutide is produced by recombinant DNA technology using Saccharomyces cerevisiae.
Victoza is a solution for injection in a pre-filled pen. One mL of solution contains 6 mg salt-free anhydrous liraglutide. One pre-filled pen contains 18 mg liraglutide in 3 mL. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Victoza is a solution for injection. It is a sterile, clear, colourless or almost colourless, isotonic solution, pH = 8.15.

4 Clinical Particulars

4.1 Therapeutic Indications

Glycaemic control.

Victoza is indicated as an adjunct to diet and exercise for treatment of adults with type 2 diabetes mellitus to achieve glycaemic control:
as monotherapy when metformin is contraindicated or is not tolerated;
in combination with other glucose lowering medicines.

Prevention of cardiovascular events.

In patients where Victoza is indicated to improve glycaemic control, Victoza is indicated to reduce the risk of cardiovascular events in those at high cardiovascular risk, as an adjunct to standard of care therapy (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Dosage.

To improve gastrointestinal tolerability, the starting dose is 0.6 mg Victoza daily. After at least one week, the dose should be increased to 1.2 mg. Based on clinical response and tolerability, and after at least one week, the dose can be increased to 1.8 mg to achieve maximum efficacy. Daily doses higher than 1.8 mg are not recommended.
Victoza may be used when previous therapies provide insufficient glycaemic control: in dual combination with metformin or a sulfonylurea; or in triple combination with metformin and sulfonylurea; or in combination with insulin with or without metformin.
When Victoza is added to existing metformin therapy, the current dose of metformin can be continued unchanged.
When Victoza is added to sulfonylurea therapy or to a combination of metformin and sulfonylurea therapy or insulin, a reduction in the dose of sulfonylurea or insulin should be considered to reduce the risk of hypoglycaemia (see Section 4.4 Special Warnings and Precautions for Use). During clinical trials physicians were advised, at their discretion, to lower the dose of the sulfonylurea by approximately half to minimise the risk of unacceptable hypoglycaemia.
Self monitoring of blood glucose is not needed in order to adjust the dose of Victoza. However, when initiating treatment with Victoza in combination with a sulfonylurea or an insulin, blood glucose self monitoring may become necessary to adjust the dose of the sulfonylurea or the insulin.
Victoza should not be used in combination with another GLP-1 receptor agonist.

Method of administration.

Victoza is administered once daily at any time, independent of meals, and can be injected subcutaneously in the abdomen, in the thigh or in the upper arm. Injection sites should always be rotated within the same region in order to reduce the risk of cutaneous amyloidosis (see Section 4.8 Adverse Effects (Undesirable Effects)). The injection site and timing can be changed without dose adjustment. However, it is preferable that Victoza is injected around the same time each day, when the most convenient time of the day has been chosen.
Victoza must not be administered intravenously or intramuscularly. The Victoza pen is for use by one person only.
Victoza can be administered with needles up to a length of 8 mm and as thin as 32G. The pen is designed to be used with NovoFine disposable needles. Needles are not included.
In case of a missed dose, Victoza should be administered as soon as possible within 12 hours from the time of the planned dose. If the dose is missed for more than 12 hours, Victoza should be taken as planned on the next day. An extra dose or an increased dose of Victoza must not be administered on the following day to make up for the missed dose.
Specific patient groups.

Elderly (> 65 years old).

No dose adjustment is required based on age (see Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

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

Patients with renal impairment.

No dose adjustment is required for patients with mild, moderate or severe renal impairment. There is no therapeutic experience in patients with end-stage renal disease and Victoza is therefore not recommended for use in these patients (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Children and adolescents.

Victoza is not recommended for use in children below 18 years of age. The safety and efficacy of Victoza in children and adolescents below age 18 have not been established. No data are available.

4.3 Contraindications

Victoza is not to be used in patients with hypersensitivity to liraglutide or any of its excipients.

4.4 Special Warnings and Precautions for Use

Victoza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Insulin is the correct treatment for these conditions.
Victoza is not a substitute for insulin. Insulin should not be discontinued in patients dependent on insulin.
Victoza must not be administered intravenously or intramuscularly.
There is no therapeutic experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and Victoza is therefore not recommended for use in these patients.
There is limited experience in patients with inflammatory bowel disease and diabetic gastroparesis. Use of Victoza is not recommended in these patients since it is associated with transient gastrointestinal adverse reactions, including nausea, vomiting and diarrhoea.

Dehydration and renal impairment.

Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported in patients treated with GLP-1 receptor agonists. Some of the events occurred in patients with pre-existing renal impairment and/or on medications that affect renal function. Although renal function improved with symptomatic treatment in most patients, some patients have required haemodialysis. Patients treated with Victoza should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Use in renal impairment.

There is no therapeutic experience in patients with end-stage renal disease and Victoza is therefore not recommended for use in these patients.

Thyroid disease.

Thyroid adverse events, such as goitre, have been reported in clinical trials, in particular in patients with pre-existing thyroid disease, and Victoza should therefore be used with caution in these patients.

Pancreatitis.

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Victoza should be discontinued; if acute pancreatitis is confirmed, Victoza should not be restarted. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis.
In glycaemic control clinical trials of Victoza in patients with type 2 diabetes, there have been 13 cases of pancreatitis among Victoza-treated patients and 1 case in a comparator (glimepiride) treated patient (2.1 vs 0.7 cases per 1000 patient-years). Nine of the 13 cases with Victoza were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a Victoza-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. In most cases, treatment of pancreatitis has led to recovery.
In the LEADER trial, acute pancreatitis was confirmed by adjudication in 18 Victoza-treated patients (1.1 cases per 1000 patient years of observation) and 23 placebo-treated patients (1.7 cases per 1000 patient years of observation), both on a background of standard of care. In addition, there were no cases of chronic pancreatitis confirmed by adjudication in Victoza-treated patients and 2 cases in placebo-treated patients. The LEADER trial enrolled 267 patients with a medical history of acute or chronic pancreatitis; of these, 2 out of 147 (1.4%) in the Victoza group and 6 out of 120 (5.0%) in the placebo group had a new event of acute pancreatitis confirmed by adjudication.

Hypoglycaemia.

Due to the glucose dependent insulinotropic mechanism of action of Victoza, when used in combination with metformin alone, no increase in the frequency of hypoglycaemia was observed over that of placebo in combination with metformin.
Patients receiving Victoza in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia (see Section 4.8 Adverse Effects (Undesirable Effects), Table 2). The risk of hypoglycaemia can be lowered by a reduction in the dose of sulfonylurea or insulin.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro assessment of drug-drug interaction.

Liraglutide has shown very low potential to be involved in pharmacokinetic interactions with other active substances related to cytochrome P450 (CYP) and plasma protein binding.

In vivo assessment of drug-drug interaction.

Drug-drug interaction has been investigated using medicines that were carefully selected to represent compounds of various degrees of solubility and permeability properties, including paracetamol (acetaminophen), digoxin, lisinopril, griseofulvin and atorvastatin. In addition, the effect of liraglutide on the absorption of ethinylestradiol and levonorgestrel administered in an oral combination contraceptive drug has been investigated.
The delay of gastric emptying caused by liraglutide may influence absorption of concomitantly administered oral medicinal products. Interaction studies did not show any clinically relevant delay of absorption of the compounds that were studied, however clinically relevant interactions with other compounds where the effect is dependent on Cmax and tmax, drugs with narrow therapeutic index, or medications associated with local gastrointestinal irritation (e.g. bisphosphonates, potassium chloride) cannot be excluded.
Few patients treated with liraglutide reported at least one episode of severe diarrhoea. Diarrhoea may affect the absorption of concomitant oral medicinal products.

Paracetamol (acetaminophen).

Liraglutide did not change the overall exposure of paracetamol following a single dose of 1000 mg. Paracetamol Cmax was decreased by 31% and median tmax was delayed up to 15 minutes. No dose adjustment for concomitant use of paracetamol is required.

Atorvastatin.

Liraglutide did not change the overall exposure of atorvastatin to a clinically relevant degree following single dose administration of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin is required when given with liraglutide. Atorvastatin Cmax was decreased by 38% and median tmax was delayed from 1 hour to 3 hours with liraglutide.

Griseofulvin.

Liraglutide did not change the overall exposure of griseofulvin following administration of a single dose of griseofulvin 500 mg. Griseofulvin Cmax increased by 37% while median tmax did not change. Dose adjustments of griseofulvin and other compounds with low solubility and high permeability are not required.

Digoxin.

A single dose administration of digoxin 1 mg with liraglutide resulted in a reduction of digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median time to maximum concentration (tmax) was delayed from 1 hour to 1.5 hours. No dose adjustment of digoxin is required based on these results.

Lisinopril.

A single dose administration of lisinopril 20 mg with liraglutide resulted in a reduction of lisinopril AUC by 15%; Cmax decreased by 27%. Lisinopril median tmax was delayed from 6 hours to 8 hours with liraglutide. No dose adjustment of lisinopril is required based on these results.

Oral contraceptives.

Liraglutide lowered ethinylestradiol and levonorgestrel Cmax by 12% and 13%, respectively, following administration of a single dose of an oral contraceptive product. Tmax was 1.5 hours later with liraglutide for both compounds. There was no clinically relevant effect on the overall exposure of either ethinylestradiol or levonorgestrel. The contraceptive effect is therefore anticipated to be unaffected when coadministered with liraglutide.

Warfarin and other coumarin derivatives.

No interaction study has been performed. A clinically relevant interaction with active substances with poor solubility or with narrow therapeutic index such as warfarin cannot be excluded. Upon initiation of Victoza treatment in patients on warfarin or other coumarin derivatives, more frequent monitoring of International Normalised Ratio (INR) is recommended.

Insulin.

No pharmacokinetic or pharmacodynamic interactions were observed between liraglutide and insulin detemir when administering a single dose of insulin detemir 0.5 U/kg with liraglutide 1.8 mg at steady state in patients with type 2 diabetes.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility were observed in male and female rats given subcutaneous doses of liraglutide at ≤ 1 mg/kg/day, yielding exposure to liraglutide (plasma AUC) 11-13 times higher than that of patients at the maximum recommended human dose.
(Category B3)
Increased embryofetal death and minor fetal skeletal abnormalities (kinked ribs) were observed in rats given liraglutide at 1 mg/kg/day by subcutaneous injection (yielding 11 times the plasma AUC in humans at the maximum recommended clinical dose). In rabbits treated at doses ≥ 0.01 mg/kg/day (relative exposure, ≥ 0.2), there was retardation of fetal growth and an increased incidence of several minor skeletal and visceral abnormalities. Postnatal bodyweight gain was reduced in the offspring of rats treated with liraglutide during gestation and lactation. These findings may have occurred secondary to reduced maternal food consumption. Placental transfer of liraglutide and/or its metabolites was demonstrated in the animal species.
There are limited data from the use of liraglutide in pregnant women. Victoza should not be used during pregnancy and the use of insulin is recommended. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Victoza should be discontinued.
It is not known whether Victoza is excreted in human milk. Studies in lactating rats have shown that the transfer of Victoza and metabolites of close structural relationship into milk is low. Due to lack of experience, Victoza must not be used during breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. It is unlikely that the ability to drive or use machines should be impaired by Victoza. Patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines, in particular when Victoza is used in combination with a sulfonylurea or insulin.

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

The most frequently reported adverse reactions during clinical trials were gastrointestinal disorders: nausea and diarrhoea were very common, whereas vomiting, constipation, abdominal pain, and dyspepsia were common. At the beginning of Victoza therapy these gastrointestinal adverse reactions may occur more frequently; these reactions usually diminish within a few days or weeks on continued treatment.
Headache and upper respiratory tract infections were also common. Furthermore, hypoglycaemia was common, and very common when Victoza was used in combination with sulfonylurea or insulin. Severe hypoglycaemia has primarily been observed when combined with a sulfonylurea.

Tabulated summary of adverse reactions.

Table 1 lists adverse reactions reported in long-term phase 3a controlled trials, the LEADER trial and spontaneous (post-marketing) reports. Frequencies for all events have been calculated based on their incidence in phase 3a clinical trials. The reactions are listed below as MedDRA preferred term by system organ class and absolute frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Description of selected adverse events.

Hypoglycaemia.

Most episodes of confirmed hypoglycaemia in clinical studies were minor.
No episodes of severe hypoglycaemia were observed in the study with Victoza used as monotherapy. Severe hypoglycaemia may occur uncommonly and has primarily been observed when Victoza is combined with a sulfonylurea (0.02 events/subject year). Very few episodes (0.001 events/subject year) were observed with administration of Victoza in combination with a non-sulfonylurea. In the LEADER trial, severe hypoglycaemic episodes were reported at a lower rate with Victoza vs placebo (0.01 vs 0.015 events per patient year; estimated rate ratio 0.69 [0.51 to 0.93]) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Table 2 presents the incidence of confirmed hypoglycaemic episodes (number of episodes divided by subject years of exposure).

Gastrointestinal adverse events.

Most episodes of nausea were mild to moderate, transient and rarely led to discontinuation of therapy (Figure 1). In long-term clinical trials, some patients (0.6%) reported decreased weight as an adverse event.
In subjects treated with Victoza combined with metformin 20.7% reported at least one episode of nausea, and 12.6% reported at least one episode of diarrhoea, respectively. When combining Victoza with a sulfonylurea 9.1% of subjects reported at least one episode of nausea and 7.9% of subjects reported at least one episode of diarrhoea.
The incidence of withdrawal due to adverse events was 7.8% for Victoza treated subjects and 3.4% for comparator treated subjects in the long-term controlled trials (26 weeks or longer). The most common adverse events leading to withdrawal for Victoza treated subjects were nausea (2.8% of subjects) and vomiting (1.5%).
Patients > 70 years may experience more gastrointestinal effects when treated with Victoza. Patients with mild and moderate renal impairment (creatinine clearance 60-90 mL/min and 30-59 mL/min, respectively) may experience more gastrointestinal effects when treated with Victoza.

Cholelithiasis and cholecystitis.

Few cases of cholelithiasis (0.4%) and cholecystitis (0.1%) have been reported during long-term, controlled phase 3a clinical trials with Victoza. In the LEADER trial, the frequency of cholelithiasis and cholecystitis was 1.5% and 1.1% for Victoza and 1.1% and 0.7% for placebo, respectively (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Skin and subcutaneous tissue disorders.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing cutaneous amyloidosis. There may be a potential risk of change in Victoza absorption or effect following Victoza injections at sites with cutaneous amyloidosis.

Injection site reactions.

Injection site reactions have been reported in approximately 2% of subjects who received Victoza in long-term controlled trials (26 weeks or longer). The majority of these reactions were mild.

Pancreatitis.

Few cases of acute pancreatitis (< 0.2%) have been reported during long-term, controlled phase 3 clinical trials with Victoza (see Section 4.4 Special Warnings and Precautions for Use). Pancreatitis was also reported from marketed use. In the LEADER trial, the frequency of acute pancreatitis confirmed by adjudication was 0.4% for Victoza and 0.5% for placebo, respectively (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Allergic reactions.

Allergic reactions including urticaria, rash and pruritus have been reported from marketed use of Victoza. Few cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnoea and oedema have been reported with marketed use of Victoza.

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

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).
From clinical trials and postmarket use, deliberate or accidental administration of doses up to 40 times the recommended maintenance dose (72 mg) have been reported, including one case of a 10-fold overdose (18 mg daily) given for 7 months. These included instances where patients needed hospitalisation either due to severe events of vomiting, nausea and diarrhoea or as a precaution. In some reports glucose infusion was administered. Severe hypoglycaemia has also been observed. All patients were reported to have recovered from the events without complications.
In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms. The patient should be observed for clinical signs of dehydration and blood glucose should be monitored.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells. Liraglutide exhibits 97% homology to human GLP-1.
Unlike native GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once daily administration. Following subcutaneous administration, the protracted action profile is based on three mechanisms: self association (which results in slow absorption), binding to albumin and enzymatic stability towards the dipeptidyl peptidase (DPP-IV) and neutral endopeptidase (NEP) enzymes, resulting in a long plasma half-life.
Liraglutide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in cyclic adenosine monophosphate (cAMP). Liraglutide stimulates insulin secretion in a glucose dependent manner and improves β-cell function. Simultaneously, liraglutide lowers inappropriately high glucagon secretion, also in a glucose dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, during hypoglycaemia liraglutide diminishes insulin secretion and does not impair glucagon secretion.
The mechanism of blood glucose lowering also may involve a minor delay in gastric emptying (see Section 4.5 Interactions with Other Medicines and Other Form of Interactions).
Liraglutide has shown antihyperglycaemic efficacy in animal models of prediabetes. Liraglutide has been shown in vitro to stimulate β-cell proliferation and prevent both cytokine and free fatty acid induced β-cell death (apoptosis). In vivo, liraglutide increases insulin biosynthesis, and β-cell mass in diabetic animal models. The relevance of this to humans is not known. When hyperglycaemia is fully normalised, in animal studies, liraglutide does not increase β-cell mass.
GLP-1 is a physiological regulator of appetite and food intake and GLP-1R is present in several areas of the brain involved in appetite regulation as well as the intestine. In animal studies, peripheral administration of liraglutide led to uptake in specific brain regions including the hypothalamus, where liraglutide, via specific activation of the GLP-1R, increased key satiety and decreased key hunger signals. Transient inhibition of gastric emptying was also observed. Liraglutide lowers body weight through decreased food intake and loss of predominantly fat mass.
GLP-1 receptors are also expressed in specific locations in the heart, vasculature, immune system, and kidneys. Human and animal studies have shown that activation of these receptors with liraglutide may mediate cardiovascular and microvascular effects, including reduced inflammation. Animal studies show that liraglutide attenuates the development of atherosclerosis.

Clinical trials.

A. Glycaemic control, phase 2 trial.

Study NN2211-1499 was a phase 2, exploratory study. It was a double blind, double dummy, randomised, parallel group, multicentre, dose titration study (with an open labelled oral agent arm i.e. glimepiride + metformin) to assess the effect on glycaemic control of individual maximum effective dose of Victoza as add on therapy to metformin compared to monotherapy (metformin or Victoza alone). Victoza was given in doses of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, as a once daily subcutaneous injection in the abdomen or thigh (in the evening). The study was of five weeks duration. One hundred and forty four patients were randomised (36 per group). They were on at least 50% of the maximal dose of their oral agent. Fasting serum glucose after five weeks of treatment was the primary endpoint. Victoza alone was superior to metformin alone but inferior to metformin + glimepiride whereas Victoza + metformin was superior to metformin + glimepiride. Results were similar for haemoglobin A1c (HbA1c) but the short duration of the study limits the interpretation of these results.

B. Glycaemic control, phase 3 individual trials.

There were 3,992 subjects with type 2 diabetes randomised in five double blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of Victoza on glycaemic control.
These studies included 3,978 exposed subjects (2,501 subjects treated with Victoza), 53.7% men and 46.3% women, 797 subjects (508 treated with Victoza) were ≥ 65 years of age and 113 subjects (66 treated with Victoza) were ≥ 75 years of age.
The studies included four studies (LEAD 1, 2, 4 and 5) assessing Victoza in various combinations with metformin, a sulfonylurea and rosiglitazone plus one study where Victoza was used as a single agent (LEAD 3). In the dual therapy studies, patients could be inadequately controlled but were not necessarily failing to respond to monotherapy at baseline.
B.i. Monotherapy. LEAD 3 (Trial 1573) enrolled 746 patients with type 2 diabetes previously treated with diet/exercise and with an HbA1c 7.0‐11.0% (inclusive), or with not more than half-maximal oral antidiabetic drug (OAD) monotherapy for at least 2 months and with an HbA1c 7.0‐10.0% (inclusive). Patients were randomised to Victoza 1.2 mg, Victoza 1.8 mg, or glimepiride 8 mg, and treated for 52 weeks. Treatment with Victoza 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA1c from baseline compared to glimepiride (Table 3).
B.ii. Combination therapy. LEAD 1 (Trial 1436) and LEAD 2 (Trial 1572) evaluated 26 weeks' of treatment with Victoza in combination with the OAD glimepiride or metformin respectively. Both trials employed a placebo comparator (LEAD 1 glimepiride alone; LEAD 2 metformin alone) and an active comparator (LEAD 1 glimepiride + rosiglitazone; LEAD 2 metformin + glimepiride).
LEAD 5 (Trial 1697) evaluated 26 weeks' treatment with Victoza in combination with metformin + glimepiride. LEAD 5 assessed the 1.8 mg Victoza dose and compared this with a placebo comparator (metformin + glimepiride) and an active comparator (insulin glargine + metformin + glimepiride).
Primary outcomes for the LEAD 1, 2 and 5 studies are presented in Tables 4 and 5. Treatment with Victoza produced clinically and statistically significant improvements versus the placebo comparators in HbA1c, fasting plasma glucose (FPG) and postprandial glucose (PPG).

B.ii.a) Victoza in combination with one OAD (LEAD 1 and 2, respectively).

LEAD 1 enrolled patients diagnosed with type 2 diabetes, treated with OAD(s) for at least 3 months, with an HbA1c: 7.0-11.0% (inclusive) in subjects on oral monotherapy or 7.0-10.0% (inclusive) in subjects on oral combination therapy. All were switched to glimepiride in the trial. The study enrolled patients on monotherapy who might need a second agent and those already on two agents that might need a third agent. In LEAD 1, the analysis of change in HbA1c from baseline showed that treatment with Victoza at both 1.2 mg and 1.8 mg (+ glimepiride) was superior to treatment with glimepiride alone, and superior to treatment with rosiglitazone + glimepiride (Table 2). For the primary efficacy outcome measure, Victoza 1.2 mg and 1.8 mg in combination with glimepiride were superior to both comparator groups, and Victoza 0.6 mg in combination with glimepiride was superior to glimepiride alone and noninferior to rosiglitazone/ glimepiride. Amongst secondary outcomes, Victoza plus glimepiride did not increase weight compared to glimepiride alone whereas glimepiride and rosiglitazone were associated with weight gain.
LEAD 2 enrolled patients diagnosed with type 2 diabetes, treated with OAD(s) for at least 3 months, with an HbA1c: 7.0-11.0% (inclusive) in subjects on oral monotherapy or 7.0-10.0% (inclusive) in subjects on oral combination therapy. All were switched to metformin in the trial. The analysis of change in HbA1c from baseline showed that treatment with Victoza (1.2 mg and 1.8 mg) + metformin was superior to metformin alone and noninferior to treatment with glimepiride and metformin (see Table 4). The primary efficacy outcome measure was the change from baseline in HbA1c after 26 weeks of treatment. Victoza 1.8 mg and 1.2 mg doses in combination with metformin were superior to metformin alone, and noninferior to glimepiride/ metformin. In combination with metformin, Victoza had similar efficacy to the glimepiride/ metformin combination. In this study, Victoza 1.2 mg daily was as effective as the higher dose.

B.ii.b) Victoza compared to a basal insulin (LEAD 5).

LEAD 5 enrolled patients diagnosed with type 2 diabetes, previously treated with oral agent(s) for at least 3 months with an HbA1c: 7.5-10.0% (inclusive) in subjects on oral monotherapy or 7.0-10.0% (inclusive) in subjects on oral combination therapy. In LEAD 5, the analysis of change in HbA1c from baseline demonstrated that treatment with Victoza 1.8 mg + glimepiride + metformin was superior to treatment with glimepiride + metformin alone and superior to treatment with insulin glargine + glimepiride + metformin (see Table 5).

B.ii.c) Victoza in combination with basal insulin (trials 1842, 1842 ext. and 3917).

An open label randomised study (trials 1842 and 1842 ext.) in patients with type 2 diabetes not reaching target with OADs was conducted. The trial started with a 12 week run-in period with Victoza + metformin, where 61% reached an HbA1c < 7%. The 39% of patients not achieving target were randomised to have insulin detemir once daily added or continue on Victoza 1.8 mg + metformin for 52 weeks. Addition of insulin detemir provided a further reduction of HbA1c from 7.6% to 7.1% after 52 weeks, no major hypoglycaemic episodes were reported with insulin detemir (see Table 6). Adding insulin detemir did not result in any further clinically significant loss of weight but the initial loss obtained with Victoza + metformin dual therapy during the run-in period was maintained.
Another 26 week double blind randomised trial (trial 3917) investigated the efficacy and safety of Victoza 1.8 mg versus placebo in patients with type 2 diabetes inadequately controlled on basal insulin (insulin glargine or insulin detemir) with or without metformin (N = 450, mean HbA1c 8.3%). The insulin dose was reduced by 20% for patients with baseline HbA1c ≤ 8.0% in order to minimise the risk of hypoglycaemia. Patients were allowed to up titrate their insulin dose to no higher than the prerandomisation dose. Mean basal insulin dose at baseline for both arms was 40.5 U. Victoza was statistically superior to placebo treatment in reducing HbA1c after 26 weeks (-1.30% for Victoza vs -0.11% for placebo; estimated treatment difference: -1.19%; 95% CI: -1.39 to -0.99). Patients treated with Victoza had a significant decrease in bodyweight compared to placebo (-3.54 kg vs -0.42 kg, estimated treatment difference -3.11 kg; 95% CI: -3.85 to -2.37). Significantly more patients achieved HbA1c below 7% with Victoza compared with placebo (59.2% vs 14.0%). More patients with Victoza achieved HbA1c < 7% with no weight gain and no hypoglycaemic episodes (41.5%) than with placebo (8.6%). Treatment with Victoza reduced the daily need for insulin compared to placebo (35.82 U vs 40.05 U). The proportion of patients with minor hypoglycaemic episodes was significantly higher when adding Victoza compared to placebo (18.2% vs 12.4%; 1.26 vs 0.83 events per patient year of exposure). No severe hypoglycaemic episodes were reported in the trial. The safety profile of Victoza was generally similar to that observed in other studies with Victoza.

C. Glycaemic control across trials.

C.i. HbA1c.

Victoza monotherapy for 52 weeks resulted in statistically significant (p ≤ 0.0014) and sustained reductions in HbA1c compared with patients receiving glimepiride (Figures 5, 6, 7 and 8). Victoza in combination therapy for 26 weeks with metformin or a sulfonylurea resulted in statistically significant (p < 0.001) and sustained reductions in HbA1c compared with subjects in the placebo comparator groups (see Figures 2, 3, 4 and 5).
The efficacy of Victoza 0.6 mg was also tested in combination with a sulfonylurea or with metformin and was found to be superior to placebo but less effective than the other Victoza doses of 1.2 mg and 1.8 mg.

C.ii. Fasting plasma glucose.

Treatment with Victoza resulted in a reduction in fasting plasma glucose of 0.72-2.42 mmol/L. This reduction was observed within the first two weeks of treatment.

C.iii. Postprandial glucose.

Victoza reduced postprandial glucose across all three daily meals by 1.68-2.71 mmol/L.

D. Glycaemic control in patients with renal impairment.

In a double-blind study (Trial 3916) comparing the efficacy and safety of Victoza 1.8 mg versus placebo as add-on to basal or premixed insulin and/or OAD in patients with type 2 diabetes and moderate renal impairment, Victoza was superior to placebo treatment in reducing HbA1c after 26 weeks (-1.05% vs -0.38%, p < 0.0001). Significantly more patients achieved HbA1c below 7% with Victoza compared with placebo (52.8% vs 19.5% p < 0.0001). Patients treated with Victoza had a statistically significant decrease in body weight compared to that of patients treated with placebo (-2.41 kg vs -1.09 kg, p = 0.0052). There was a comparable risk of hypoglycaemic episodes between the two treatment groups. The safety profile of Victoza was generally similar to that observed in other studies with Victoza.

E. Body weight across trials.

Bodyweight was assessed amongst predefined secondary endpoints. Specific weight loss studies have not been assessed in type 2 diabetes. In the clinical programme, statistically significant reductions in mean bodyweight from baseline were consistently observed. Treatment with Victoza was associated with an initial reduction in mean bodyweight within the first 8 weeks, that was sustained over the duration of studies (see Figures 6, 7 and 8). Larger weight reduction was observed with increasing body mass index at baseline. Reductions in bodyweight were seen, irrespective of the occurence of nausea.
No morbidity data or mortality data are presently available to support long-term benefit from Victoza induced weight loss in patients with type 2 diabetes.

F. Cardiovascular evaluation.

F.i. Phase 2 and 3a trials.

F.i.a) Major adverse cardiovascular events.

Post-hoc analysis of serious major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke) from all intermediate and long-term phase 2 and 3a trials (ranging from 26 and up to 100 weeks' duration) including 5,607 patients (3,651 exposed to Victoza), showed no increase in cardiovascular risk (incidence ratio of 0.75 (95% CI: 0.35; 1.63) for Victoza versus all comparators.

F.i.b) Blood pressure.

Victoza reduced systolic blood pressure with a mean range of 2-6 mmHg within the first two weeks of treatment in long-term clinical trials. The reduction in systolic blood pressure occurred before weight loss.

F.i.c) Lipids.

Victoza showed no adverse effects on lipid parameters.
F.ii. Cardiovascular outcomes, phase 3b LEADER trial. The Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results (LEADER) trial was a multicentre, placebo-controlled, double-blind clinical trial. 9,340 patients were randomly allocated to either Victoza (4,668) or placebo (4,672), both in addition to standards of care for managing HbA1c and cardiovascular (CV) risk factors. Patients had type 2 diabetes and were anti-diabetic medication naïve or treated with one or more OADs or insulin (human NPH insulin, long-acting insulin or premixed insulin - either alone or in combination with OAD(s)) - at baseline (SOC). Patients were also at high risk of cardiovascular events, defined as either 50 years of age and with concomitant cardiovascular, cerebrovascular, peripheral vascular disease, chronic renal failure or chronic heart failure, or 60 years of age and other specified risk factors of vascular disease.
Primary outcome or vital status at end of trial was available for 99.7% and 99.6% of participants randomised to Victoza and placebo, respectively. The duration of observation was minimum 3.5 years and up to a maximum of 5 years. The study population included patients ≥ 65 years (n = 4,329) and ≥ 75 years (n = 836), and patients with mild (n = 3,907), moderate (n = 1,934) or severe (n = 224) renal impairment. The mean age was 64 years and the mean BMI was 32.5 kg/m2. The mean duration of diabetes was 12.8 years.

F.ii.a) Cardiovascular events.

The primary endpoint was the time from randomisation to first occurrence of any major adverse cardiovascular events (MACE): CV death, non-fatal myocardial infarction, or non-fatal stroke. Victoza significantly reduced the risk of MACE vs placebo with an estimated hazard ratio [95% CI] of 0.87 [0.78, 0.97] (p = 0.005), corresponding to a relative risk reduction of 13% (Figure 9). The number of subjects that needed to be treated with Victoza for 3 years to prevent the first MACE was 66. The estimated hazard ratio (HR) was consistently below 1 for all 3 MACE components.
Victoza also significantly reduced the time to first expanded MACE (primary MACE, unstable angina pectoris leading to hospitalisation, coronary revascularisation, or hospitalisation due to heart failure) and other secondary endpoints (Figure 10).

F.ii.b) Blood pressure and heart rate.

In the LEADER trial, systolic blood pressure was reduced with Victoza vs placebo (-1.4 mmHg vs -0.2 mmHg; estimated treatment difference [ETD]: -1.20 mmHg [-1.92; -0.48]) whereas diastolic blood pressure decreased less with Victoza vs placebo (-0.8 mmHg vs -1.4 mmHg, respectively, ETD: 0.59 [0.19; 0.99]) after 36 months. A mean increase in heart rate from baseline of 2 to 3 beats per minute has been observed with Victoza in long-term clinical trials including LEADER. In the LEADER trial, although the study was not designed to specifically investigate clinical effects of increased heart rate, no long-term clinical impact of increased heart rate on the risk of cardiovascular events was observed.

F.ii.c) Microvascular events.

In the LEADER trial, microvascular events comprised nephropathy (new onset of persistent macroalbuminuria, persistent doubling of serum creatinine and eGFR ≤ 45 mL/min/1.73 m2 per Modification of Diet in Renal Disease (MDRD), need for continuous renal replacement therapy and death due to renal disease) and retinopathy (need for retinal photocoagulation or treatment with intravitreal agents, vitreous haemorrhage and diabetes-related blindness) outcomes. The analysis of time to first microvascular event for Victoza vs placebo had an HR of 0.84 [0.73, 0.97]. The HR for Victoza vs placebo was 0.78 [0.67, 0.92] for time to first nephropathy event and 1.15 [0.87, 1.52] for time to first retinopathy event.
The estimated treatment ratio for change in urinary albumin/creatinine excretion from baseline to month 36 was 0.81 [0.76, 0.86].

F.ii.d) Glycaemic control in patients at high cardiovascular risk.

A significant and sustained reduction in HbA1c from baseline (mean baseline HbA1c was 8.7%) to month 36 was observed with Victoza vs placebo, in addition to standard of care (-1.16% vs -0.77%; ETD -0.40% [-0.45; -0.34], p < 0.001). The need for treatment intensification with insulin was reduced by 48% with Victoza vs placebo in insulin-naive patients at baseline (HR 0.52 [0.48; 0.57]).

F.ii.e) Body weight.

In the LEADER trial, a significant and sustained reduction in body weight from baseline to month 36 was also seen with Victoza vs placebo (-2.74 kg vs -0.47 kg, respectively; ETD -2.26 [-2.54; -1.99]).

G. Immunogenicity across trials.

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop antiliraglutide antibodies following treatment with Victoza. On average, 8.6% of subjects developed antibodies. Antibody formation has not been associated with reduced efficacy of Victoza.

H. Other effects.

Victoza improved insulin sensitivity compared to a sulfonylurea for 52 weeks as assessed by HOMA-IR. The clinical significance of this has not been established.

I. Other clinical data.

In an open label study (Trial 1860) comparing efficacy and safety of Victoza (1.2 mg and 1.8 mg) and sitagliptin (a DPP-4 inhibitor, 100 mg) in patients inadequately controlled on metformin therapy (mean HbA1c 8.5%), Victoza at both doses was statistically superior to sitagliptin treatment in reducing HbA1c after 26 weeks (-1.24%, -1.50%, -0.90%, for Victoza 1.2 mg, 1.8 mg and sitagliptin, respectively; p < 0.0001). Patients treated with Victoza had a significant decrease in bodyweight compared to that of patients treated with sitagliptin (-2.9 kg, -3.4 kg, -1.0 kg in Victoza 1.2 mg, 1.8 mg and sitagliptin treatment groups, respectively, p < 0.0001). Greater proportions of patients treated with Victoza experienced transient nausea compared to patients treated with sitagliptin (20.8%, 27.1%, 4.6% in Victoza 1.2 mg, 1.8 mg and sitagliptin treatment groups, respectively). The reductions in HbA1c and superiority vs sitagliptin observed after 26 weeks of Victoza treatment (1.2 mg and 1.8 mg) were sustained after 52 weeks of treatment (-1.29%, -1.51%, -0.88% in Victoza 1.2 mg, 1.8 mg and sitagliptin treatment groups, respectively, p < 0.0001).
In an open label study (Trial 1797) comparing efficacy and safety of Victoza 1.8 mg once daily and exenatide 10 microgram twice daily in patients inadequately controlled on metformin and/or sulphonylurea therapy (mean HbA1c 8.3%), Victoza was statistically superior to exenatide treatment in reducing HbA1c after 26 weeks (-1.12% vs -0.79%, respectively, with the estimated treatment difference being -0.33% (95% CI: -0.47% to -0.18%), p < 0.0001). More patients achieved HbA1c below 7% with Victoza compared with exenatide (54.2% vs 43.4%, respectively, p = 0.0015). Both treatments resulted in mean bodyweight loss of approximately 3 kg.
In an open label study (Trial 3867) comparing the efficacy and safety of Victoza 1.8 mg with lixisenatide 20 microgram in 404 patients inadequately controlled on metformin therapy (mean HbA1c 8.4%), Victoza was superior to lixisenatide in reducing HbA1c after 26 weeks of treatment (-1.83% vs -1.21%, with the estimated treatment difference being -0.62% (95% CI: -0.80% to -0.44%), p < 0.0001). Significantly more patients achieved HbA1c below 7% with Victoza compared to lixisenatide (74.2% vs 45.5%, p < 0.0001), as well as the HbA1c target below or equal to 6.5% (54.6% vs 26.2%, p < 0.0001). Significantly greater reduction in fasting plasma glucose was achieved with Victoza than lixisenatide (-2.85 vs -1.70 mmol/L, p < 0.0001). Body weight loss was observed in both treatment arms (-4.3 kg with Victoza and -3.7 kg with lixisenatide). The safety profiles of Victoza and lixisenatide were overall comparable. However, gastrointestinal adverse events were more frequently reported with liraglutide treatment (43.6% vs 37.1%). No new safety information was identified with Victoza.

Pharmacodynamics.

Liraglutide has 24 hour duration of action and improves glycaemic control by lowering fasting and postprandial blood glucose in subjects with type 2 diabetes mellitus.
The difference between liraglutide 1.8 mg/1.2 mg and placebo in reduction of mean fasting glucose was found to be 3.90 mmol/L/3.33 mmol/L (see Figures 11 and 12). Following a standard meal, the difference in mean 2 hour postprandial glucose concentration was 6.02 mmol/L/5.63 mmol/L. In addition, liraglutide decreased postprandial glucose excursion (incremental postprandial glucose) on average by 1.1 mmol/L/1.08 mmol/L.

Glucose dependent insulin secretion.

Liraglutide increased insulin secretion in relation to increasing glucose concentrations. Using a stepwise graded glucose infusion, the insulin secretion rate was increased following a single injection of liraglutide in subjects with type 2 diabetes to a level indistinguishable to that observed in healthy subjects (see Figure 13).

Beta-cell function.

Liraglutide improved β-cell function as measured by first and second phase insulin response and maximal β-cell secretory capacity. A pharmacodynamic study in subjects with type 2 diabetes demonstrated restoration of first phase insulin secretion (intravenous bolus of glucose), improved second phase insulin secretion (hyperglycaemic clamp) and maximal insulin secretory capacity (arginine stimulation test) (see Figure 14).
Clinical studies up to 52 weeks have shown a durable secretagogue effect with liraglutide, as well as improvements from baseline in the homeostasis model assessment for β-cell function (HOMA-B) and the proinsulin to insulin ratio. Liraglutide has not yet been evaluated for use in individuals with impaired glucose tolerance or those who do not yet meet the diagnostic criteria for diabetes mellitus.

Glucagon secretion.

Liraglutide lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. Liraglutide did not impair glucagon response to low glucose concentration. Furthermore, a lower endogenous glucose release has been observed with liraglutide.

Gastric emptying.

Liraglutide caused a minor delay in gastric emptying, thereby reducing the rate at which postprandial glucose appeared in the circulation.

Bodyweight.

In clinical studies up to 52 weeks involving subjects with elevated bodyweight liraglutide was observed to significantly lower bodyweight (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials). Specific weight loss studies have not been assessed in type 2 diabetes mellitus.

Cardiac electrophysiology (QTc).

In a cardiac repolarisation study liraglutide at steady-state concentrations with daily doses up to 1.8 mg did not produce QTc prolongation.

5.2 Pharmacokinetic Properties

Absorption.

The absorption of liraglutide following subcutaneous administration is slow, reaching maximum concentration 8-12 hours postdosing. Estimated maximum liraglutide concentration was 9.4 nanomol/L for a subcutaneous single dose of liraglutide 0.6 mg. At 1.8 mg liraglutide, the average steady-state concentration of liraglutide (AUCTau/24) reached approximately 34 nanomol/L. Liraglutide exposure increased proportionally with dose. The intrasubject coefficient of variation for liraglutide AUC was 11% following single dose administration. Liraglutide can be administered subcutaneously in the abdomen, thigh, or upper arm.

Distribution.

The apparent volume of distribution after subcutaneous administration is 11-17 L. The mean volume of distribution after intravenous administration of liraglutide is 0.07 L/kg. Liraglutide is extensively bound to plasma protein (> 98%).

Metabolism/ biotransformation.

During the 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Two minor plasma metabolites were detected (≤ 9% and ≤ 5% of total plasma radioactivity exposure). Liraglutide is endogenously metabolised in a similar manner to large proteins without a specific organ as major route of elimination.

Excretion.

Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or faeces. Only a minor part of the administered radioactivity was excreted as liraglutide related metabolites in urine or faeces (6% and 5%, respectively). The urine and faeces radioactivity was mainly excreted during the first 6-8 days, and corresponded to three minor metabolites.
The mean clearance following subcutaneous administration of a single dose of liraglutide is approximately 1.2 L/hour with an elimination half-life of approximately 13 hours.

Special populations.

Elderly.

No dosage adjustment is required based on age. Age had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results from a pharmacokinetic study in healthy subjects and population pharmacokinetic data analysis of subjects (18 to 80 years).

Gender.

No dosage adjustment is required based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic data analysis of male and female subjects and a pharmacokinetic study in healthy subjects.

Ethnicity.

No dosage adjustment is required based on ethnicity. Ethnicity had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic analysis.

Obesity.

No dosage adjustment is required based on obesity. Population pharmacokinetic analysis suggests that body mass index (BMI) has no significant effect on the pharmacokinetics of liraglutide.

Hepatic impairment.

The pharmacokinetics of liraglutide were evaluated in subjects with varying degrees of hepatic impairment in a single dose trial. Liraglutide exposure was decreased by 23% and 13% in subjects with mild or moderate hepatic impairment, respectively, compared to healthy subjects.
Exposure was significantly lower (44%) in subjects with severe hepatic impairment (Child-Pugh score > 9).

Renal impairment.

Liraglutide exposure was mildly reduced in subjects with renal impairment compared to individuals with normal renal function in a single-dose trial. Liraglutide exposure was lowered by 33%, 14%, 27% and 26%, respectively, in subjects with mild (creatinine clearance, CrCL 50-80 mL/min), moderate (CrCL 30-50 mL/min), and severe (CrCL < 30 mL/min) renal impairment and in end stage renal disease requiring dialysis.

Paediatrics.

Liraglutide has not been studied in paediatric subjects.

5.3 Preclinical Safety Data

Genotoxicity.

Liraglutide was not mutagenic in the bacterial Ames assay, and not clastogenic in human lymphocytes in vitro, or in rat lymphocytes and bone marrow in vivo.

Carcinogenicity.

Liraglutide caused thyroid C-cell adenomas and carcinomas in two year studies in mice and rats. C-cell neoplasia was observed in mice at subcutaneous doses ≥ 1 mg/kg/day (relative exposure based on plasma AUC, ≥ 7.7) and in rats at all doses tested (≥ 0.075 mg/kg/day subcutaneously; relative exposure, ≥ 0.5). No tumours or other C-cell proliferative changes were seen in monkeys treated with liraglutide for 20 months (≤ 5 mg/kg/day subcutaneously; relative exposure, ≤ 64). The findings in mice and rats are mediated by a specific GLP-1 receptor mediated mechanism to which rodents are particularly sensitive. The relevance for humans is likely to be low but cannot presently be completely excluded.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each mL of Victoza contains the following inactive ingredients: 1.42 mg dibasic sodium phosphate dihydrate, 14.0 mg propylene glycol, 5.5 mg phenol, hydrochloric acid q.s., sodium hydroxide q.s. and water for injections to 1 mL.

6.2 Incompatibilities

Substances added to Victoza may cause degradation of liraglutide. Victoza must not be mixed with other medicinal products, e.g. infusion fluids.

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

Store in a refrigerator (2°C to 8°C). Keep away from the cooling element. Do not freeze Victoza and do not use Victoza if it has been frozen.
After first use of the Victoza pen, the product can be stored for 1 month at room temperature (below 30°C) or in a refrigerator (2°C to 8°C).
Keep the pen cap on when the Victoza pen is not in use in order to protect from light.
Victoza should be protected from excessive heat and sunlight.
Always remove the injection needle after each injection and store the Victoza pen without an injection needle attached. This prevents contamination, infection, and leakage. It also ensures that the dosing is accurate.

6.5 Nature and Contents of Container

Cartridge (type 1 glass) with a plunger (bromobutyl) and a laminate rubber sheet (bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polyolefin and polyacetal.
Each pen contains 3 mL solution, delivering 30 doses of 0.6 mg, 15 doses of 1.2 mg or 10 doses of 1.8 mg.
Pack sizes of 1, 2, 3, 5 or 10 pre-filled pens. Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.
Victoza should not be used if it does not appear clear and colourless, or almost colourless.
Victoza should not be used if it has been frozen.

6.7 Physicochemical Properties

In liraglutide, the lysine at position 34 has been replaced with arginine, and a palmitic acid has been attached via a glutamoyl spacer to lysine at position 26.

Chemical structure.

Liraglutide (rys) has the molecular formula C172H265N43O51 and a molecular weight of 3751.20 daltons.

CAS number.

204656-20-2.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes