Consumer medicine information

Xigduo XR

Dapagliflozin; Metformin hydrochloride

BRAND INFORMATION

Brand name

Xigduo XR

Active ingredient

Dapagliflozin; Metformin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xigduo XR.

SUMMARY CMI

XIGDUO XR®

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 taking XIGDUO XR?

XIGDUO XR contains two active ingredients, dapagliflozin and metformin hydrochloride. XIGDUO XR is used to lower blood sugar in people with type 2 diabetes mellitus. It can also reduce hospitalisation for heart failure in patients with type 2 diabetes.

For more information, see Section 1. Why am I taking XIGDUO XR? in the full CMI.

2. What should I know before I take XIGDUO XR?

Do not use if you have ever had an allergic reaction to dapagliflozin or metformin hydrochloride, 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 take XIGDUO XR? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with XIGDUO XR and affect how it works.

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

4. How do I take XIGDUO XR?

  • Your Doctor will tell you how many XIGDUO XR tablets to take and how often you should take them.
  • XIGDUO XR should be taken with or immediately after food in the evening. Swallow tablet whole with a full glass of water.

More instructions can be found in Section 4. How do I take XIGDUO XR? in the full CMI.

5. What should I know while taking XIGDUO XR?

Things you should do
  • Make sure that you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia (low blood sugar) and hyperglycaemia (high blood sugar) and know how to treat them.
  • Talk to your doctor if you are about to have surgery (including dental surgery), an X-ray or scan requiring an injection of iodinated contrast (dye) to discuss when to stop and start taking it again.
  • Remind any doctor, dentist or pharmacist you visit that you are taking XIGDUO XR.
  • If you become pregnant while taking XIGDUO XR, tell your doctor immediately.
Things you should not do
  • Do not stop taking your medicine or change the dosage without checking with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how XIGDUO XR affects you
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep your XIGDUO XR tablets in the blister until it is time to take them.
  • Keep your tablets in a cool dry place where the temperature stays below 30°C.

For more information, see Section 5. What should I know while taking XIGDUO XR? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, some can be minor and temporary. However, some side effects may be serious and could require urgent medical attention or hospitalisation. See Section 6. Are there any side effects? in the full CMI and, if you need to, ask your doctor if you have any further questions about side effects. Tell your doctor if you experience any side effects, including those not listed in this leaflet.

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

XIGDUO XR®

Active ingredient(s): dapagliflozin/metformin hydrochloride

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking XIGDUO XR?

XIGDUO XR contains two active ingredients dapagliflozin and metformin hydrochloride. Dapagliflozin is a member of a class of medicines you take by mouth called SGLT-2 (Sodium Glucose Cotransporter-2) inhibitors and metformin belongs to a class of medicines called biguanides.

XIGDUO XR is used with diet, exercise and sometimes other medicines such as insulin, a sulfonylurea, or a dipeptidyl peptidase (DPP-4) inhibitor, or a glucagon like peptide 1 (GLP-1) receptor agonist such as exenatide to control the levels of blood sugar (glucose) in patients with type 2 diabetes mellitus. It can also reduce hospitalisation for heart failure in patients with type 2 diabetes.

Type 2 diabetes mellitus

Type 2 diabetes mellitus (also called non-insulin-dependent diabetes mellitus, or NIDDM) is the condition of having high levels of blood sugar (hyperglycaemia). This is usually because your body does not make enough insulin and /or the insulin that your body produces does not work as well as it should. Left uncontrolled, the build-up of high levels of sugar in your blood can lead to serious medical problems.

The main goal of treating type 2 diabetes is to control your blood sugar to a normal level. Lowering and controlling blood sugar may help prevent or delay complications of diabetes, which include kidney disease, blindness and amputation.

2. What should I know before I take XIGDUO XR?

Warnings

Do not take XIGDUO XR if you:

  • are allergic to dapagliflozin or metformin hydrochloride, 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 or
    - you may feel faint
  • Always check the ingredients to make sure you can take this medicine.
  • have type 1 diabetes mellitus that is well controlled by insulin alone
  • have type 2 diabetes that is already well controlled by diet alone
  • have any type of metabolic acidosis such as lactic acidosis or diabetic ketoacidosis. Symptoms of lactic acidosis may include feeling weak and tired, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting or diarrhoea, feeling cold specially in arms or legs, felling dizzy or light-headed, having slow or irregular heart beat or your medical condition suddenly changes. Diabetic ketoacidosis is a symptom of uncontrolled diabetes, in which substances called ketone bodies build up in the blood. You may notice this as rapid weight loss, feeling sick or being sick, stomach pain, excessive thirst, fast and deep breathing, confusion, unusual sleepiness or tiredness, a sweet smell to your breath, a sweet or metallic taste in your mouth, or a different odour to your urine or sweat).
  • have had a diabetic pre-coma
  • have problems with your liver
  • drink excessive alcohol, binge drinking, alcohol dependence
  • have poorly functioning kidneys, severe kidney disease or kidney failure
  • have dehydration, severe blood loss, shock
  • have a severe infection
  • have certain heart or blood vessel problems, including a recent heart attack or severe heart failure (when the heart fails to pump blood effectively)
  • have severe breathing difficulties
  • have blood clots in the lungs (symptoms include coughing, shortness of breath, chest pain and a fast heart rate)
  • have gangrene
  • have inflammation of the pancreas (pancreatitis), symptoms include severe upper stomach pain, often with nausea and vomiting.

Talk to your doctor about when to stop taking XIGDUO XR and when to start taking it again if you:

  • are going to have an X-ray or scan where you will be injected with an iodinated contrast (dye)
  • are planning to have surgery (including where the use of insulin is essential).

XIGDUO XR contains dapagliflozin and metformin. If you have more than one medicine containing dapagliflozin or metformin in your possession, you may accidentally take too much (overdose). Accidentally taking too much metformin can cause a very serious side effect called lactic acidosis.

ACCIDENTAL METFORMIN OVERDOSING IS A SIGNIFICANT SAFETY RISK.

Ask your doctor or pharmacist if you are unsure if you have any other medicines containing metformin.

Metformin is sold under many different brand names in Australia. Your doctor or pharmacist will know which other medicines also contain metformin.

Check with your doctor if you:

  • have any allergies to any other medicines, foods, dyes or preservatives.
  • Have or have had any other medical conditions:
    - kidney, liver or pancreas problems
    - heart failure
    - frequently get genital or urinary tract infections (infections of the bladder, kidney, or tubes that carry urine)
    - an illness that will make you dehydrated such as diarrhoea or a severe infection.
  • drink alcohol
  • take any medicines for any other condition
  • are lactose intolerant. XIGDUO XR tablets contain lactose.

Your doctor will do some tests for kidney function at the start of treatment and regularly while you are on treatment.

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

Do not take XIGDUO XR if you are pregnant or plan to become pregnant.

Tell your doctor if you are pregnant or intend to become pregnant.

The safety of XIGDUO XR in pregnant women has not been established. Insulin is more suitable for controlling blood glucose during pregnancy. Your doctor will replace XIGDUO XR with insulin while you are pregnant.

Do not take XIGDUO XR if you are breastfeeding.

Tell your doctor if you are breastfeeding or plan to breastfeed.

XIGDUO XR is not recommended while you are breastfeeding. Your doctor will discuss the options available to you.

Children

XIGDUO XR is not recommended for use in children.

It has not been studies in children younger than 18 years old.

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.

Discard any other medicines containing dapagliflozin or metformin that your doctor might have prescribed to you in the past and that you may still have in your possession.

XIGDUO XR contains dapagliflozin and metformin. If you have more than one medicine containing dapagliflozin or metformin in your possession, you may accidentally take too much (overdose).

XIGDUO XR may affect how well other medicines work and some medicines can affect how well XIGDUO XR works. These include:

  • other medicines used to treat diabetes
  • medicines that contain alcohol, such as cough and cold syrups
  • tetracosactrin, a medicine used in people with multiple sclerosis, and in young children to treat some types of seizures (fits)
  • danazol, a medicine used to treat endometriosis
  • some medicines used to treat high blood pressure and some heart conditions, including beta-blockers, calcium channel blockers and ACE inhibitors
  • medicines used to prevent blood clots, such as warfarin
  • diuretics, also called fluid tablets
  • chlorpromazine, a medicine used to treat schizophrenia and other mental illnesses
  • NSAIDs (non-steroidal anti-inflammatory drugs), medicines used to relieve pain, swelling and other symptoms of inflammation, such as aspirin, diclofenac, ibuprofen, meloxicam, naproxen or piroxicam
  • cimetidine, a medicine used to treat reflux and ulcers
  • corticosteroids such as prednisone or cortisone
  • some medicines used to treat asthma such as salbutamol or terbutaline
  • lithium, a medicine to treat and prevent mental illness, including mania or depression in a condition called bipolar disorder

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

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

4. How do I take XIGDUO XR?

How to take XIGDUO XR

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

They may differ from the information contained in this leaflet.

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

  • Swallow your XIGDUO XR tablet whole with a full glass of water.
  • XIGDUO XR tablets must not be chewed or crushed.

How much to take

  • Your Doctor will tell you how many XIGDUO XR tablets to take and how often you should take them.
  • The dose varies from person to person. Your doctor will decide the right dose for you.
  • Your doctor may prescribe XIGDUO XR along with certain other medicines that lower blood sugar.

When to take XIGDUO XR

  • XIGDUO XR should be taken with or immediately after food in the evening. This will reduce the chance of a stomach upset.
  • XIGDUO XR should be taken at approximately the same time each day. Taking your tablets at the same time each day will have the best effect. It will also help you remember when to take the tablets.

How long to take

  • Continue taking your medicine for as long as your doctor tells you. Make sure you keep enough XIGDUO XR to last over weekends and holidays.

XIGDUO XR helps control your condition, but does not cure it. Therefore, you must take XIGDUO XR every day.

If you forget to use XIGDUO XR

XIGDUO XR should be taken regularly at the same time each day. If you miss your dose at the usual time take it as soon as you remember, and then go back to taking your medicine as you would normally.

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

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 take too much XIGDUO XR

If you think that you have used too much XIGDUO XR, 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.

5. What should I know while taking XIGDUO XR?

Things you should do

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking XIGDUO XR.

Talk to your doctor if you are having surgery (including dental surgery) or an X-ray or scan where you will be injected with a iodinated contrast (dye) to discuss when to stop taking XIGDUO XR and when to start taking it again.

If you become pregnant while taking XIGDUO XR, tell your doctor immediately.

If you need to have any medical tests while you are taking XIGDUO XR, tell your doctor.

XIGDUO XR may affect the results of some tests.

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

Like for all patients with diabetes it is important to check your feet regularly and adhere to any other advice regarding foot care given by your doctor.

Your doctor may want to perform blood tests to check your kidneys, liver, heart, vitamin B12 level and levels of cholesterol and fats in your blood while you are taking XIGDUO XR.

Metformin may reduce Vitamin B12 levels. Periodic monitoring may be necessary in patients at risk for Vitamin B12 deficiency.

Tell your doctor if you:

  • become ill
  • become dehydrated
  • are injured
  • have a fever
  • have a serious infection
  • are having surgery (including dental surgery).

Your blood glucose may become difficult to control at these times. You may also be more at risk of developing a serious condition called lactic acidosis or diabetic ketoacidosis. At these times, your doctor may temporarily replace XIGDUO XR with insulin.

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

Make sure that you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia and hyperglycaemia and know how to treat them.

Hypoglycaemia

XIGDUO XR does not normally cause hypoglycaemia, although you may experience it if you take certain other medicines, such as insulin or a sulfonylurea.

Hypoglycaemia can occur suddenly. Initial signs may include:

  • weakness, trembling or shaking
  • sweating
  • light-headedness, dizziness, headache or lack of concentration
  • irritability, tearfulness or crying
  • hunger
  • numbness around the lips and tongue.

If not treated promptly, these may progress to:

  • loss of co-ordination
  • slurred speech
  • confusion
  • fits or loss of consciousness.

If you experience any of the symptoms of hypoglycaemia, you need to raise your blood glucose immediately.

  • You can do this by doing one of the following:
  • eating 5 to 7 jelly beans
  • eating 3 teaspoons of sugar or honey
  • drinking half a can of non-diet soft drink
  • taking 2 to 3 concentrated glucose tablets.

Unless you are within 10 to 15 minutes of your next meal or snack, follow up with extra carbohydrates such as plain biscuits, fruit or milk.

Taking this extra carbohydrate will prevent a second drop in your blood glucose level.

Hyperglycaemia

If you notice the return of any of the signs of hyperglycaemia, contact your doctor immediately.

Your doctor may need to consider additional or other treatments for your diabetes.

The risk of hyperglycaemia is increased in the following situations:

  • uncontrolled diabetes
  • illness, infection or stress
  • taking less XIGDUO XR than prescribed
  • taking certain other medicines
  • too little exercise
  • eating more carbohydrates than normal.

Things you should not do

  • Do not stop taking your medicine or change the dosage without checking with your doctor.
  • Do not take XIGDUO XR to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if their symptoms seem similar or they have the same condition as you.

Driving or using machines

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

Although rare, XIGDUO XR may cause dizziness in some people. Low blood sugar levels may also slow your reaction time and affect your ability to drive or operate machinery.

Make sure you know how you react to XIGDUO XR before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or lightheaded.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol can affect the control of your diabetes. Drinking excessive amounts of alcohol while you are being treated with XIGDUO XR may also lead to serious side effects. Your doctor may suggest you stop drinking or reduce the amount of alcohol you drink.

Looking after your medicine

  • Keep your XIGDUO XR tablets in the blister until it is time to take them. If you take XIGDUO XR out of the blister, it will not keep well.
  • Keep your tablets in a cool dry place where the temperature stays below 30°C.

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

Store it in a cool dry place 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.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

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.

6. Are there any side effects?

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.

Less serious side effects

Less serious side effectsWhat to do
Gut-related:
  • nausea, vomiting or diarrhoea
  • stomach pain or discomfort
Nervous system-related:
  • loss of appetite
  • loss of taste
  • headache
Others:
  • back pain
  • rash
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergic reaction:
  • Shortness of breath, wheezing or severe difficulty in breathing; shock, swelling of the face, lips, tongue or other parts of the body; skin rash, itching or hives on the skin, hayfever, or you may feel faint.
Hypoglycaemia:
  • low blood sugar that persist despite administering sugar as described in Section 5. What should I know while taking XIGDUO XR? in this leaflet. Signs of low blood sugar may include weakness, trembling or shaking, sweating, light-headedness, headache, dizziness, rapid heart beat, lack of concentration, tearfulness or crying, irritability, hunger and numbness around the lips and fingers. Do not drive a car if you have signs of low blood sugar.
Serious kidney problems:
  • If you have kidney problems, you should take XIGDUO XR only if your doctor tells you to.
Dehydration:
  • Volume depletion (loss of needed fluids from the body). If you are unable to keep fluids down or if you have any of these symptoms of too much loss of body fluids (volume depletion or dehydration) while taking XIGDUO XR: dry sticky mouth, severe thirst, severe diarrhoea or vomiting, dizziness, or urinating less often than normal or not at all.
Infections related:
  • Genital infections. If you experience painful urination, soreness and more severe irritation or redness and swelling of your genitals, or an unpleasant odour or discharge associated with your genitals.
  • Urinary tract infection. If you have symptoms, such as burning or pain when you pass urine, more frequent or urgent need to urinate, fever, chills, or blood in the urine, contact your doctor as soon as possible.
  • If you experience pain or tenderness, redness, swelling of the genitals or the area from the genitals to the rectum, fever, and generally feeling unwell. These may be symptoms of a rare but serious and potentially life-threating infection called Necrotising fasciitis of the perineum (Fournier's gangrene) and you will require prompt treatment.
Diabetic ketoacidosis:
  • In rare cases dapagliflozin one of the active ingredients in XIGDUO XR, may cause a serious condition called diabetic ketoacidosis. Symptoms of diabetic ketoacidosis may include feeling sick or being sick, difficulty breathing, severe thirst, feeling weak and tired, confusion, a sweet smell to your breath, a sweet or metallic taste in your mouth, a strange odour to your urine or sweat and frequent urination. The risk of developing diabetic ketoacidosis may be increased with prolonged fasting, excessive alcohol consumption, dehydration, sudden reductions in insulin dose, or a higher need of insulin due to major surgery or serious illness. Diabetes ketoacidosis is a life-threatening condition.
Lactic Acidosis
IN RARE CASES, METFORMIN, ONE OF THE MEDICINES IN XIGDUO XR, CAN CAUSE A SERIOUS SIDE EFFECT CALLED LACTIC ACIDOSIS.
LACTIC ACIDOSIS IS A MEDICAL EMERGENCY THAT CAN CAUSE DEATH AND MUST BE TREATED IN THE HOSPITAL. LACTIC ACIDOSIS IS CAUSED BY A BUILD-UP OF LACTIC ACID IN YOUR BLOOD.
STOP TAKING XIGDUO XR IF YOU GET ANY OF THE FOLLOWING SYMPTOMS OF LACTIC ACIDOSIS AND SEE YOUR DOCTOR IMMEDIATELY or go straight to the Emergency Department at your nearest hospital:
  • You feel very weak and tired.
  • You have unusual (not normal) muscle pain.
  • You have trouble breathing.
  • You have stomach pain with nausea and vomiting, or diarrhoea.
  • You feel cold, especially in your arms and legs.
  • You feel dizzy or light-headed.
  • You have a slow or irregular heart beat
  • Your medical condition suddenly changes.
The risk of lactic acidosis is higher in the elderly, those whose diabetes is poorly controlled, those with prolonged fasting, those with certain heart conditions, those who drink alcohol and those with kidney or liver problems.		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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.

Occasionally, XIGDUO XR may be associated with changes in your cholesterol or fats in your blood. These can only be found when your doctor does tests from time to time 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 XIGDUO XR contains

Active ingredient
(main ingredient)
  • dapagliflozin 10 mg and metformin 500 mg
  • dapagliflozin 10 mg and metformin 1000 mg
  • dapagliflozin 5 mg and metformin 1000 mg
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • lactose
  • carmellose sodium
  • hypromellose
  • crospovidone
  • silicon dioxide
  • magnesium stearate
  • polyvinyl alcohol
  • titanium dioxide
  • macrogol 3350
  • purified talc
  • iron oxide yellow (10mg/1000mg tablets)
  • iron oxide red (10mg/500mg and 5mg/1000mg tablets)
Potential allergensLactose

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

XIGDUO XR tablets do not contain gluten or sucrose.

What XIGDUO XR looks like

  • XIGDUO XR 10mg/500mg, pink, biconvex, capsule shaped, film-coated tablets with ‘1072’ and ‘10/500’ debossed on one side and plain on the other side. Available in blister packs of 7 and 28 tablets. (AUST R 211294).
  • XIGDUO XR 10mg/1000mg, yellow to dark yellow, biconvex, oval shaped, film-coated tablets with ‘1073’ and ‘10/1000’ debossed on one side and plain on the other side. Available in blister packs of 7 and 28 tablets. (AUST R 211295).
  • XIGDUO XR 5mg/1000mg, pink to dark pink, biconvex, oval shaped, film-coated tablets with ‘1071’ and ‘5/1000’ debossed on one side and plain on the other side. Available in blister packs of 14 and 56 tablets. (AUST R 211296).

Who distributes XIGDUO XR

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113

Telephone:- 1800 805 342

This leaflet was prepared in July 2023.

® XIGDUO XR is a registered trade mark of the AstraZeneca group of companies.

© AstraZeneca, 2023

Doc ID-005219445 v1.0

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Xigduo XR

Active ingredient

Dapagliflozin; Metformin hydrochloride

Schedule

S4

 

1 Name of Medicine

Xigduo XR (dapagliflozin propanediol monohydrate/metformin hydrochloride) modified release tablets contain two oral antihyperglycaemic drugs used in the management of type 2 diabetes: dapagliflozin propanediol monohydrate and metformin hydrochloride.

2 Qualitative and Quantitative Composition

Dapagliflozin.

Dapagliflozin drug substance is a white to off-white powder, is non-hygroscopic, crystalline. Dapagliflozin is non-ionisable; thus, its aqueous solubility and partition coefficient are not affected by changes in pH. Dapagliflozin is a Biopharmaceutical Classification System (BCS) Class III drug.

Metformin hydrochloride.

Metformin hydrochloride is a white to off-white crystalline compound. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Xigduo XR.

Xigduo XR is available for oral administration as tablets containing the following active ingredients:
Xigduo XR 10/500: 10 mg dapagliflozin (as dapagliflozin propanediol monohydrate) and 500 mg metformin hydrochloride.
Xigduo XR 10/1000: 10 mg dapagliflozin (as dapagliflozin propanediol monohydrate) and 1000 mg metformin hydrochloride.
Xigduo XR 5/1000: 5 mg dapagliflozin (as dapagliflozin propanediol monohydrate) and 1000 mg metformin hydrochloride.

Excipient with known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Xigduo XR 10/500 (dapagliflozin 10 mg/ metformin HCl extended release 500 mg) tablets are pink biconvex, capsule-shaped, film-coated tablet with "1072" and "10/500" debossed on one side and plain on the reverse side.
Xigduo XR 10/1000 (dapagliflozin 10 mg/ metformin HCl extended-release 1000 mg) tablets are yellow to dark yellow, biconvex, oval-shaped, film-coated tablet with "1073" and "10/1000" debossed on one side and plain on the reverse side.
Xigduo XR 5/1000 (dapagliflozin 5 mg/ metformin HCl extended-release 1000 mg) tablets are pink to dark pink, biconvex, oval-shaped, film-coated tablet with "1071" and "5/1000" debossed on one side and plain on the reverse side.

4 Clinical Particulars

4.1 Therapeutic Indications

Glycaemic control.

Xigduo XR is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control when treatment with both dapagliflozin and metformin is appropriate.

Prevention of hospitalisation for heart failure.

Xigduo XR is indicated in adults with type 2 diabetes mellitus and established cardiovascular disease or risk factors for cardiovascular disease to reduce the risk of hospitalization for heart failure.
(See Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use for available data on the combination therapy.)

4.2 Dose and Method of Administration

Life threatening lactic acidosis can occur due to accumulation of metformin. The main risk factor is renal impairment, other risk factors include old age associated with reduced renal function and high doses of metformin above 2 g per day.
The dosage of antihyperglycaemic therapy with Xigduo XR should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended dose of dapagliflozin 10 mg and metformin extended-release 2000 mg.
Xigduo XR should generally be administered once daily with the evening meal. The following tablet strengths are available:
Xigduo XR 10/500 (dapagliflozin 10 mg/metformin HCl extended-release 500 mg);
Xigduo XR 10/1000 (dapagliflozin 10 mg/metformin HCl extended-release 1000 mg);
Xigduo XR 5/1000 (dapagliflozin 5 mg/metformin HCl extended-release 1000 mg).

Initial therapy.

If therapy with a combination tablet containing dapagliflozin and metformin is considered appropriate, the recommended dose of dapagliflozin is 10 mg once daily. The recommended starting dose of metformin extended-release is 500 mg once daily, which can be titrated to 2000 mg once daily. The maximum dose of Xigduo XR is dapagliflozin 10 mg/metformin extended-release 2000 mg taken as two 5 mg/1000 mg tablets once daily.

Add on combination therapy.

In patients treated with metformin, the dose of Xigduo XR should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin immediate-release to metformin extended-release, glycaemic control should be monitored closely and dosage adjustments made accordingly.
When dapagliflozin is used as an add-on therapy with insulin or an insulin secretagogue, a lower dose of insulin or an insulin secretagogue may be considered to reduce the risk of hypoglycaemia.
No studies have been performed specifically examining the safety and efficacy of Xigduo XR in patients previously treated with other antihyperglycaemic agents and switched to Xigduo XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycaemic control can occur.
If no adequate strength of Xigduo XR is available, individual mono-components should be used instead of the fixed dose combination.
Patients should be informed that Xigduo XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of Xigduo XR will be eliminated in the faeces as a soft, hydrated mass that may resemble the original tablet.

Renal impairment.

Assess renal function prior to initiation of Xigduo XR and periodically thereafter (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
Factors that may increase the risk of lactic acidosis (see Section 4.4 Special Warnings and Precautions for Use) should be reviewed before considering initiation of metformin in patients with eGFR < 60 mL/min/1.73 m2.

Mild renal impairment.

No dose adjustment of Xigduo XR is required for patients with mild renal impairment (estimated glomerular filtration [eGFR] 60-89 mL/min/1.73 m2 by Modified Diet in Renal Disease [MDRD] eGFR equation).

Moderate renal impairment.

No dose adjustment is required for patients with eGFR ≥ 45 mL/min/1.73 m2. Xigduo XR is contraindicated in patients with eGFR persistently below 45 mL/min/1.73 m2 (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Severe renal impairment.

Xigduo XR is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) (see Section 4.3 Contraindications).
See Table 1.

Hepatic impairment.

Since impaired hepatic function has been associated with some cases of lactic acidosis in patients taking metformin, Xigduo XR should not be used in patients with clinical or laboratory evidence of hepatic impairment. (See Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment.)

Paediatric and adolescent.

Safety and effectiveness of Xigduo XR in paediatric and adolescent patients have not been established.

Use in the elderly.

Because metformin is eliminated by the kidney, and because elderly patients are more likely to have decreased renal function, Xigduo XR should be used with caution as age increases.

4.3 Contraindications

Xigduo XR is contraindicated in patients with:
patients with a history of any serious hypersensitivity reaction to the active substance or to any of the excipients;
metabolic acidosis: acute or chronic metabolic acidosis, including lactic acidosis or diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin;
diabetic pre-coma;
eGFR persistently < 45 mL/min/1.73 m2 (see Section 4.4 Special Warnings and Precautions for Use);
acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, or intravascular administration of iodinated contrast agents (see Section 4.4 Special Warnings and Precautions for Use);
acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, pulmonary embolism, recent myocardial infarction, shock, acute significant blood loss, sepsis, gangrene, pancreatitis;
during or immediately following surgery where insulin is essential, elective major surgery;
hepatic impairment;
acute alcohol intoxication, alcoholism;
lactation.

4.4 Special Warnings and Precautions for Use

General.

Xigduo XR should not be used in patients with type 1 diabetes mellitus (see Section 4.1 Therapeutic Indications) or for the treatment of diabetic ketoacidosis (see Section 4.4 Special Warnings and Precautions for Use, Ketoacidosis).

Lactic acidosis.

Metformin hydrochloride.

Lactic acidosis is a very rare, but serious and potentially fatal in the absence of prompt treatment, metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in patients with diabetes with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency, dehydration, any acute conditions associated with hypoxia or impacting renal function (see Section 4.4 Special Warnings and Precautions for Use).
Medicinal products that can acutely impair renal function, such as antihypertensives, diuretics and nonsteroidal anti-inflammatory drug (NSAIDs), should be initiated with caution in metformin-treated patients.
Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis is characterized by symptoms such as acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. Lactic acidosis is a medical emergency that must be treated in a hospital setting. If lactic acidosis is suspected, treatment with Xigduo XR should be discontinued and the patient hospitalized immediately.

Use in renal impairment.

Dapagliflozin increases serum creatinine and decreases eGFR (see Section 4.8 Adverse Effects (Undesirable Effects)). Renal function abnormalities can occur after initiating dapagliflozin. Patients with hypovolaemia may be more susceptible to these changes.
There have been postmarketing reports of acute kidney injury, some requiring hospitalisation and dialysis, in patients receiving SGLT2 inhibitors, including dapagliflozin; some reports involved patients younger than 65 years of age.
Xigduo XR should not be used for the treatment of diabetes in patients with eGFR persistently below 45 mL/min/1.73 m2 as the glycaemic efficacy of dapagliflozin is dependent on renal function (see Section 4.2 Dose and Method of Administration).
Dapagliflozin has not been studied in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2 by MDRD) or end stage renal disease (ESRD). Based on the mechanism of action, dapagliflozin was not anticipated to be effective in these populations.
Metformin is excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function.
Monitoring of renal function is recommended as follows:
prior to initiation of Xigduo XR and at least yearly thereafter;
prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter;
for renal function approaching eGFR 45 mL/min/1.73 m2 and in elderly patients, at least 2 to 4 times per year. If renal function falls persistently eGFR < 45 mL/min/1.73 m2, treatment with Xigduo XR should be discontinued.

Change in clinical status of patients with previously controlled type 2 diabetes.

A patient with type 2 diabetes previously well controlled on Xigduo XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Xigduo XR must be stopped immediately and other appropriate corrective measures initiated.

Use in hepatic impairment.

Dapagliflozin.

There is limited experience in clinical trials in patients with hepatic impairment. Dapagliflozin exposure is increased in patients with severe hepatic impairment. Dapagliflozin should not be used in patients with severe hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Metformin hydrochloride.

Since impaired hepatic function has been associated with some cases of metformin associated lactic acidosis, Xigduo XR should be avoided in patients with clinical or laboratory evidence of hepatic disease.

Radiologic studies with intravascular iodinated contrast materials.

Metformin hydrochloride.

Intravascular administration of iodinated contrast agents in radiological studies can lead to an acute decrease in renal function and has been associated with lactic acidosis in patients receiving metformin. Therefore, Xigduo XR should temporarily be discontinued prior to, or at the time of the procedure and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be stable (see Section 4.3 Contraindications).

Acute conditions associated with hypoxia or impacting renal function.

Metformin hydrochloride.

Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions characterised by hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. Acute conditions such as dehydration, severe infections, and hypoperfusion, have potential to alter renal function. In these situations, metformin must be discontinued.

Surgery.

Treatment with Xigduo XR should be ceased at least 48 hours prior to major surgery (also see Section 4.4 Special Warnings and Precautions for Use, Lactic acidosis, Diabetic ketoacidosis). An increase in other glucose lowering agents may be required during this time.
Patients scheduled for non-urgent surgery who have not ceased treatment with Xigduo XR should be assessed and consideration should be given to postponing the procedure.
Treatment with Xigduo XR may be restarted not earlier than 48 hours following the surgery once the patient's condition has stabilised, oral intake is normal and only after renal function has been evaluated and found to be normal.

Use in patients at risk for volume depletion and/or hypotension.

Dapagliflozin.

The diuretic effect of dapagliflozin is a potential concern for volume depleted patients. Due to its mechanism of action, dapagliflozin induces osmotic diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
When considering initiating dapagliflozin, there may be patients for whom the additional diuretic effect of dapagliflozin is a potential concern either due to acute illness (such as gastrointestinal illness) or a history of hypotension or dehydration with diuretic therapy for patients who may become volume depleted. Initiation of therapy with dapagliflozin is therefore not recommended in these patients.
In case of intercurrent conditions that may lead to volume depletion, such as gastrointestinal illness, heat stress or severe infections, careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including electrolytes) is recommended. Temporary interruption of Xigduo XR is recommended for patients who develop volume depletion until the depletion is corrected (see Section 4.8 Adverse Effects (Undesirable Effects)).
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on antihypertensive therapy with a history of hypotension or elderly patients.

Urinary tract infections.

Dapagliflozin.

There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in patients receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors, including dapagliflozin. Urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to control in a placebo-pooled analysis up to 24 weeks (4.7% vs. 3.5%, respectively). Urinary glucose excretion may be associated with an increased risk of urinary tract infection. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (see Section 4.8 Adverse Effects (Undesirable Effects)). Temporary interruption of dapagliflozin should be considered when treating pyelonephritis or urosepsis. Discontinuation of dapagliflozin may be considered in cases of recurrent urinary tract infections; see Section 4.8 Adverse Effects (Undesirable Effects).

Necrotising fasciitis of the perineum (Fournier's gangrene).

Postmarketing cases of necrotising fasciitis of the perineum (also known as Fournier's gangrene), a rare, but serious and potentially life-threatening necrotising infection, have been reported in female and male patients with diabetes mellitus treated with SGLT2 inhibitors, including dapagliflozin (see Section 4.8 Adverse Effects (Undesirable Effects)). Serious outcomes have included hospitalisation, multiple surgeries, and death.
Patients treated with Xigduo XR who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, Xigduo XR should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).

Lower limb amputations.

Dapagliflozin.

In one long-term clinical study with another SGLT2 inhibitor, an increase in cases of lower limb amputation (primarily of the toe) has been observed. The medicine in that study is not dapagliflozin. However, it is unknown whether this constitutes a class effect. It is important to regularly examine the feet and counsel all patients with diabetes on routine preventative footcare.

Vitamin B12 decrease/deficiency.

Metformin hydrochloride.Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contraindicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines (see Section 4.8 Adverse Effects (Undesirable Effects)).

Excessive alcohol intake.

Metformin hydrochloride.

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake, while receiving Xigduo XR.

Ketoacidosis.

Xigduo XR should not be used for the treatment of diabetic ketoacidosis (DKA).
There have been reports of ketoacidosis, including DKA, a serious life-threatening condition requiring urgent hospitalisation in patients taking dapagliflozin and other SGLT2 inhibitors. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin.
Patients treated with Xigduo XR who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath, should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L (250 mg/dL). If ketoacidosis is suspected, Xigduo XR should be suspended, the patient should be evaluated and prompt treatment initiated.
Treatment of ketoacidosis generally requires insulin, fluid, potassium and carbohydrate replacement.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved.
Before initiating Xigduo XR, consider factors in the patient history that may predispose to ketoacidosis.
Factors that predispose patients to ketoacidosis include insulin deficiency from any cause (including insulin pump failure, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, low carbohydrate diet, acute illness, surgery, a previous ketoacidosis, dehydration and alcohol abuse. Xigduo XR should be used with caution in these patients. Consider monitoring patients for ketoacidosis and temporarily discontinuing Xigduo XR in clinical situations known to predispose to ketoacidosis.

Loss of control of blood glucose.

Metformin hydrochloride.

When a patient stabilised on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycaemic control may occur. At such times, it may be necessary to withhold Xigduo XR and temporarily administer insulin. Xigduo XR may be reinstituted after the acute episode is resolved.

Use with medications known to cause hypoglycaemia.

Dapagliflozin.

Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycaemia. Therefore, a lower dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with Xigduo XR (see Section 4.8 Adverse Effects (Undesirable Effects)).

Metformin hydrochloride.

Hypoglycaemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication, are particularly susceptible to hypoglycaemic effects. Hypoglycaemia may be difficult to recognise in the elderly and in people who are taking beta-adrenergic blocking drugs.

Paediatric use.

Safety and effectiveness of Xigduo XR in paediatric patients have not been established.

Use in the elderly.

Because metformin is eliminated by the kidney, and because elderly patients are more likely to have decreased renal function, Xigduo XR should be used with caution as age increases. The renal function recommendations provided for all patients also apply to elderly patients (see Section 4.4 Special Warnings and Precautions for Use).

Metformin hydrochloride.

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney and the risk of serious adverse reactions to the drug is greater in patients with impaired renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special populations).

Cardiac failure.

Dapagliflozin.

There is no experience in clinical studies with dapagliflozin in NYHA class IV.

Effects on laboratory tests.

Interference with 1,5-anhydroglucitol (1,5-AG) assay.

Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycaemic control.

Haematocrit.

In the pool of 13 short-term placebo-controlled studies (see Section 4.8 Adverse Effects (Undesirable Effects)), increases from baseline in mean haematocrit values were observed in dapagliflozin-treated patients starting at week 1. At week 24, the mean changes from baseline in haematocrit were -0.33% in the placebo group and 2.30% in the dapagliflozin 10 mg group. By Week 24, haematocrit values > 55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg treated patients.
In the pool of 9 placebo-controlled studies with short-term and long-term data, at week 102, the mean changes in haematocrit values were 2.68% vs. -0.46%, respectively. Results for haematocrit values > 55% during the short-term plus long-term phase (the majority of patients were exposed to treatment for more than one year), were similar to week 24.
Most patients with marked abnormalities of elevated haematocrit or haemoglobin had elevations measured a single time that resolved at subsequent visits.

Serum inorganic phosphorus.

In the pool of 13 short-term placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at week 24 in dapagliflozin-treated patients compared with placebo-treated patients (mean increase of 0.042 mmol/L versus -0.0013 mmol/L, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphataemia (≥ 1.81 mmol/L for age 17-65 years or ≥ 1.65 mmol/L for age ≥ 66 years) were reported on dapagliflozin at Week 24 (0.9% versus 1.7% for placebo and dapagliflozin 10 mg, respectively).
In the pool of 9 placebo-controlled studies with short-term and long-term data, at week 102, reported increases in mean serum phosphorus were similar to week 24 results. During the short-term plus long-term phase laboratory abnormalities of hyperphosphataemia were reported in a higher proportion of patients in the dapagliflozin group compared to placebo (3.0% vs. 1.6%, respectively). The clinical relevance of these findings is unknown.

Lipids.

In the 13-study short-term placebo-controlled pool (see Section 4.8 Adverse Effects (Undesirable Effects)), small changes from baseline in mean lipid values were reported at week 24 in dapagliflozin 10 mg treated patients compared with placebo. Mean percent change from baseline at week 24 for dapagliflozin 10 mg vs. placebo, respectively was as follows: total cholesterol 2.5% vs. 0.0%; HDL cholesterol 6.0% vs. 2.7%; LDL cholesterol 2.9% vs. -1.0%; triglycerides -2.7% vs. -0.7%. The ratio between LDL cholesterol and HDL cholesterol decreased for both treatment groups at week 24.
In the pool of 9 placebo-controlled studies with short-term and long-term data, the mean percent change from baseline at week 102 for dapagliflozin 10 mg vs. placebo, respectively was as follows: total cholesterol 2.1% vs. -1.5%; HDL cholesterol 6.6% vs. 2.1%; LDL cholesterol 2.9% vs. -2.2%; triglycerides -1.8% vs. -1.8%.
In the cardiovascular outcomes study, no clinical important differences in total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides were seen.

Liver function tests.

In the 21-study active and placebo-controlled pool (see Section 4.8 Adverse Effects (Undesirable Effects)), there was no imbalance across treatment groups in the incidence of elevations of ALT or AST. ALT > 3 x ULN was reported in 1.2% of patients treated with dapagliflozin 10 mg and 1.6% treated with comparator. ALT or AST > 3 x ULN and bilirubin > 2 x ULN was reported in 0.1% of patients on any dose of dapagliflozin, 0.2% of patients on dapagliflozin 10 mg, and 0.1% of patients on comparator.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Dapagliflozin.

The metabolism of dapagliflozin is primarily mediated by UGT1A9-dependent glucuronide conjugation. The major metabolite, dapagliflozin 3-O-glucuronide, is not an SGLT2 inhibitor.
In in-vitro studies, dapagliflozin neither inhibited CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, nor induced CYP1A2, 2B6 or 3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of coadministered drugs that are metabolised by these enzymes and drugs which inhibit or induce these enzymes are not expected to alter the metabolic clearance of dapagliflozin. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.
In interaction studies conducted in healthy subjects, using mainly single dose design, the pharmacokinetics of dapagliflozin were not altered by metformin (an hOCT-1 and hOCT-2 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (an hOAT-3 substrate, and P-glycoprotein substrate), glimepiride (a CYP2C9 substrate), voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin (a CYP3A4 substrate). Therefore, meaningful interaction of dapagliflozin with other substrates of hOCT-1, hOCT-2, hOAT-3, P-gp, CYP2C8, CYP2C9, CYP3A4, and other α-glucosidase inhibitors would not be expected.
Concomitant use of dapagliflozin and lithium may lead to a reduction in serum lithium concentrations due to a possible increased urinary clearance of lithium. The dose of lithium may need to be adjusted.
Dapagliflozin also did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, simvastatin, digoxin (a P-gp substrate), or warfarin (S-warfarin is a CYP2C substrate). Therefore, dapagliflozin is not a clinical meaningful inhibitor of hOCT-1, hOCT-2, hOAT-3, P-gp transporter pathway, and CYP2C8, CYP2C9, CYP2C19 and CYP3A4 mediated metabolism.
Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolizing enzymes) or mefenamic acid (an inhibitor of UGT1A9), a 22% decrease and a 51% increase, respectively, in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion in either case.
No dose adjustment of dapagliflozin is recommended when dapagliflozin is coadministered with either rifampicin or mefenamic acid.

Metformin hydrochloride.

Cationic drugs.

Cationic drugs (e.g. amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Glibenclamide.

In a single-dose interaction study in patients with type 2 diabetes, coadministration of metformin and glibenclamide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glibenclamide AUC and maximum concentration (Cmax) were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glibenclamide blood levels and pharmacodynamic effects makes the clinical significance of this interaction uncertain.

Frusemide.

A single-dose, metformin-frusemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Frusemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of frusemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in frusemide renal clearance. No information is available about the interaction of metformin and frusemide when coadministered chronically.

Nifedipine.

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Use with other drugs.

Certain drugs tend to produce hyperglycaemia and may lead to loss of glycaemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving metformin, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, the patient should be observed closely for hypoglycaemia.
In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.
Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

Other interactions.

The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of Xigduo XR have not been specifically studied.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Dapagliflozin.

In a study of fertility in rats, no effects on mating, fertility, or early embryonic development were seen when males received oral doses up to 210 mg/kg/day or when females received oral doses up to 75 mg/kg/day (yielding plasma AUC values at least 1000 times the clinical exposure at the maximum recommended human dose [MRHD] of 10 mg/day). However, at 210 mg/kg/day, a dose associated with profound toxicity (including mortality), seminal vesicle and epididymal weights were reduced; sperm motility and sperm counts were reduced; and there were increased numbers of morphologically abnormal sperm. No adverse effects on sperm or male reproductive organs were seen at 75 mg/kg/day (700 times the clinical exposure at the MRHD).
(Category D)
There are no adequate and well-controlled studies of Xigduo XR or its individual components in pregnant women. When pregnancy is detected, treatment with Xigduo XR should be discontinued.

Dapagliflozin.

Studies in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy (see Section 4.4 Special Warnings and Precautions for Use). Therefore, dapagliflozin must not be used during the second and third trimesters of pregnancy.
In conventional studies of embryofoetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the period of organogenesis in humans. An increased incidence of embryofoetal lethality, decreased foetal weight and an increased incidence of foetal visceral and skeletal anomalies were seen in rats at maternotoxic doses (oral doses greater than or equal to 150 mg/kg/day). The no observed effect level for embryofoetal effects in rats was an oral dose of 75 mg/kg/day (1530 times the exposure in patients at the maximum recommended human dose [MRHD]). No developmental toxicities were observed in rabbits at oral doses up to 180 mg/kg/day (1265 times the exposure in patients at the MRHD).

Metformin hydrochloride.

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 3 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively.
Determination of foetal concentrations demonstrated a partial placental barrier to metformin.
 Xigduo XR must not be used by breastfeeding women.
No studies in lactating animals have been conducted with the combined components of Xigduo XR. In studies performed with the individual components, both dapagliflozin and metformin are excreted in the milk of lactating rats.
Studies in rats have shown excretion of dapagliflozin in milk. Direct and indirect exposure of dapagliflozin to weanling juvenile rats and during late pregnancy are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny. The long-term functional consequences of these effects are unknown. These periods of exposure coincide with a critical window of renal maturation in rats. As functional maturation of the kidneys in humans continues in the first 2 years of life, dapagliflozin-associated dilated renal pelvis and tubules noted in juvenile rats could constitute potential risk for human renal maturation during the first 2 years of life. Additionally, the negative effects on body weight gain associated with lactational exposure in weanling juvenile rats suggest that dapagliflozin must be avoided during the first 2 years of life.
It is not known whether dapagliflozin or metformin are secreted in human milk.

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 with Xigduo XR or dapagliflozin. It should be taken into account that dizziness has been reported in studies with dapagliflozin.
Patients should be alerted to the risk of hypoglycaemia when Xigduo XR is used with a sulphonylurea or insulin.

4.8 Adverse Effects (Undesirable Effects)

Significant adverse events are also described in Section 4.4 Special Warnings and Precautions for Use.

Clinical experience - dapagliflozin.

Two major pools of patients were used to evaluate adverse effects with dapagliflozin 10 mg versus control; a pool of 13 placebo-controlled studies and a larger pool comprised of 21 active- and placebo-controlled studies.
In the dedicated cardiovascular outcomes study in patients with type 2 diabetes mellitus, 8574 patients received dapagliflozin 10 mg and 8569 received placebo for a median exposure time of 48 months. In total, there were 30,623 patient-years of exposure to dapagliflozin.
Placebo-controlled studies. The first pool is a pre-specified pool of patients from 13 short-term, placebo-controlled studies including the monotherapy studies, add-on studies, and the initial combination with metformin study. In the pool, 2360 patients were treated with dapagliflozin 10 mg and 2295 were treated with placebo with a mean duration of exposure of 22 weeks.
The overall incidence of adverse events in patients treated with dapagliflozin 10 mg was 60.0% compared to 55.7% for the placebo group. The incidence of discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg was 4.3% compared to 3.6% for the placebo group. The most commonly reported events leading to discontinuation in patients and reported in at least 3 dapagliflozin 10 mg treated patients were renal impairment (0.8%), decrease in creatinine clearance (0.6%), increased blood creatinine (0.3%), urinary tract infections (0.2%), and vulvovaginal mycotic infection (0.1%).
Active- and placebo-controlled studies. The second pool is a pool of patients from 21 active- and placebo-controlled studies used to evaluate and present data for malignancies and liver tests. In this pool, 5936 patients were treated with dapagliflozin and 3403 were treated with control (either as monotherapy or in combination with other antidiabetic therapies). These 21 studies provide a mean duration of exposure to dapagliflozin 10 mg of 55 weeks (6247 patient-years).
The adverse events in the 13-study placebo controlled pool reported (regardless of investigator assessment of causality) in ≥ 2% of patients treated with dapagliflozin 10 mg and ≥ 1% more and at least 3 patients more than treated with placebo are shown in Table 2.
Additional adverse reactions in ≥ 5% of patients treated with dapagliflozin 10 mg, ≥ 1% more than patients in placebo/ comparator, and reported in at least three more patients treated with dapagliflozin 10 mg and regardless of relationship to dapagliflozin reported by investigator, are described below by treatment regimen.
In the add-on to metformin studies: headache (5.3% dapagliflozin 10 mg and 3.1% placebo).
Diabetic ketoacidosis was identified with a frequency of rare (≥ 1/10,000 to < 1/1000), based on annual rate, in a large cardiovascular outcomes study with dapagliflozin in patients with type 2 diabetes.
Description of selected adverse events.

Hypoglycaemia.

The frequency of hypoglycaemia depended on the type of background therapy used in each study. Studies with add-on sulfonylurea and add-on insulin therapies had higher rates of hypoglycaemia with dapagliflozin treatment than with placebo treatment (see Section 4.4 Special Warnings and Precautions for Use).
In studies of dapagliflozin in initial combination therapy with metformin, add-on to metformin alone up to 102 weeks there were no major episodes of hypoglycaemia reported. In a study of dapagliflozin added on to sitagliptin (with or without metformin) for up to 48 weeks, one major episode of hypoglycaemia was reported in a patient treated with dapagliflozin 10 mg plus sitagliptin (without metformin). In these studies, the frequency of minor episodes of hypoglycaemia was similar (< 5%) between treatment groups, including placebo.
In a study with dapagliflozin 10 mg added on to glimepiride for up to 48 weeks, that also included other doses of dapagliflozin, one episode of major hypoglycaemia in a patient in the dapagliflozin 2.5 mg plus glimepiride group was reported. Minor episodes of hypoglycaemia were reported in 7.9% patients in the dapagliflozin 10 mg plus glimepiride group and 2.1% patients in the placebo plus glimepiride group.
In an add-on to metformin study that compared dapagliflozin to glipizide up to 104 weeks, there were 3 episodes of major hypoglycaemia in the glipizide plus metformin group and none in the dapagliflozin plus metformin group. Minor episodes of hypoglycaemia were reported in 2.5% of patients in the dapagliflozin plus metformin group and 42.4% of patients in the glipizide plus metformin group.
In an add-on to metformin and a sulfonylurea study, up to 52 weeks, no episodes of major hypoglycaemia were reported. Minor episodes of hypoglycaemia were reported in 15.6% of subjects who received dapagliflozin 10 mg plus metformin and a sulfonylurea and in 4.6% of subjects who received placebo plus metformin and a sulfonylurea.
In the analysis of pooled safety data of 1169 patients from trials evaluating saxagliptin in combination with dapagliflozin at 24 weeks, the overall incidence of hypoglycaemia for the pooled safety data was low (≤ 1.8% in any treatment group); there was no increase in hypoglycaemia in saxagliptin plus dapagliflozin plus metformin treatment group compared to the saxagliptin plus metformin or dapagliflozin plus metformin treatment groups. The combined use of saxagliptin plus dapagliflozin plus metformin was not associated with an increase in the risk of hypoglycaemia when compared to the individual agents as monotherapy. This was consistent with prior clinical trial experience regardless of whether the combination was added to metformin concurrently or sequentially.
In a study of dapagliflozin 10 mg initiated concomitantly with extended release exenatide (on a background of metformin), there were no episodes of major or minor hypoglycaemia reported.
In an add-on to insulin study up to 24 weeks, episodes of major hypoglycaemia were reported in 1 (0.5%) and 1 (0.5%) patient in dapagliflozin 10 mg plus insulin and placebo plus insulin groups, respectively. Up to 104 weeks, 2 (1.0%) and 1 (0.5%) of patients in dapagliflozin 10 mg plus insulin and placebo plus insulin groups reported major episodes. Up to 24 weeks, minor episodes were reported in 79 (40.3%) patients in the dapagliflozin 10 mg plus insulin group and in 67 (34%) patients in placebo plus insulin group. Up to 104 weeks, minor episodes were reported in patients were 53.1% for dapagliflozin 10 mg plus insulin and 41.6% for placebo. Patients in this study could also be treated with a maximum of two oral anti-diabetes medications (OADs) including metformin.
In the dapagliflozin cardiovascular outcomes study, no increased risk of major hypoglycaemia was observed with dapagliflozin therapy compared with placebo. Major events of hypoglycaemia were reported in 58 patients (0.7%) treated with dapagliflozin and 83 (1.0%) patients treated with placebo.

Volume depletion.

In the pooled analysis of 13 short-term, placebo-controlled studies, events suggestive of volume depletion (including reports of dehydration, hypovolaemia or hypotension) were reported in 1.1% and 0.7% of patients who received dapagliflozin 10 mg and placebo, respectively. Across the pool of 21 active and placebo-controlled studies, serious events occurred in ≤ 0.2% of patients and were balanced between dapagliflozin 10 mg and comparator (see Section 4.4 Special Warnings and Precautions for Use).
Adverse events of volume depletion were more commonly seen in patients with moderate renal impairment.
In the cardiovascular outcomes study, the numbers of patients with events suggestive of volume depletion were balanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the dapagliflozin and placebo groups, respectively. Serious adverse events were reported in 81 (0.9%) and 70 (0.8%) in the dapagliflozin and placebo group, respectively. Events were generally balanced between treatment groups across subgroups of age, diuretic use, blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use. In patients with eGFR < 60 mL/min/1.73 m2 at baseline, there were 19 events of serious adverse events suggestive of volume depletion in 604 patients in the dapagliflozin group and 13 events in 658 patients in the placebo group.

Genital infections.

In the pooled analysis of 13 short-term, placebo-controlled studies, events of genital infections were reported in 5.5% and 0.6% of patients who received dapagliflozin 10 mg and placebo, respectively. The events of genital infections reported in patients treated with dapagliflozin 10 mg were all mild to moderate. Most events of genital infection responded to an initial course of standard treatment and rarely resulted in discontinuation from the study (0.2% dapagliflozin 10 mg vs. 0% placebo). Subjects with a history of recurrent genital infection were more likely to experience an infection. Infections were more frequently reported in females (8.4% dapagliflozin 10 mg vs. 1.2% placebo) than in males (3.4% dapagliflozin 10 mg vs. 0.2% placebo). The most frequently reported genital infections were vulvovaginal mycotic infections in females, and balanitis in males.
In 9 of the 13 studies in the placebo-controlled pool, long-term data was available. In this short-term plus long-term placebo-pooled analysis (mean duration of treatment was 439.5 days for dapagliflozin 10 mg and 419.0 days for placebo); the proportions of patients with events of genital infections were 7.7% (156/2026) in the dapagliflozin 10 mg group and 1.0% (19/1956) in the placebo group. Of the patients treated with dapagliflozin 10 mg who experienced an infection, 67.9% had only one and 10.9% had 3 or more. Of the patients treated with placebo who experienced an infection, 89.5% had only one and none had 3 or more.
In the cardiovascular outcomes study, the number of patients with serious adverse events of genital infections were few and balanced: 2 (< 0.1%) patients in each of the dapagliflozin and placebo groups. There were 74 and 7 patients with non-serious adverse events of genital infections leading to study drug discontinuation in the dapagliflozin group and placebo group, respectively.

Necrotising fasciitis of the perineum (Fournier's gangrene).

In the dapagliflozin cardiovascular outcomes study with 17,160 patients with type 2 diabetes mellitus and a median exposure time of 48 months, a total of 6 cases of Fournier's gangrene were reported on treatment, one in the dapagliflozin-treated group and 5 in the placebo group.

Urinary tract infections.

In the pooled analysis of 13 short-term, placebo-controlled studies, events of urinary tract infections were reported in 4.7% and 3.5% of patients who received dapagliflozin 10 mg and placebo, respectively. Most events of urinary tract infections reported in patients treated with dapagliflozin 10 mg were mild to moderate. Most patients responded to an initial course of standard treatment, and urinary tract infections rarely caused discontinuation from the study (0.2% dapagliflozin 10 mg vs. 0.1% placebo). Subjects with a history of recurrent urinary tract infection were more likely to experience an infection. Infections were more frequently reported in females (8.5% dapagliflozin 10 mg vs. 6.7% placebo) than in males (1.8% dapagliflozin 10 mg vs. 1.3% placebo) (see Section 4.4 Special Warnings and Precautions for Use).
In the short-term plus long-term placebo-pooled analysis of 9 short-term studies with long-term data available, the proportions of patients with events of urinary tract infections were 8.6% in the dapagliflozin 10 mg group and 6.2% in the placebo group. Of the 59 patients treated with dapagliflozin 10 mg who experienced an infection, 77.6% had only one and 6.3% had 3 or more. Of the patients treated with placebo who experienced an infection, 77.7% had only one and 9.9% had 3 or more.
In the cardiovascular outcomes study there were fewer patients with serious adverse events of urinary tract infections in the dapagliflozin group compared with the placebo group: 79 (0.9%) and 109 (1.3%), respectively.

Diabetic ketoacidosis (DKA).

In a large cardiovascular outcomes study with dapagliflozin in patients with type 2 diabetes, where 8574 patients received dapagliflozin 10 mg and 8569 patients received placebo, with a median exposure time of 48 months, events of DKA were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. The events occurred evenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozin group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population (see Section 4.4 Special Warnings and Precautions for Use).

Events related to decreased renal function.

Use of dapagliflozin was associated with increases in serum creatinine and decreases in eGFR. These changes were observed to reverse after treatment discontinuation, suggesting acute haemodynamic changes play a role in the renal function abnormalities observed with dapagliflozin.
Renal-related adverse reactions (e.g. acute kidney injury, renal impairment, acute prerenal failure) may occur in patients treated with dapagliflozin.
In the 13-study, short-term, placebo-controlled pool, mean serum creatinine levels increased a small amount at Week 1 (mean change from baseline: 0.041 mg/dL dapagliflozin 10 mg versus 0.008 mg/dL placebo) and decreased toward baseline by Week 24 (mean change from baseline: 0.019 mg/dL dapagliflozin 10 mg versus 0.008 mg/dL placebo). There were no further changes through Week 102.
In the cardiovascular outcomes study, there were fewer patients with marked laboratory abnormalities of creatinine, creatinine clearance, eGFR, and urine albumin to creatinine ration (UACR) in the dapagliflozin group compared with the placebo group. Fewer renal events (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine, and decreased glomerular filtration rate) were reported in the dapagliflozin group compared with the placebo group: 422 (4.9%) and 526 (6.1%), respectively. There were fewer patients with events reported as acute kidney injury in the dapagliflozin group compared with the placebo group: 125 (1.5%) and 175 (2.0%), respectively. There were fewer patients with SAEs of renal events in the dapagliflozin group compared with the placebo group: 80 (0.9%) and 136 (1.6%), respectively. eGFR decreased over time in both treatment groups. At 1 year, mean eGFR was slightly lower, and at 4 years, mean eGFR was slightly higher in the dapagliflozin group compared with the placebo group.

Metformin hydrochloride.

Metformin adverse reactions by system organ class and by frequency category. Frequency categories are based on information available from the product information for metformin available in Australia.

Gastrointestinal.

Very common: mild gastrointestinal symptoms (such as diarrhoea, nausea, vomiting, abdominal pain and loss of appetite) are the most frequent reactions to metformin (> 1/10), especially during the initial treatment period. These symptoms are generally transient and resolve spontaneously during continued treatment.
Occurrence of gastrointestinal symptoms, once a patient is stabilised on any dose of metformin, could be due to lactic acidosis or other serious disease.

Systemic/metabolic.

Very rare: lactic acidosis (see Section 4.4 Special Warnings and Precautions for Use) is a very rare (< 1/10,000) but serious metabolic complication that can occur due to metformin accumulation during treatment with metformin.
The onset of lactic acidosis is often subtle and accompanied only by non-specific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and non-specific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonaemia).
Lactic acidosis is a medical emergency that must be treated in hospital. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted.

Nervous system disorders.

Common: taste disturbance (3%) is common.

Dermatological.

Very rare: skin reactions such as erythema, pruritus and urticaria have been reported, but the incidence is very rare (< 1/10,000).

Haematological.

Common: a decrease of vitamin B12 absorption with a decrease in serum levels has been observed in patients treated long-term with metformin (> 1/100, < 1/10). Consideration of such an aetiology is recommended if a patient presents with megaloblastic anaemia. Therefore, serum B12 levels should be appropriately monitored or periodic parenteral B12 supplementation considered (see Section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary disorders.

Isolated reports: liver function tests abnormalities or hepatitis resolving upon metformin discontinuation, have been reported.
In clinical trials in children and adolescents with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

Postmarketing experience.

The following postmarketing case reports have been reported during post-approval use of Xigduo XR. Because these cases are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency.

Metabolism and nutrition disorders.

Ketoacidosis, vitamin B12 decrease/deficiency.

Infections and infestations.

Pyelonephritis, urosepsis, necrotising fasciitis of the perineum (Fournier's gangrene).

Skin and subcutaneous tissue disorders.

Rash, angioedema.

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

Dapagliflozin.

Orally-administered dapagliflozin has been shown to be safe and well-tolerated in healthy subjects at single doses up to 500 mg (50 times the MRHD). These subjects had detectable glucose in the urine for a dose-related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration, hypotension, or electrolyte imbalance, and with no clinically meaningful effect on QTc interval. The incidence of hypoglycaemia was similar to placebo. In clinical studies where once-daily doses of up to 100 mg (10 times the MRHD) were administered for 2 weeks in healthy subjects and patients with type 2 diabetes, the incidence of hypoglycaemia was slightly higher than placebo and was not dose-related. Rates of adverse events including dehydration or hypotension were similar to placebo, and there were no clinically meaningful dose-related changes in laboratory parameters including serum electrolytes and biomarkers of renal function.
In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. The removal of dapagliflozin by haemodialysis has not been studied.

Metformin hydrochloride.

High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital. The most effective method to remove lactate and metformin is haemodialysis. Events of hypoglycaemia have been reported with overdoses of metformin, although a causal association has not been established.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Xigduo XR combines two anti-hyperglycaemic agents with complementary mechanisms of action to improve both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) in patients with type 2 diabetes: dapagliflozin, a SGLT2 inhibitor, and metformin hydrochloride, a member of the biguanide class.

Dapagliflozin.

Dapagliflozin is a reversible competitive inhibitor of sodium glucose co-transporter 2 (SGLT2) with nanomolar potency that improves glycaemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to urinary glucose excretion (glucuresis).
SGLT2 is selectively expressed in the kidney with no expression detected in more than 70 other tissues including liver, skeletal muscle, adipose tissue, breast, bladder and brain. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. This glucose excretion (glucuretic effect) is observed after the first dose, is continuous over the 24-hour dosing interval, and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Thus, in healthy subjects with normal glucose, dapagliflozin has a low propensity to cause hypoglycaemia. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Over time, improvement in beta-cell function (HOMA-2) has been observed in clinical studies with dapagliflozin.
Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and reduction in weight. The majority of the weight reduction was body fat loss, including visceral fat rather than lean tissue or fluid loss as demonstrated by dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging.
Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is approximately 1000-3000 times more selective for SGLT2 vs. SGLT1, the major transporter in the gut responsible for glucose absorption.

Metformin hydrochloride.

Metformin is an antihyperglycaemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation. Unlike sulfonylureas, metformin does not produce hypoglycaemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see Section 4.4 Special Warnings and Precautions for Use) and does not cause hyperinsulinaemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
In humans, independently of its action on glycaemia metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

Pharmacodynamics.

General.

Dapagliflozin.

Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in patients with type 2 diabetes mellitus for 12 weeks. Evidence of sustained glucose excretion was seen in patients with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years.
This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases in urinary volume. Urinary volume increases in patients with type 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted to approximately 375 mL/day. The increase in urinary volume was associated with a small and transient increase in urinary sodium excretion that was not associated with changes in serum sodium concentrations.
Urinary uric acid excretion was also increased transiently (for 3-7 days) and accompanied by a reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from 18.3 to 48.3 micromol/L.
Cardiac electrophysiology.

Dapagliflozin.

Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended dose) dapagliflozin in healthy subjects.

Clinical trials.

There have been no clinical efficacy studies conducted with Xigduo XR; however, bioequivalence of Xigduo XR with coadministered dapagliflozin and metformin hydrochloride extended release tablets was demonstrated.

Addition of dapagliflozin to metformin.

The coadministration of dapagliflozin and metformin has been studied in patients with type 2 diabetes inadequately controlled on metformin alone or in combination with a sulfonylurea, dipeptidyl peptidase 4 (DPP4) inhibitor or insulin, in treatment-naive patients inadequately controlled on diet and exercise alone, and compared with a sulfonylurea in combination with metformin in patients with inadequate glycaemic control on metformin alone. Additionally, dapagliflozin 10 mg or placebo were studied in patients with type 2 diabetes with cardiovascular disease (approximately 37% of patients across 2 studies received dapagliflozin 10 mg or placebo plus metformin alone [with or without insulin]) and patients with type 2 diabetes with hypertension (approximately 90% of patients across 2 studies received dapagliflozin 10 mg or placebo plus metformin).

Initial combination therapy with metformin.

641 patients were randomised to one of three treatment arms following a 1-week lead-in period: dapagliflozin 10 mg plus metformin XR (up to 2000 mg per day), dapagliflozin 10 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin dose was up-titrated weekly in 500 mg increments, as tolerated, with the maximum and median dose achieved being 2000 mg. The patients were treatment-naïve, defined as either never having received diabetes medication or having had such for less than 24 weeks since the diagnosis of diabetes, not for more than 14 days during the 12 weeks prior to enrolment, and not at all during the 4 weeks prior to enrolment.
The combination treatment of dapagliflozin 10 mg plus metformin provided significant improvements in haemoglobin A1c (HbA1c) and FPG, compared with either of the monotherapy treatments and significant improvements in body weight compared with metformin alone (see Table 3). Dapagliflozin 10 mg as monotherapy also provided significant improvements in FPG and bodyweight compared with metformin alone and was non-inferior to metformin monotherapy in lowering HbA1c. The proportion of patients who were rescued or discontinued for lack of glycaemic control during the 24 week double-blind treatment period (adjusted for baseline HbA1c) was higher on treatment with metformin plus placebo (13.5%) than on dapagliflozin 10 mg plus placebo and dapagliflozin 10 mg plus metformin (7.8%, and 1.4%).

Add-on to metformin.

As add-on treatment to metformin, dapagliflozin 10 mg provided significant improvements in HbA1c at week 24 (see Table 4). See Figure 1.

Active glipizide controlled study add-on to metformin.

In a 52 week, active-controlled non-inferiority study (with 52 week and 104 week extension periods), dapagliflozin was evaluated as add-on therapy to metformin compared with a sulfonylurea (glipizide) as add-on therapy to metformin in subjects with inadequate glycaemic control (HbA1c > 6.5% and ≤ 10%). The results showed a similar mean reduction in HbA1c from baseline to Week 52, compared to glipizide, thus demonstrating noninferiority (see Table 5). At Week 104, adjusted mean change from baseline in HbA1c was -0.32% for dapagliflozin and -0.14% for glipizide. At Week 208, the secondary endpoint of adjusted mean change from baseline in HbA1c was 0.10% for Forxiga and 0.20% for glipizide (see Figure 2). At 52, 104 and 208 weeks, a significantly lower proportion of subjects in the group treated with dapagliflozin (3.5%, 4.3% and 5.0%, respectively) experienced at least one event of hypoglycaemia compared to the group treated with glipizide (40.8%, 47.0% and 50.0%, respectively). The proportions of subjects remaining in the study at Week 104 and Week 208 were 56.2% and 39%, respectively for the group treated with dapagliflozin and 50.0% and 34.6%, respectively for the group treated with glipizide.

Combination therapy with other antihyperglycaemic agents.

Dapagliflozin as an add-on with either sitagliptin (with or without metformin), metformin with saxagliptin, metformin with a sulfonylurea, or insulin, resulted in statistically significant reductions in HbA1c at 24 weeks compared with subjects receiving placebo (p < 0.0001; Tables 6, 7, 8 and 9).
The reductions in HbA1c observed at Week 24 were sustained in add on combination studies and up to 104 week data (insulin, see Figure 3). At Week 48 when added to sitagliptin (with or without metformin), the adjusted mean change from baseline for dapagliflozin 10 mg and placebo was -0.30% and 0.38%, respectively. For the add-on to metformin study, HbA1c reductions were sustained through Week 102 (-0.78% and 0.02% adjusted mean change from baseline for 10 mg and placebo, respectively, also see Figure 3). At Week 104 for insulin (with or without additional oral glucose lowering medicinal products), the HbA1c reductions were -0.71% and -0.06% adjusted mean change from baseline for dapagliflozin 10 mg and placebo, respectively. At Weeks 48 and 104, the insulin dose remained stable compared to baseline in subjects treated with dapagliflozin 10 mg at an average dose of 76 IU/day (see Figure 4). In the placebo group there was a mean increase of 10.5 IU/day and 18.3 IU/day from baseline at Weeks 48 and 104, respectively. The proportion of subjects remaining in the study at Week 104 was 72.4% for the group treated with dapagliflozin 10 mg and 54.8% for the placebo group.

Fasting plasma glucose.

Treatment with dapagliflozin 10 mg as an add on to either metformin, metformin and a sulfonylurea, sitagliptin (with or without metformin) or insulin resulted in statistically significant reductions in fasting plasma glucose (-1.90 to -1.20 mmol/L) compared to placebo (-0.33 to 0.21 mmol/L) at 24 weeks. This effect was observed at Week 1 of treatment and maintained in studies extended through Week 104.

Concomitant initiation therapy with saxagliptin and dapagliflozin in patients inadequately controlled on metformin.

In a 24-week randomised, double-blind, active comparator-controlled superiority study comparing the combination of saxagliptin and dapagliflozin added concomitantly to metformin, versus saxagliptin (DPP4-inhibitor) or dapagliflozin (SGLT2 inhibitor) added to metformin in patients with type 2 diabetes mellitus with inadequate glycaemic control on metformin alone (HbA1c ≥ 8% and ≤ 12%). The saxagliptin and dapagliflozin group achieved significantly greater reductions in HbA1c versus either the saxagliptin group or dapagliflozin group at 24 weeks (see Table 10).

Concomitant initiation of dapagliflozin and extended release exenatide in patients inadequately controlled on metformin.

A total of 694 adult patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA1c ≥ 8.0 and ≤ 12.0%) on metformin alone (≥ 1,500 mg/day) participated in this 28-week randomised, double‑blind, active‑controlled trial to compare the concomitant initiation of dapagliflozin 10 mg once daily and extended release exenatide 2 mg once weekly on a background of metformin versus extended release exenatide 2 mg once weekly (GLP-1 receptor agonist) alone and dapagliflozin 10 mg once daily alone when added to metformin. Following a 1 week placebo lead in period, patients were randomised equally to one of three double‑blind treatment groups to receive either dapagliflozin 10 mg and extended release exenatide, dapagliflozin 10 mg and placebo or extended release exenatide and placebo. During the treatment period, patients continued on the same type and dose of metformin as when they entered the study. At baseline, patients had a mean age of 54.2 years and a BMI of 32.73 kg/m2. Randomisation was stratified by HbA1c at baseline (< 9.0% or ≥ 9.0%) and patients were regularly monitored every 4 weeks in this study.
The primary endpoint was the change in HbA1c from baseline to Week 28 (Figure 5). Compared to dapagliflozin 10 mg alone and extended release exenatide alone, concomitant initiation of dapagliflozin 10 mg and extended release exenatide resulted in statistically significant reductions in HbA1c from baseline at Week 28 (see Table 11).

Post prandial glucose.

Treatment with dapagliflozin 10 mg as an add on to sitagliptin (with or without metformin) resulted in reductions in 2 hour postprandial glucose at 24 weeks that were maintained up to Week 48.

Body weight.

Dapagliflozin 10 mg as an add on to metformin, metformin and a sulfonylurea, sitagliptin (with metformin) or insulin resulted in a statistically significant body weight reduction at 24 weeks (see Tables 4, 6, 8 and 9) with placebo-corrected reductions of 1.97 kg (2.43%), 2.07 kg (2.25%), 1.87 kg (2.08%) and 1.68 kg (1.83%), respectively. These effects were sustained in longer-term trials (see Figure 6 for add-on to insulin). At 48 weeks, the difference for dapagliflozin as add on to sitagliptin (with or without metformin) compared to placebo was -2.22 kg. At 102 weeks, the differences for dapagliflozin as add on to metformin compared to placebo, or as add on to insulin (at 104 weeks) compared to placebo were -2.14 kg and -2.88 kg, respectively.
As an add on therapy to metformin in an active controlled non inferiority study, dapagliflozin resulted in a statistically significant body weight reduction compared with glipizide of 4.65 kg at 52 weeks (see Table 5) compared to glipizide, that was sustained at 104 and 208 weeks (-5.06 kg and -4.38 kg respectively) (see Figure 7).
The adjusted mean change from baseline in body weight at Week-24 when dapagliflozin 10 mg and saxagliptin were added concomitantly to metformin was -2.05 kg (-2.27%) in the saxagliptin plus dapagliflozin 10 mg plus metformin group and -2.39 kg (-2.67%) in the dapagliflozin 10 mg plus metformin group, while the saxagliptin plus metformin group had no change (0.00) (also see Table 10). At Week 24 in the dapagliflozin 10 mg as add-on to saxagliptin with metformin study, change from baseline in body weight was -1.91 kg (-2.23%) in the dapagliflozin 10 mg plus saxagliptin plus metformin group (see Table 7).

Cardiovascular outcomes.

Dapagliflozin Effect on Cardiovascular Events (DECLARE) was an international, multicenter, randomized, double-blind, placebo-controlled clinical study conducted to determine the effect of dapagliflozin compared with placebo on cardiovascular (CV) and renal outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either at least two additional CV risk factors (age ≥ 55 years in men or ≥ 60 years in women and one or more of dyslipidemia, hypertension or current tobacco use) without having had a CV event at baseline (primary prevention) or established CV disease (secondary prevention).
Of 17,160 randomized patients, 6974 (40.6%) had established CV disease and 10,186 (59.4%) did not have established CV disease. 8582 patients were randomized to dapagliflozin 10 mg and 8578 to placebo, and were followed for a median of 4.2 years.
The mean age of the study population was 63.9 years, 37.4% were female, 79.6% were White, 3.5% Black or African-American and 13.4% Asian. In total, 22.4% had had diabetes for ≤ 5 years, mean duration of diabetes was 11.9 years. Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m2.
At baseline, 10.0% of patients had a history of heart failure. Mean eGFR was 85.2 mL/min/1.73 m2, 7.4% of patients had eGFR < 60 mL/min/1.73 m2 and 30.3% of patients had micro- or macroalbuminuria (urine albumin to creatinine ration [UACR] ≥ 30 to ≤ 300 mg/g or > 300 mg/g, respectively).
Most patients (98.1%) used one or more diabetic medications at baseline, 82.0% of the patients were being treated with metformin, 40.9% with insulin, 42.7% with a sulfonylurea, 16.8% with a DPP4 inhibitor, and 4.4% with a GLP-1 agonist.
Approximately 81.3% of patients were treated with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0% with thiazide diuretics and 10.5% with loop diuretics.
Results on primary and secondary endpoints are displayed in Figure 8.

Hospitalisation for heart failure or cardiovascular death.

Dapagliflozin 10 mg was superior to placebo in preventing the primary composite endpoint of hospitalization for heart failure or CV death (HR 0.83 [95% CI 0.73, 0.95]; p = 0.005) (Figure 9).
Exploratory analyses of the single components suggest that the difference in treatment effect was driven by hospitalization for heart failure (HR 0.73 [95% CI 0.61, 0.88]) (Figure 8), with no clear difference in CV death (HR 0.98 [95% CI 0.82 to 1.17]).

Major adverse cardiovascular events.

Dapagliflozin demonstrated cardiovascular safety (tested as non-inferiority versus placebo for the composite of CV death, myocardial infarction or ischemic stroke [MACE]; one-sided p < 0.001).

Nephropathy.

The composite of confirmed sustained eGFR decrease, ESRD, renal or CV death was a secondary variable in the DECLARE study. Because confirmatory testing stopped before the secondary variables were assessed, the analyses of the secondary variables should be considered exploratory.
Dapagliflozin reduced the incidence of events of the composite of confirmed sustained eGFR decrease, ESRD, renal or CV death (HR 0.76 [95% CI 0.67, 0.87], Figure 10). The difference between groups was driven by reductions in events of the renal components; sustained eGFR decrease, ESRD and renal death (Figure 8), and was observed both in patients with and without CV disease.
When evaluating the renal components, there were 127 and 238 events of new or worsening nephropathy (sustained eGFR decrease, ESRD or renal death) in patients in the dapagliflozin and placebo groups, respectively. The HR for time to nephropathy was 0.53 (95% CI 0.43, 0.66) for dapagliflozin versus placebo.
Beneficial effects of dapagliflozin on renal outcomes were also observed for albuminuria, e.g. in patients without pre-existing albuminuria, dapagliflozin reduced the incidence of sustained albuminuria (UACR > 30 mg/g) compared with placebo (HR 0.79 [95% CI 0.72, 0.87]); in patients without pre-existing macroalbuminuria, new onset of macroalbuminuria (UACR > 300 mg/g) was reduced in the dapagliflozin group compared with the placebo group (HR 0.54 [95% CI 0.45, 0.65]); in patients with pre-existing macroalbuminuria, regression of macroalbuminuria was greater in the dapagliflozin group compared with the placebo group (HR 1.82 [95% CI 1.51, 2.20]).
The treatment benefit of dapagliflozin over placebo was observed both in patients with and without existing renal impairment.

Supportive studies.

Dual energy X-ray absorptiometry in patients with diabetes.

Due to the mechanism of action of dapagliflozin a study was done to evaluate body composition and bone mineral density. Dapagliflozin 10 mg added on to metformin in 182 patients with type 2 diabetes over a 24 week period provided significant improvements compared with placebo plus metformin, respectively, in body weight (mean change from baseline: -2.96 kg vs. -0.88 kg); waist circumference (mean change from baseline: -2.51 cm vs. -0.99 cm), and body fat mass as measured by DXA (mean change from baseline -2.22 kg vs. -0.74 kg) rather than lean tissue or fluid loss. Dapagliflozin plus metformin treatment showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment (change from baseline -322.6 cm3 vs. -8.7 cm3) in an MRI substudy. In an ongoing extension of this study to week 50, there was no important change in bone mineral density for the lumbar spine, femoral neck or total hip seen in either treatment group (mean change from baseline for all anatomical regions < 0.5%, 7/89 dapagliflozin and 4/91 comparator subjects showed a decrease of 5% or more). These effects were sustained in a further extension of the study to 102 weeks where no important changes in BMD for the lumbar spine, femoral neck or total hip in either treatment group were observed.

Special populations.

Renal impairment.

Dapagliflozin.

Patients with mild renal impairment (eGFR ≥ 60 to < 90 mL/min/1.73 m2). In the clinical trial program more than 3000 patients with mild renal impairment were treated with dapagliflozin. Efficacy was assessed in a pooled analysis across 9 clinical studies consisting of 2226 patients with mild renal impairment. The mean change from baseline in haemoglobin A1c (HbA1c) and the placebo-corrected mean HbA1c change at 24 weeks was -1.03% and -0.54%, respectively for Forxiga 10 mg (n = 562). The safety profile in patients with mild renal impairment is similar to that in the overall population.
Patients with moderate renal impairment (eGFR ≥ 30 to < 60 mL/min/1.73 m2). The efficacy and safety of dapagliflozin was evaluated in two dedicated studies of patients with moderate renal impairment.
In a randomized, double blind, placebo-controlled trial a total of 321 adult patients with type 2 diabetes mellitus and eGFR ≥ 45 to < 60 mL/min/1.73 m2 (moderate renal impairment subgroup Chronic Kidney Disease [CKD 3A]), with inadequate glycaemic control on current treatment regimen, were treated with dapagliflozin 10 mg or placebo. At Week 24, dapagliflozin 10 mg (n = 159) provided significant improvements in HbA1c, FPG, Body Weight and SBP compared with placebo (n = 161) (see Table 12). The mean change from baseline in HbA1c and the placebo-corrected mean HbA1c change was -0.37% and -0.34%, respectively. The mean change from baseline in FPG and the placebo-corrected mean FPG was -1.19 mmol/L and -0.92 mmol/L, respectively. The mean body weight reduction (percentage) and the placebo-corrected mean body weight reduction was -3.42% and -1.43%, respectively. The mean reduction in seated systolic blood pressure (SBP) and the placebo-corrected mean reduction in SBP was -4.8 mmHg and -3.1 mmHg, respectively.
The safety profile of dapagliflozin in the study was consistent with that in the general population of patients with type 2 diabetes. Mean eGFR decreased initially during the treatment period in the dapagliflozin group and subsequently remained stable during the 24-week treatment period (dapagliflozin: -3.39 mL/min/1.73 m2 and placebo: -0.90 mL/min/1.73 m2). At 3 weeks after termination of dapagliflozin, the mean change from baseline in eGFR in the dapagliflozin group was similar to the mean change in the placebo group (dapagliflozin: 0.57 mL/min/1.73 m2 and placebo: -0.04 mL/min/1.73 m2).
The efficacy and safety of dapagliflozin was also assessed in a study of 252 patients with diabetes with eGFR ≥ 30 to < 60 mL/min/1.73 m2 (moderate renal impairment subgroup CKD 3A, eGFR ≥ 45 to < 60 mL/min/1.73 m2 and CKD 3B, eGFR ≥ 30 to < 45 mL/min/1.73 m2). Dapagliflozin treatment did not show a significant placebo corrected change in HbA1c in the overall study population (CKD 3A and CKD 3B combined) at 24 weeks. At Week 52, dapagliflozin was associated with a greater reduction in mean eGFR (dapagliflozin 10 mg -4.46 mL/min/1.73 m2 and placebo -2.58 mL/min/1.73 m2). At Week 104, these changes persisted (eGFR: dapagliflozin 10 mg -3.50 mL/min/1.73 m2 and placebo -2.38 mL/min/1.73 m2) with dapagliflozin 10 mg, this eGFR reduction were evident at Week 1 and remained stable through Week 104, while placebo-treated patients had a slow continuous decline through Week 52 that stabilized through Week 104.
At Week 52 and persisting through Week 104, greater increases in mean parathyroid hormone (PTH) and serum phosphorus were observed in this study with dapagliflozin 10 mg compared to placebo, where baseline values of these analytes were higher. Elevations of potassium of ≥ 6 mEq/L were more common in patients treated with placebo (12.0%) than those treated with dapagliflozin 10 mg (4.8%) during the cumulative 104-week treatment period. The proportion of patients discontinued for elevated potassium, adjusted for baseline potassium, was higher for the placebo group (14.3%) than for the dapagliflozin 10 mg group (6.7%).
Overall, there were 13 patients with an adverse event of bone fracture reported in the dapagliflozin group. Eight (8) of these 13 fractures were in patients who had eGFR 30 to 45 mL/min/1.73 m2 and 10 of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the site of fracture. No bone fractures were reported in the dedicated study of patients with eGFR ≥ 45 to < 60 mL/min/1.73 m2 (CKD 3A). No fractures were reported in the placebo group.

Blood pressure.

In the prespecified pooled analysis of 13 placebo-controlled studies (see Section 4.8 Adverse Effects (Undesirable Effects)), treatment with dapagliflozin 10 mg resulted in a systolic blood pressure change from baseline of -3.7 mmHg and diastolic blood pressure of -1.8 mmHg versus -0.5 mmHg systolic and 0.5 mmHg diastolic blood pressure for the placebo group at Week 24. Similar reductions were observed up to 104 weeks.
In two 12-week, placebo-controlled studies a total of 1,062 patients with inadequately controlled type 2 diabetes and hypertension (despite pre-existing stable treatment with an ACE-I or ARB in one study and an ACE-I or ARB plus one additional antihypertensive treatment in another study) were treated with dapagliflozin 10 mg or placebo. At Week 12 for both studies, dapagliflozin 10 mg plus usual antidiabetic treatment provided improvement in HbA1c and decreased the placebo-corrected systolic blood pressure on average by 3.1 and 4.3 mmHg, respectively.

5.2 Pharmacokinetic Properties

The results of bioequivalence studies in healthy subjects demonstrated that Xigduo XR combination tablets are bioequivalent to coadministration of corresponding doses of dapagliflozin and metformin hydrochloride modified release as individual tablets.
The following statements reflect the pharmacokinetic properties of the individual active substances of Xigduo XR.

Absorption.

Dapagliflozin.

Dapagliflozin was rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state. The Cmax and AUC values increased proportional to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food had relatively modest effects on the pharmacokinetics of dapagliflozin in healthy subjects. Administration with a high-fat meal decreased dapagliflozin Cmax by up to 50% and prolonged Tmax by approximately 1 hour, but did not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful.

Metformin hydrochloride.

Following a single oral dose of metformin extended-release, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and Cmax are less than dose proportional for metformin extended-release within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 microgram/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. Although the extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin extended-release.

Distribution.

Dapagliflozin.

Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment).

Metformin hydrochloride.

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. After repeated administration of metformin extended release, metformin did not accumulate in plasma. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism.

Dapagliflozin.

Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide. Dapagliflozin 3-O-glucuronide, with a molar plasma AUC 52% higher than that of dapagliflozin itself at the clinical dose, is an inactive metabolite and does not contribute to the glucose lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP mediated metabolism was a minor clearance pathway in humans.

Metformin hydrochloride.

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.

Excretion.

Dapagliflozin.

Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which less than 2% is unchanged dapagliflozin. After oral administration of 50 mg [14C]-dapagliflozin dose, 96% was recovered, 75% in urine and 21% in faeces. In faeces, approximately 15% of the dose was excreted as parent drug. The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects.

Metformin hydrochloride.

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

Special populations.

Renal impairment. Xigduo XR should not be used in patients with eGFR persistently < 45 mL/min/1.73 m2 (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Dapagliflozin.

At steady-state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes and mild, moderate or severe renal impairment (as determined by iohexol clearance) had mean systemic exposures of dapagliflozin that were 32%, 60% and 87% higher, respectively, than those of patients with type 2 diabetes and normal renal function. At dapagliflozin 20 mg once-daily, higher systemic exposure to dapagliflozin in patients with type 2 diabetes mellitus and renal impairment did not result in a correspondingly higher renal glucose clearance or 24 hour glucose excretion. The renal glucose clearance and 24 hour glucose excretion was lower in patients with moderate or severe renal impairment as compared to patients with normal and mild renal impairment. The steady-state 24-h urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by patients with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. There were no differences in the protein binding of dapagliflozin between renal impairment groups or compared to healthy subjects. The impact of haemodialysis on dapagliflozin exposure is not known. Dapagliflozin should not be used in patients with eGFR persistently < 45 mL/min/1.73 m2 (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Metformin hydrochloride.

In patients with renal impairment function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged in proportion to the decrease in renal function.
Hepatic impairment.

Dapagliflozin.

A single dose (10 mg) dapagliflozin clinical pharmacology study was conducted in patients with mild, moderate or severe hepatic impairment (Child-Pugh classes A, B, and C, respectively) and healthy matched controls in order to compare the pharmacokinetic characteristics of dapagliflozin between these populations. There were no differences in the protein binding of dapagliflozin between hepatic impairment groups or compared to healthy subjects. In patients with mild or moderate hepatic impairment mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful and no dose adjustment from the proposed usual dose of 10 mg once daily for dapagliflozin is proposed for these populations. In patients with severe hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher than matched healthy controls, respectively. Dapagliflozin should not be used in patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

Metformin hydrochloride.

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Age.

Dapagliflozin.

No dosage adjustment for dapagliflozin is recommended on the basis of age. The effect of age (young: ≥ 18 to < 40 years [n = 105] and elderly: ≥ 65 years [n = 224]) was evaluated as a covariate in a population pharmacokinetic model and compared to patients ≥ 40 to < 65 years using data from healthy subject and patient studies). The mean dapagliflozin systemic exposure (AUC) in young patients was estimated to be 10.4% lower than in the reference group [90% CI: 87.9, 92.2%] and 25% higher in elderly patients compared to the reference group [90% CI: 123, 129%]. However, an increased exposure due to age-related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients > 70 years old.

Metformin hydrochloride.

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Paediatric and adolescent.

Dapagliflozin.

Pharmacokinetics in the paediatric and adolescent population have not been studied.

Metformin hydrochloride.

After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between paediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.
Gender.

Dapagliflozin.

No dosage adjustment from the dose of 10 mg once daily is recommended for dapagliflozin on the basis of gender. Gender was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. The mean dapagliflozin AUCss in females (n = 619) was estimated to be 22% higher than in males (n = 634) [90% CI: 117,124].

Metformin hydrochloride.

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analysed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycaemic effect of metformin was comparable in males and females.
Race.

Dapagliflozin.

No dosage adjustment from the dapagliflozin dose of 10 mg once daily is recommended on the basis of race. Race (white, black [African descent] or Asian) was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. Differences in systemic exposures between these races were small. Compared to whites (n = 1147), Asian subjects (n = 47) had no difference in estimated mean dapagliflozin systemic exposures [90% CI range 3.7% lower, 1% higher]. Compared to whites, black (African descent) subjects (n = 43) had 4.9% lower estimated mean dapagliflozin systemic exposures [90% CI range 7.7% lower, 3.7% lower].

Metformin hydrochloride.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycaemic effect was comparable in whites (n = 249), blacks (n = 51), and Hispanics (n = 24).
Body weight.

Dapagliflozin.

No dose adjustment is recommended on the basis of weight.
In a population pharmacokinetic analysis using data from healthy subject and patient studies, systemic exposures in high body weight subjects (≥ 120 kg, n = 91) were estimated to be 78.3% [90% CI: 78.2, 83.2%] of those of reference subjects with body weight between 75 and 100 kg. This difference is considered to be small, therefore, no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in type 2 diabetes mellitus patients with high body weight (≥ 120 kg) is recommended.
Subjects with low body weights (< 50 kg) were not well represented in the healthy subject and patient studies used in the population pharmacokinetic analysis. Therefore, dapagliflozin systemic exposures were simulated with a large number of subjects. The simulated mean dapagliflozin systemic exposures in low body weight subjects were estimated to be 29% higher than subjects with the reference group body weight. This difference is considered to be small and based on these findings no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in patients with type 2 diabetes mellitus with low body weight (< 50 kg) is recommended.

5.3 Preclinical Safety Data

Genotoxicity.

Dapagliflozin.

Dapagliflozin was positive in an in-vitro clastogenicity assay in the presence of metabolic activation. However, dapagliflozin was negative in the Ames mutagenicity assay and in a series of in-vivo clastogenicity studies evaluating micronuclei or DNA repair in rats at exposure multiples at least 2100 times the human exposure at the MRHD. The weight of evidence from these studies, along with the absence of tumour findings in the rat and mouse carcinogenicity studies, support that dapagliflozin is not genotoxic.

Metformin hydrochloride.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Carcinogenicity.

Dapagliflozin.

Dapagliflozin did not induce tumours in two-year carcinogenicity studies in mice or rats at oral doses up to 40 mg/kg/day and 10 mg/kg/day respectively. These doses correspond to AUC exposure levels at least 78 times the human AUC at the MRHD of 10 mg/day.

Metformin hydrochloride.

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each film-coated tablet of Xigduo XR contains the following inactive ingredients: carmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, lactose, crospovidone, silicon dioxide, polyvinyl alcohol, macrogol 3350, titanium dioxide, purified talc, iron oxide red (Xigduo XR 10/500 and Xigduo XR 5/1000 tablets), iron oxide yellow (Xigduo XR 10/1000 tablets).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

The tablets should be stored below 30°C.

6.5 Nature and Contents of Container

Xigduo XR 10/500: available in aluminium/ aluminium blister packs of 7 and 28 tablets.
Xigduo XR 10/1000: available in aluminium/ aluminium blister packs of 7 and 28 tablets.
Xigduo XR 5/1000: available in aluminium/ aluminium blister packs of 14 and 56 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

Chemical structure.

Dapagliflozin.

Dapagliflozin propanediol monohydrate is an orally-active inhibitor of the human renal sodium-glucose co-transporter 2 (SGLT2), the major transporter responsible for renal glucose reabsorption. Dapagliflozin is described chemically as (1S)-1,5-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, (S)-propylene glycol, monohydrate.
The chemical structure of dapagliflozin propanediol monohydrate is:
Molecular formula: C21H25ClO6.C3H8O2.H2O.
Molecular weight: 502.98.

CAS number.

960404-48-2.

Metformin hydrochloride.

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a biguanide with antihyperglycaemic effects.
The chemical structure of metformin hydrochloride is:
Molecular formula: C4H11N5.HCl.
Molecular weight: 165.63.

CAS number.

1115-70-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes