Xigduo XR

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Dapagliflozin propanediol monohydrate 12.3 mg equivalent to Dapagliflozin 10 mg; Metformin hydrochloride 500 mg (with 0.5% Magnesium stearate);  
Available from:
AstraZeneca Limited
INN (International Name):
Dapagliflozin propanediol monohydrate 12.3 mg (equivalent to Dapagliflozin 10 mg)
Dosage:
10mg/500mg
Pharmaceutical form:
Modified release tablet
Composition:
Active: Dapagliflozin propanediol monohydrate 12.3 mg equivalent to Dapagliflozin 10 mg Metformin hydrochloride 500 mg (with 0.5% Magnesium stearate)   Excipient: Carmellose sodium Colloidal silicon dioxide Crospovidone Hypromellose Microcrystalline cellulose (PH302) Hypromellose (2910) Lactose Magnesium stearate Microcrystalline cellulose Opadry Pink 85F94333
Prescription type:
Prescription
Manufactured by:
Swords Laboratories Limited Subsidiary of Bristol-Myers Squibb Company
Therapeutic indications:
Glycaemic control XIGDUO XR is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control when treatment with both dapagliflozin and metformin is appropriate (see sections 5.1 and 4.4 for available data on the combination therapy). Prevention of hospitalisation for heart failure Dapagliflozin is indicated in adults with type 2 diabetes mellitus and established cardiovascular disease or risk factors for cardiovascular disease to reduce the risk of hospitalisation for heart failure (see section 5.1 Pharmacodynamic properties – Clinical Efficacy and Safety). Prevention of new or worsening nephropathy Dapagliflozin is indicated in adults with type 2 diabetes mellitus and established cardiovascular disease or risk factors for cardiovascular disease for the prevention of new or worsening nephropathy (see section 5.1 Pharmacodynamic properties – Clinical Efficacy and Safety).
Product summary:
Package - Contents - Shelf Life: Blister pack, Al/Al - 7 tablets - 36 months from date of manufacture stored at or below 30°C - Blister pack, Al/Al - 28 tablets - 36 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-9683
Authorization date:
2014-12-11

Read the complete document

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Xigduo

®

XR

Dapagliflozin/metformin hydrochloride modified release tablets

CONSUMER MEDICINE INFORMATION

What is in this leaflet

This leaflet answers some common questions about Xigduo XR. It does not contain all the available

information. It does not take the place of talking to your doctor or pharmacist. All medicines have

risks and benefits. Your doctor has weighed the risks of you taking Xigduo XR against the benefits

they expect it will have for you. If you have any concerns about taking this medicine, ask your

doctor or pharmacist.

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

What Xigduo XR is used for

Xigduo XR is a prescription medicine used with diet, exercise and sometimes other medicines such

as insulin , a sulphonylurea, 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 help prevent hospitalisation for heart failure and kidney

disease in patients with type 2 diabetes mellitus.

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 mellitus 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.

Xigduo XR contains two active ingredients, dapagliflozin and metformin hydrochloride. Dapagliflozin

member

class

medicines

take

mouth

called

SGLT-2

(Sodium

Glucose

Cotransporter-2)

inhibitors

metformin

belongs

class

medicines

called

biguanides.

Dapagliflozin and metformin work together to lower blood sugar levels in patients with type 2 diabetes

mellitus. Type 2 diabetes mellitus is also called non-insulin dependent diabetes mellitus or NIDDM.

Your doctor may have prescribed this medicine for another reason. Ask your doctor if you have any

questions about why this medicine has been prescribed for you.

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

Xigduo XR is not addictive.

Before you take Xigduo XR

When you must not take it

Do not take Xigduo XR if you have an allergy to dapagliflozin, or metformin, the active ingredients in

Xigduo XR or any of the other 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.

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

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type 1 diabetes mellitus that is well controlled by insulin alone

type 2 diabetes that is already well controlled by diet alone

diabetic ketoacidosis (a symptom of uncontrolled diabetes, in which substances called ketone

bodies build up in the blood - you may notice this as an unusual fruity odour on your breath,

difficulty breathing, confusion and frequent urination)

liver disease

excessive alcohol intake, binge drinking, alcohol dependence

severe kidney disease or kidney failure

dehydration, severe blood loss, shock

a severe infection

certain heart or blood vessel problems, including a recent heart attack or severe heart failure

(when the heart fails to pump blood effectively)

severe breathing difficulties

blood clots in the lungs (symptoms include coughing, shortness of breath, chest pain and a fast

heart rate)

gangrene

Do not take this medicine if you are pregnant or plan 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. Xigduo XR is not recommended while you are

breastfeeding. Your doctor will discuss the options available to you.

Do not take Xigduo XR after the use by (expiry) date printed on the pack or if the packaging is

torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for

disposal.

Xigduo XR is not recommended for use in children. It has not been studied in children younger

than 18 years old.

If you are not sure whether you should start taking Xigduo XR, talk to your doctor or pharmacist.

Before you start to take it

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).

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 New Zealand. Your doctor or

pharmacist will know which other medicines also contain metformin.

Tell your doctor if you have any allergies to:

any other medicines

any other substances such as foods, dyes or preservatives

Tell your doctor or pharmacist if you have, or have had, any medical conditions, especially the

following:

kidney or liver problems

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heart failure

are taking a water pill (diuretic)

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

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

on treatment.

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.

Tell your doctor if you are lactose intolerant. Xigduo XR tablets contain lactose.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a

prescription from your pharmacy, supermarket or health food shop. 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

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

taking this medicine.

If you have not told your doctor about any of these things, tell them before you take any Xigduo XR.

How to use 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.

How take it

Swallow your Xigduo XR tablets whole with a full glass of water. Xigduo XR tablets must not be

chewed or crushed.

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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 it

Take Xigduo XR during 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 it

Continue taking the tablets 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 take it

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

meant to. Otherwise, take it as soon as you remember, and then go back to taking your medicine as

you would normally.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist. If you have trouble remembering when

to take your medicine, ask your pharmacist for some hints.

If you take too much

Immediately telephone your doctor or the National Poisons Centre Phone: 0800 POISON (0800 764

766) or go to Accident and Emergency at your nearest hospital immediately if you think that you or

anyone else may have taken too much Xigduo XR, even if there are no signs of discomfort or

poisoning. You may need urgent medical attention.

While you are using Xigduo XR

Things you must do

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking Xigduo XR.

If you are about to be started on any new medicines, tell your doctor, dentist or pharmacist that you

are taking Xigduo XR.

Talk to your doctor if you are having surgery 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.

Visit your doctor regularly for check ups. Your doctor may want to perform blood tests to check

your kidneys, liver, heart and vitamin B12 level and levels of cholesterol and fats in your blood while

you are taking Xigduo XR.

Tell your doctor if you:

become ill

become dehydrated

are injured

have a fever

have a serious infection

are having surgery (including dental surgery)

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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. At these times, your doctor may temporarily

replace Xigduo XR with insulin.

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 sulphonylurea.

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 must not do

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

Do not give this medicine to anyone else, even if their symptoms seem similar or they have the

same condition as you.

Do not stop taking your medicine or change the dosage without checking with your doctor.

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Things to be careful of

Be careful driving or operating machinery 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.

Side effects

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

Xigduo XR. All medicines can have side effects. Sometimes they are serious, most of the time they

are not. You may need medical treatment if you get some of the side effects.

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

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

headache

nausea, vomiting or diarrhoea

stomach pain or discomfort

rash

loss of appetite

loss of taste

back pain

These side effects are usually mild.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency

at your nearest hospital.

Signs of hypoglycaemia (low blood sugar) that persist despite administering sugar as described

under While you are taking Xigduo XR in this leaflet. Signs of hypoglycaemia 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

Severe allergic reaction (may include 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)

Volume depletion (loss of needed fluids from the body; dehydration). Tell your doctor 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

Genital infections. If you take Xigduo XR, you may be at a greater risk for genital infections.

Tell your doctor 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 take Xigduo XR, you may be at a greater risk for urinary tract

infections. 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.

Diabetic ketoacidosis. In rare cases dapagliflozin one of the active ingredients in Xigduo XR,

cause

serious

side

effect

called

diabetic

ketoacidosis.

Symptoms

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,

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dehydration, sudden reductions in insulin dose, or a higher need of insulin due to major surgery

or serious illness.

These are very serious side effects. You may need urgent medical attention or hospitalisation.

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:

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 lightheaded

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.

Occasionally, Xigduo XR may be associated with changes in your blood. These can only be found

when your doctor does tests from time to time to check your progress.

Other side effects not listed here may occur in some patients. Tell your doctor or pharmacist

if you notice anything that is making you feel unwell.

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

After using Xigduo XR

Storage

Keep your Xigduo XR tablets in the blister pack until it is time to take them. If you take Xigduo

XR out of the blister pack it will not keep well.

Keep it in a cool dry place where the temperature stays below 30ºC.

Do not store Xigduo XR or any other medicine in the bathroom or near a sink. Do not leave it

in the car or on a window sill. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above

the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Xigduo XR or the tablets have passed their expiry date, ask your

pharmacist what to do with any that are left over.

Product Description

What Xigduo XR looks like

Xigduo XR tablets are available in three strengths:

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

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

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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

Ingredients

Each Xigduo XR tablet contains the active ingredients:

Dapagliflozin 10mg and metformin 500mg;

Dapagliflozin 10mg and metformin 1000mg; or

Dapagliflozin 5mg and metformin 1000mg

Plus the following inactive ingredients:

microcrystalline cellulose

anhydrous lactose

carmellose sodium

hypromellose

crospovidone

silicon dioxide

magnesium stearate

polyvinyl alcohol

titanium dioxide

polyethylene glycol

talc

yellow iron oxide (10mg/1000mg tablets)

red iron oxide (10mg/500mg and 5mg/1000mg tablets)

Xigduo XR tablets do not contain gluten or sucrose.

Marketed by:

AstraZeneca Limited

PO Box 87453, Meadowbank

Auckland 1742

Telephone: (09) 306 5650.

Date of Preparation

This leaflet was revised on 18 May 2020

Xigduo is a registered trademark of the AstraZeneca group of companies.

© AstraZeneca 2020

Read the complete document

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XR Data Sheet 180520

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NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

IGDUO

XR 5mg/1000mg, modified release tablet

IGDUO

XR 10mg/500mg, modified release tablet

IGDUO

XR 10mg/1000mg, modified release tablet

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

IGDUO

5 mg/1000 mg:

Each

film-coated

tablet

contains

5 mg

dapagliflozin

dapagliflozin propanediol and 1000 mg metformin HCl extended-release.

IGDUO

10 mg/500 mg:

Each

film-coated

tablet

contains

10 mg

dapagliflozin

dapagliflozin propanediol and 500 mg metformin HCl extended-release.

IGDUO

XR 10 mg/1000 mg: Each film-coated tablet contains 10 mg dapagliflozin as

dapagliflozin propanediol and 1000 mg metformin HCl extended-release.

For the full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

IGDUO

XR 5 mg/1000 mg tablets are pink to dark pink, biconvex, oval shaped, film-coated

tablets debossed with “1071” and “5/1000” on one side and plain on the other side.

IGDUO

XR 10 mg/500 mg tablets are pink, biconvex, capsule shaped, film-coated tablets

debossed with “1072” and “10/500” on one side and plain on the other side.

IGDUO

XR 10 mg/1000 mg tablets are yellow to dark yellow, biconvex, oval shaped,

film-coated tablets debossed with “1073” and “10/1000” on one side and plain on the other

side.

DAPAGLIFLOZIN

Dapagliflozin

described

chemically

(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:

.

.

XIGDUO

XR Data Sheet 180520

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METFORMIN HYDROCHLORIDE

chemical

structure

metformin

hydrochloride

(N,N-dimethylimidodicarbonimidic

diamide hydrochloride) is:

4.

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

Glycaemic control

IGDUO

XR is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and

exercise to improve glycemic control when treatment with both dapagliflozin and metformin

is appropriate (see sections 5.1 and 4.4 for available data on the combination therapy).

Prevention of hospitalisation for heart failure

Dapagliflozin

indicated

adults

with

type

diabetes

mellitus

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

Efficacy and Safety).

Prevention of new or worsening nephropathy

Dapagliflozin

indicated

adults

with

type

diabetes

mellitus

established

cardiovascular disease or risk factors for cardiovascular disease for the prevention of new

or worsening nephropathy (see section 5.1 Pharmacodynamic properties – Clinical Efficacy

and Safety).

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.

IGDUO

XR should be administered once daily with the evening meal.

Initial Therapy

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 with gradual dose escalation to reduce the gastrointestinal side effects due to

metformin.

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XR Data Sheet 180520

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Add on combination therapy

In patients treated with metformin, the dose of X

IGDUO

XR should provide metformin at the

dose already being taken, or the nearest therapeutically appropriate dose.

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.

If no adequate strength of X

IGDUO

XR is available, individual mono-components should be

used instead of the fixed dose combination.

Patients should be informed that X

IGDUO

XR tablets must be swallowed whole and

never crushed, cut or chewed. Occasionally, the inactive ingredients of X

IGDUO

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 X

IGDUO

XR and periodically thereafter (see

sections 4.4 and 5.2).

Mild renal impairment

No dose adjustment of X

IGDUO

XR is required for patients with mild renal impairment

(eGFR 60-89 mL/min/1.73 m

by Modified Diet in Renal Disease [MDRD] eGFR equation).

Moderate renal impairment

IGDUO

XR is not recommended for the treatment of diabetes in patients with eGFR

persistently below 45 mL/min/1.73 m

(see section 4.4). No dose adjustment is required for

patients with eGFR ≥ 45 mL/min/1.73 m

Severe renal impairment

Due to the metformin component, X

IGDUO

XR is contraindicated in patients with severe

renal impairment (eGFR <30 mL/min/1.73 m

), (see section 4.3).

Hepatic Impairment

Since impaired hepatic function has been associated with some cases of lactic acidosis in

patients taking metformin, X

IGDUO

XR should not be used in patients with clinical or

laboratory evidence of hepatic impairment (see section 4.4).

Paediatric and Adolescent

Safety and effectiveness of X

IGDUO

XR in paediatric and adolescent patients have not been

established.

Elderly

Because metformin is eliminated by the kidney, and because elderly patients are more likely

to have decreased renal function, X

IGDUO

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).

4.3

CONTRAINDICATIONS

IGDUO

XR is contraindicated in patients with:

XIGDUO

XR Data Sheet 180520

Copyright

Hypersensitivity to the active substances or to any of the excipients listed in section

6.1;

Metabolic acidosis;

severe renal impairment (eGFR< 30mL/min/1.73 m

) (see section 4.4);

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);

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

IGDUO

XR should not be used in patients with type 1 diabetes mellitus or for the treatment

of diabetic 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 diabetic patients

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).

Medicinal products that can acutely impair renal function, such as antihypertensives,

diuretics and NSAIDs, should be initiated with caution in metformin-treated patients (see

section 4.5).

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. If metabolic acidosis is suspected, treatment with X

IGDUO

XR should

be discontinued and the patient hospitalized immediately.

Use in Patient with Renal Impairment

IGDUO

XR is not recommended for the treatment of diabetes in patients with eGFR

persistently below 45 mL/min/1.73 m

as the glycemic efficacy of dapagliflozin is dependent

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on renal function (see section 4.2). The maximum dose of metformin in patients with an

eGFR of 30 to less than 45 mL/min/1.73 m

is 1000 mg once daily.

Due to metformin, X

IGDUO

XR is contraindicated in patients with severe renal impairment

(eGFR < 30 mL/min/1.73 m

) (see section 4.3).

Dapagliflozin has not been studied in patients with severe renal impairment (eGFR

<30 mL/min/1.73 m

by MDRD) or end stage renal disease (ESRD).

Metformin is excreted by the kidney and the risk of metformin accumulation and lactic

acidosis increases with the degree of impairment of renal function.

Assess renal function prior to initiation of X

IGDUO

XR and periodically thereafter as follows:

at least yearly;

prior to initiation of concomitant medicines that may reduce renal function and

periodically thereafter;

for renal function approaching eGFR 45 mL/min/1.73 m

and in elderly patients, at

least

4 times

year.

renal

function

falls

persistently

below

eGFR < 45 mL/min/1.73 m

, treatment with X

IGDUO

XR should be discontinued.

Acute conditions associated with hypoxia or impacting renal function

Metformin hydrochloride

Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction,

and other conditions characterized by hypoxaemia have been associated with lactic

acidosis and may also cause pre-renal azotaemia. Acute conditions such as dehydration,

severe infections, and hypoperfusion, have potential to alter renal function. In these

situations, metformin must be discontinued.

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

Metformin hydrochloride

A patient with type 2 diabetes mellitus previously well controlled on X

IGDUO

XR who

develops laboratory abnormalities or clinical illness (especially vague and poorly defined

illness) should be evaluated promptly for evidence lactic acidosis. Evaluation should

include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate,

pyruvate and metformin levels. If acidosis occurs, X

IGDUO

XR must be stopped immediately

and other appropriate corrective measures initiated.

Use in patients with 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 sections 4.2 and 5.2).

Metformin hydrochloride

Since impaired hepatic function has been associated with some cases of metformin

associated lactic acidosis, X

IGDUO

XR should be avoided in patients with clinical or

laboratory evidence of hepatic disease.

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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. X

IGDUO

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.

Surgical procedures

Metformin hydrochloride

Use of X

IGDUO

XR should be temporarily suspended for any surgical procedure (except

minor procedures not associated with restricted intake of food and fluids) and should not be

restarted until the patient’s oral intake has resumed and renal function has been evaluated

as stable.

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).

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, and laboratory tests including electrolytes) is

recommended. Temporary interruption of X

IGDUO

XR is recommended for patients who

develop volume depletion until the depletion is corrected (see section 4.8).

Excessive alcohol intake

Metformin hydrochloride

Alcohol potentiates the effect of metformin on lactate metabolism. Patients, should be

warned against excessive alcohol intake while receiving X

IGDUO

Ketoacidosis

Dapagliflozin

There have been reports of ketoacidosis, including diabetic ketoacidosis, in patients with

type 1 and type 2 diabetes mellitus taking dapagliflozin and other SGLT2 inhibitors. X

IGDUO

XR is not indicated for the treatment of patients with type 1 diabetes mellitus.

Patients treated with X

IGDUO

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

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mg/dL). If ketoacidosis is suspected, discontinuation or temporary interruption of X

IGDUO

XR should be considered and the patient should be promptly evaluated.

Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from

pancreatic disorders (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery),

insulin dose reduction, reduced caloric intake or increased insulin requirements due to

infections, illness or surgery and alcohol abuse. X

IGDUO

XR should be used with caution in

these patients.

Use with Medications Known to Cause Hypoglycaemia

Dapagliflozin

Insulin

insulin

secretagogues,

such

sulphonylureas,

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 X

IGDUO

XR (see section 5.1).

Metformin hydrochloride

Hypoglycaemia

does

occur

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 sulphonylureas 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 X

IGDUO

XR in paediatric patients have not been established.

Use in elderly

Because metformin is eliminated by the kidney, and because elderly patients are more likely

to have decreased renal function, X

IGDUO

XR should be used with caution as age increases.

The renal function recommendations provided for all patients also apply to elderly patients.

Dapagliflozin

A total of 2403 (26%) of the 9339 treated patients were 65 years and older and 327 (3.5%)

patients were 75 years and older in the pool of 21 double-blind, controlled, clinical studies

of dapagliflozin assessing the safety and efficacy of dapagliflozin in improving glycaemic

control, as monotherapy or in combination with other antidiabetic therapies. After controlling

for level of renal function (eGFR), there was no conclusive evidence suggesting that age is

an independent factor affecting efficacy. Overall, the proportion of patients reporting

adverse events was consistent between those

65 and <65 years of age.

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.

Cardiac failure

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

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4.5

INTERACTION

WITH

OTHER

MEDICINES

AND

OTHER

FORMS

OF

INTERACTION

4.5.1

Interaction with dapagliflozin and metformin

Coadministration of multiple doses of dapagliflozin and metformin did not meaningfully alter

the pharmacokinetics of either dapagliflozin or metformin in healthy subjects.

There have been no formal interaction studies for X

IGDUO

XR. The following statements

reflect the information available on the individual active substances.

4.5.2

Drug interactions with 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 CYP 1A2, 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.

4.5.3 Effect of Other Drugs on Dapagliflozin

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

P-glycoprotein

substrate),

glimepiride

CYP2C9

substrate),

voglibose (an α-glucosidase inhibitor), 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 inhibitor would not be expected.

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.

Coadministration

dapagliflozin

bumetanide

meaningfully

change

pharmacodynamic effect of dapagliflozin to increase urinary glucose excretion in healthy

subjects.

4.5.4

Effect of Dapagliflozin on Other Drugs

In interaction studies conducted in healthy subjects, using mainly a single dose design,

dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin,

glimepiride,

hydrochlorothiazide,

bumetanide,

valsartan,

simvastatin,

digoxin

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.

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Coadministration of dapagliflozin and bumetanide did not meaningfully alter the steady-

state pharmacodynamic responses (urinary sodium excretion, urine volume) to bumetanide

in healthy subjects.

Dapagliflozin did not affect the anticoagulant activity of warfarin as measured by the

prothrombin time (International Normalised Ratio [INR]).

4.5.5 Interactions between metformin hydrochloride and other drugs

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 type 2 diabetes patients, coadministration of metformin

and glibenclamide did not result in any changes in either metformin pharmacokinetics or

pharmacodynamics. Decreases in glibenclamide AUC and maximum concentration (C

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 C

by 22% and blood AUC by 15%,

without any significant change in metformin renal clearance. When administered with

metformin, the C

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 C

AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T

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,

oestrogens,

oral

contraceptives,

phenytoin,

nicotinic

acid,

sympathomimetics, calcium channel blocking drugs and isoniazid. When such drugs are

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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, sulphonamides, chloramphenicol, and

probenecid, as compared to the sulphonylureas, which are extensively bound to serum

proteins.

Other interactions

The effects of smoking, diet, herbal products and alcohol use on the pharmacokinetics of

IGDUO

XR have not been specifically studied.

Effect 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.

4.6

FERTILITY, PREGNANCY AND LACTATION

Pregnancy

Category D

IGDUO

XR must not be used in the second and third trimesters of pregnancy. In the time

period corresponding to second and third trimester of pregnancy with respect to human

renal maturation, maternal exposure to dapagliflozin in rat studies was associated with

increased incidence and/or severity of renal pelvic and tubular dilatations in progeny (see

section 5.3).

There

adequate

well-controlled

studies

IGDUO

individual

components in pregnant women. When pregnancy is detected, treatment with X

IGDUO

should be discontinued.

Dapagliflozin

In conventional studies of embryo-foetal 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).

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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.

Breast-feeding

IGDUO

XR must not be used by breastfeeding women.

No studies in lactating animals have been conducted with the combined components of

IGDUO

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 TO USE MACHINES

No studies on the effects on the ability to drive and use machines have been performed

with X

IGDUO

XR or dapagliflozin.

should

taken

into

account

that

dizziness

been

reported

studies

with

dapagliflozin.

4.8

UNDESIRABLE EFFECTS

Clinical Experience

Dapagliflozin and metformin hydrochloride

Data from a prespecified pool of patients from 8 short-term, placebo-controlled studies of

dapagliflozin co-administered with metformin immediate- or extended-release was used to

evaluate safety data. This pool included several add-on studies (metformin alone and in

combination with a DPP4 inhibitor and metformin, or insulin and metformin, 2 initial

combination with metformin studies, and 2 studies of patients with cardiovascular disease

(CVD) and type 2 diabetes who received their usual treatment (with metformin as

background therapy). For studies that included background therapy with and without

metformin, only patients who received metformin were included in the 8-study placebo-

controlled pool. Across these 8 studies 983 patients were treated once daily with

dapagliflozin 10 mg and metformin and 1185 were treated with placebo and metformin.

These 8 studies provide a mean duration of exposure of 23 weeks. The mean age of the

population was 57 years and 2% were older than 75 years. Fifty-four percent (54%) of the

population was male; 88% White, 6% Asian, and 3% Black or African American. At

baseline, the population had diabetes for an average of 8 years, mean haemoglobin A1c

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(HbA1c) was 8.4%, and renal function was normal or mildly impaired in 90% of patients and

moderately impaired in 10% of patients.

Dapaglifozin

The safety profile of dapagliflozin in type 2 diabetes mellitus has been evaluated in clinical

studies

including

more

than

15000

subjects

treated

with

dapagliflozin.

further

information about the clinical studies, see section 5.1.

The incidence of adverse reactions was determined using a pre-specified pool of patients

from 13 short-term (mean duration 22 weeks), placebo-controlled studies in type 2 diabetes.

Across these 13 studies, 2360 patients were treated once daily with dapagliflozin 10 mg

and 2295 were treated with placebo (either as monotherapy or in combination with other

antidiabetic therapies).

Additionally, dapagliflozin 5 mg was evaluated in a 12-study, short-term, placebo-controlled

pool of patients that included 1145 patients treated with dapagliflozin 5 mg (mean exposure

= 22 weeks) and 1393 patients treated with (mean exposure = 21 weeks), either as

monotherapy or in combination with other antidiabetic therapies.

In the dedicated cardiovascular (CV) 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 30623 patient-years of exposure

to dapagliflozin.

Adverse reactions

The adverse reactions in patients treated with dapagliflozin 10 mg with and without

metformin in clinical trials in type 2 diabetes mellitus and post-marketing are shown in Table

Table 1

Adverse Drug Reactions by Frequency and System Organ Class (SOC)

System Organ Class

Common

Rare

Unknown

Infections and Infestations

Genital infection

Urinary tract infection

Metabolism

and

Nutrition

Disorders

Diabetic

ketoacidosis

Skin

and

subcutaneous

tissue disorders

Rash

Musculoskeletal

and

Connective

Tissue

Disorders

Back pain

Renal Urinary Disorders

Pollakiuria

polyuria

Identified from 8 placebo-controlled studies, including 2 initial combination with metformin, 2 add-on to metformin, 1

add-on to insulin, 1 add-on to sitagliptin, and 2 studies with combination add-on therapy.

Multiple adverse events terms, including vulvovaginal infections and candidiasis, balanoposthitis, balanitis candida,

penile abscess, penile infection, vulval abscess and vaginitis bacterial.

Multiple adverse events terms, including genitourinary tract infection, cystitis, pyelonephritis, trigonitis, urethritis and

prostatitis.

Additional events identified from 13 placebo-controlled studies with dapagliflozin 10 mg in type 2 diabetes mellitus

including 3 monotherapy, 1 initial combination with metformin, 2 add-on to metformin, 2 add-on to insulin, 1 add-on to

pioglitazone, 1 add-on to sitagliptin, 1 add-on to glimepiride, and 2 studies with combination add-on therapy.

Represents multiple adverse events terms, including polyuria, urine output increased.

Identified from the cardiovascular outcomes study in patients with type 2 diabetes. Frequency is based on annual rate.

Identified during post-marketed use of dapagliflozin. Because these reactions are reported voluntarily from a population

of an uncertain size, it is not always possible to reliably estimate their frequency.

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Rash includes the following preferred terms, listed in order of frequency in clinical trials: Rash, Rash generalized, Rash

pruritic, Rash macular, Rash maculo-papular, Rash pustular, Rash vesicular, Rash erythematous. In active- and

placebo-controlled clinical trials (Dapagliflozin, N=5936, All control, N=3403), the frequency of Rash was similar for

Dapagliflozin (1.4%) and All control (1.4%), respectively, corresponding to the frequency ‘Common’.

Genital Infections

Events of genital infections were reported in 5.5% and 0.6% of patients who received

dapagliflozin 10 mg and placebo, respectively, in the 13-study, short-term, placebo-

controlled

pool.

events

genital

infections

reported

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% in placebo). 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 the CV outcomes study, the number of patients with serious adverse events (SAE) of

genital infections were few and balanced: 2 (<0.1%) patients in each of the dapagliflozin

and placebo groups.

Urinary Tract Infections

Events of urinary tract infections (UTI) were reported in 4.7% and 3.5% of patients who

received dapagliflozin 10 mg and placebo, respectively, in the 13-study short term, placebo-

controlled pool. 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). 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).

In the CV outcomes study there were fewer patients with SAEs of UTI in the dapagliflozin

group compared with the placebo group: 79 (0.9%) and 109 (1.3%), respectively.

Diabetic ketoacidosis (DKA)

In the CV outcomes study 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).

Events Related to Decreased Renal Function

There have been post-marketing reports of acute kidney injury (including acute renal failure)

in patients receiving dapagliflozin. In the DECLARE study, there was no increased risk for

events of acute kidney injury in dapagliflozin-treated patients 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 metformin Product

Information available in Australia.

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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) 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

Very rare: A decrease of vitamin B12 absorption with a decrease in serum levels has been

observed in patients treated long term with metformin (< 1/10,000). Consideration of such

an aetiology is recommended if a patient presents with megaloblastic anaemia. Therefore,

serum

levels

should

appropriately

monitored

periodic

parenteral

supplementation considered.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

XIGDUO

XR Data Sheet 180520

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professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/.

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 type 2 diabetes patients, 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 dose 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 advice on the management of overdose contact the National Poisons Centre on 0800

POISON (0800 764 766).

5.

PHARMACOLOGICAL PROPERTIES

MECHANISM OF ACTION

IGDUO

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 highly potent, selective and reversible inhibitor of sodium glucose co-

transporter 2 (SGLT2) 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. Despite the presence of hyperglycaemia in type

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2 diabetes mellitus, reabsorption of filtered glucose continues. Dapagliflozin reduces

maximum tubular glucose transport by 55% and reduces renal glucose reabsorption such

that glucose appears in the urine at normal plasma glucose levels. Thus, 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. Inhibition of glucose and

sodium co-transport by dapagliflozin is also associated with mild diuresis and transient

natriuresis.

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 utilization. Unlike

sulphonylureas, metformin does not produce hypoglycaemia in either patients with type 2

diabetes or normal subjects (except in special circumstances, see section 4.4) 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.

5.1

PHARMACODYNAMIC PROPERTIES

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

(Figure 1). 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. This glucose elimination rate approached the maximum glucose excretion

observed at 20 mg/day dose of dapagliflozin. Evidence of sustained glucose excretion was

seen in patients with type 2 diabetes mellitus given dapagliflozin 10mg/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

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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 μmol/L.

Figure 1:

Scatter Plot and Fitted Line of Change from Baseline in 24-hr Urinary

Glucose Amount vs. Dapagliflozin Dose in Healthy Subjects and Subjects

with T2DM (Semi-Log Plot)

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 Efficacy and Safety

Glycaemic Efficacy

There have been no clinical efficacy studies conducted with X

IGDUO

XR; however,

bioequivalence

IGDUO

with

coadministered

dapagliflozin

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

diabetes

inadequately

controlled

metformin

alone

combination

with

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sulphonylurea, or insulin, in treatment-naive patients inadequately controlled on diet and

exercise alone, and compared with a sulphonylurea in combination with metformin in

patients with inadequate glycaemic control on metformin alone. Additionally, dapagliflozin

10 mg or placebo were studied in type 2 diabetes patients with cardiovascular disease

(approximately 37% of patients across 2 studies received dapagliflozin 10 mg or placebo

plus metformin alone [with or without insulin]) and type 2 diabetes patients 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 (Table 2). Dapagliflozin 10 mg as monotherapy also provided significant

improvements in FPG and body weight 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%).

Table 2:

Results at Week 24 (LOCF

*

) in an Active-Controlled Study of Dapagliflozin

Initial Combination Therapy with Metformin XR

Efficacy Parameter

Dapagliflozin

10 mg +

Metformin XR

Dapagliflozin

10 mg

Metformin XR

N=211

N=219

N=208

HbA1c (%)

Baseline (mean)

9.10

9.03

9.03

Change from baseline (adjusted mean

−1.98

−1.45

−1.44

Difference from dapagliflozin (adjusted mean

(95% CI)

−0.53

(−0.74, −0.32)

Difference

from

metformin

(adjusted

mean

(95% CI)

−0.54

(−0.75, −0.33)

−0.01

(−0.22, 0.20)

Percent of patients achieving HbA1c <7%

adjusted for baseline

46.6%

31.7%

35.2%

Change from baseline in HbA1c in patients with

baseline HbA1c ≥9% (adjusted mean

‡)

−2.59

−2.14

−2.05

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Table 2:

Results at Week 24 (LOCF

*

) in an Active-Controlled Study of Dapagliflozin

Initial Combination Therapy with Metformin XR

Efficacy Parameter

Dapagliflozin

10 mg +

Metformin XR

Dapagliflozin

10 mg

Metformin XR

FPG (mmol/L)

Baseline (mean)

10.5

11.0

10.5

Change from baseline (adjusted mean

−3.4

−2.6

−1.9

Difference from dapagliflozin (adjusted mean

(95% CI)

−0.8

(−1.2, −0.4)

Difference

from

metformin

(adjusted

mean

(95% CI)

−1.4

(−1.8, −1.0)

−0.6

(−1.0, −0.3)

Body Weight (kg)

Baseline (mean)

88.56

88.53

87.24

Change from baseline (adjusted mean

−3.33

−2.73

−1.36

Difference

from

metformin

(adjusted

mean

(95% CI)

−1.97

(−2.64, −1.30)

−1.37

(−2.03, −0.71)

LOCF: last observation (prior to rescue for rescued patients) carried forward.

All randomised patients who took at least one dose of double-blind study medication during the short-term

double-blind period.

Least squares mean adjusted for baseline value.

p-value <0.0001.

Non-inferior versus metformin.

p-value <0.05.

Add-on to Metformin

As add-on treatment to metformin, dapagliflozin 10 mg provided significant improvements

in HbA1c at week 24 (Table 3).

Table 3:

Results of a 24-Week (LOCF

*

) Placebo-Controlled Study of Dapagliflozin in

Add-On Combination with Metformin

Efficacy Parameter

Dapagliflozin 10 mg

+ Metformin

N=135

Placebo

+ Metformin

N=137

HbA1c (%)

Baseline mean

Change from baseline (adjusted mean

Difference

from

placebo

(adjusted

mean

(95% CI)

7.92

−0.84

−0.54

(−0.74, −0.34)

8.11

−0.30

Percent of patients achieving HbA1c <7%

adjusted for baseline

40.6%

25.9%

Change from baseline in HbA1c in patients with baseline

HbA1c ≥9% (adjusted mean

−1.32

(N= 18)

−0.53

(N= 22)

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Table 3:

Results of a 24-Week (LOCF

*

) Placebo-Controlled Study of Dapagliflozin in

Add-On Combination with Metformin

Efficacy Parameter

Dapagliflozin 10 mg

+ Metformin

N=135

Placebo

+ Metformin

N=137

Body Weight (kg)

Baseline mean

Change from baseline

(adjusted mean

Difference

from

placebo

(adjusted

mean

(95% CI)

86.28

−2.86

−1.97

(−2.63, −1.31)

87.74

−0.89

LOCF: last observation (prior to rescue for rescued patients) carried forward.

All randomised patients who took at least one dose of double-blind study medication during the short-term

double-blind period.

Least squares mean adjusted for baseline value.

p-value <0.00001 vs placebo + metformin.

p-value <0.05 vs placebo + metformin.

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Figure 2:

Adjusted Mean Change from Baseline Over Time in HbA1c in a 102-Week

Placebo-Controlled Study of Dapagliflozin in Combination with Metformin

(Longitudinal Repeated Measures Analysis, Excluding Data after Rescue)

Active Glipizide Controlled Study Add-on to Metformin

In a 52 week, active-controlled non-inferiority study (with a 52 week and 104 week extension

periods), dapagliflozin was evaluated as add on therapy to metformin compared with a

sulphonylurea (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 non-

inferiority (Table 4). 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 dapagliflozin and 0.20% for

glipizide (see Figure 3). 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 proportion of subjects remaining in

the study at Week 104 and Week 208 was 56.2% and 39% respectively for the group treated

with dapagliflozin and 50.0% and 34.6% for the group treated with glipizide.

Study Week

HbA1c (%) Adjusted Mean Change from Baseline

-1.0

-0.8

-0.6

-0.4

-0.2

24(LOCF)

PLACEBO + METFORMIN

TRADEMARK 10 MG + METFORMIN

LOCF: Last observation (prior to rescue for rescued subjects) carried forward

Values for 24(LOCF) represent adjusted mean and 95% confidence intervals based on an ANCOVA model

Values for other weeks represent adjusted means based on a longitudinal repeated measures model

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Table 4:

Results

at

Week

52

(LOCF

*

)

in

an

Active-Controlled

Study

Comparing

Dapagliflozin to Glipizide as Add-on to Metformin

Efficacy Parameter

Dapagliflozin

+Metformin

N=400

Glipizide

+Metformin

N=401

HbA1c (%)

Baseline (mean)

Change from baseline (adjusted mean

Difference from Glipizide+Metformin (adjusted mean

(95% CI)

7.69

−0.52

0.00

(−0.11, 0.11)

7.74

−0.52

Body Weight (kg)

Baseline (mean)

Change from baseline (adjusted mean

Difference from Glipizide+Metformin (adjusted mean

(95% CI)

88.44

−3.22

−4.65

(−5.14, −4.17)

87.60

1.44

2.5%

*LOCF: last observation carried forward.

Randomised and treated patients with baseline and at least 1 post-baseline efficacy measurement.

Least squares mean adjusted for baseline value.

p-value <0.0001.

non-inferior to glipizide + metformin

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Figure 3

Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 208-Week Active-

Controlled Study Comparing Dapagliflozin to Glipizide as Add-on to Metformin

(Longitudinal Repeated Measures Analysis)

Combination therapy with Other Anti-hyperglycaemic Agents

Dapagliflozin as an add on with either sitagliptin (with or without metformin) or insulin

resulted in statistically significant reductions in HbA1c at 24 weeks compared with subjects

receiving placebo (p<0.0001; Tables 5,6 and 7).

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Table 5:

Results of a 24-Week (LOCF*) Placebo-Controlled Study of Dapagliflozin in

Add-On Combination with Sitagliptin (Stratum with Metformin)

Efficacy Parameter

Dapagliflozin 10 mg

+ Sitagliptin

+Metformin

N=113

Placebo

+ Sitagliptin

+Metformin

N=113

HbA1c (%)

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo (adjusted mean

(95% CI)

7.80

-0.43

-0.40

(-0.58; -0.23)

7.87

-0.02

Body Weight (kg)

Baseline (mean)

Change from baseline

(adjusted mean

Difference from placebo

(adjusted mean

(95% CI)

93.95

-2.35

-1.87

(-2.61; -1.13)

94.17

-0.47

LOCF: last observation (prior to rescue for rescued patients) carried forward.

Randomised and treated patients with baseline and at least 1 post-baseline efficacy measurement.

Least squares mean adjusted for baseline value.

p-value <0.0001 versus placebo.

Table 6.

Results of a 24-Week Placebo-Controlled Study of Dapagliflozin in Add-On

Combination with Metformin and a Sulphonylurea

Efficacy Parameter

Dapagliflozin 10 mg

+ Metformin

a

+ Sulphonylurea

N=108

Placebo

+Metformin

a

+ Sulphonylurea

N=108

HbA1c (%)

^

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo (adjusted mean

(95% CI)

8.08

-0.86

-0.69

(-0.89; -0.49)

8.24

-0.17

Subjects (%) achieving HbA1c < 7% (LOCF)

*

Adjusted for baseline

31.8

11.1

Body Weight (kg) LOCF

*

Baseline (mean)

Change from baseline

(adjusted mean

Difference from placebo

(adjusted mean

(95% CI)

88.57

-2.65

-2.07

(-2.79; -1.35)

90.07

-0.58

Metformin (immediate- or extended-release formulations) ≥1500 mg/day plus maximum tolerated dose,

which must be at least half maximum dose, of a sulphonylurea for at least 8 weeks prior to enrollment.

HbA1c analysed using Longitudinal Repeated Measures (LRM) analysis

LOCF: last observation (prior to rescue for rescued patients) carried forward.

Randomised and treated patients with baseline and at least 1 post-baseline efficacy measurement.

Least squares mean adjusted for baseline value.

p-value <0.0001 versus placebo.

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Table 7:

Results of 24-Week (LOCF*) Placebo-Controlled Study of Dapagliflozin in

Combination with Insulin (alone or with oral glucose-lowering medicinal

products)

Efficacy Parameter

Dapagliflozin

10 mg + insulin ± oral

glucose-lowering

medicinal products^

Placebo + insulin

± oral glucose-

lowering medicinal

products^

Intent-to-Treat Population

N=194

N=193

HbA1c (%)

Baseline (mean)

Change from baseline (adjusted mean

Difference

from

placebo

(adjusted

mean

(95% CI)

8.58

−0.90

−0.60

(−0.74, −0.45)

8.46

−0.30

Mean Daily Insulin Dose (IU)

††

Baseline (mean)

Change from baseline (adjusted mean

Difference

from

placebo

(95% CI)

Percent of patients with mean daily insulin dose

reduction of at least 10% adjusted for baseline

77.96

−1.16

−6.23

(−8.84, −3.63)

19.7%**

73.96

5.08

11.0%

Body Weight (kg)

Baseline (mean)

Change from baseline

(adjusted mean

Difference

from

placebo

(adjusted

mean

(95% CI)

94.63

−1.67

−1.68

(−2.19, −1.18)

94.21

0.02

LOCF: last observation (prior to or on the date of the first insulin up-titration, if needed) carried forward.

All randomised subjects who took at least one dose of double-blind study medicinal product during the

short-term double blind period.

Least squares mean adjusted for baseline value and presence of oral glucose lowering-medicinal product.

p-value <0.0001 versus placebo+ insulin ± oral glucose-lowering medicinal product.

p-value <0.05 versus placebo+ insulin ± oral glucose-lowering medicinal product.

Fifty percent of subjects were on insulin therapy monotherapy at baseline: 50% were on 1 or 2 oral glucose-

lowering medicinal product(s) in addition to insulin: Of this latter group 80% were on metformin alone, 12

% were on metformin plus sulphonylurea therapy and the rest were on other oral glucose-lowering

medicinal products

††

Up-titration of insulin regimens (including short acting, intermediate and basal insulin) was only allowed if

subjects met pre-defined FPG criteria.

The reductions in HbA1c observed at Week 24 were sustained in add on combination

studies and up to 104 week data (insulin, see Figure 4). 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, see also Figure

4). 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

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insulin dose remained stable compared to baseline in subjects treated with dapagliflozin 10

mg at an average dose of 76 IU/day (see Figure 5). In the placebo group there was a mean

increase of 10.5 IU/day and 18.3 IU/day from baseline (mean average dose of 84 and 92

IU/day) 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.

Figure 4:

HbA1c (%) Adjusted Mean Change from Baseline Over Time Short-term

and

Long-term

Treatment

Period

in

a

Placebo-controlled

Study

of

Dapagliflozin in Combination with Insulin with or without up to 2 Oral Anti-

diabetic Therapies Excluding Data After Insulin Up-titration.

Error bars represent 95% confidence intervals for the adjusted mean change from baseline

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

HbA1c (%) Adjusted Mean Change from Baseline

Study Week

Treatment Group

PLA + INS

DAPA 2.5MG + INS

DAPA 5/10MG + INS

DAPA 10MG + INS

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Figure 5:

Mean Daily Insulin Dose (IU/day) Adjusted Mean Change from Baseline

Over Time in a Placebo-controlled Study of Dapagliflozin in Combination

with Insulin with or without up to 2 Oral Anti-diabetic Therapies Short-

term and Long-term Treatment Period Including Data After Insulin Up-

titration

Error bars represent 95% confidence intervals for the adjusted mean change from baseline

Fasting plasma glucose

Treatment with dapagliflozin 10 mg as an add on to either metformin, metformin and a

sulphonylurea, 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.

Mean Daily Insulin Dose (IU/day)

Adjusted Mean Change from Baseline

Study Week

Treatment Group

PLA + INS

DAPA 2.5MG + INS

DAPA 5/10MG + INS

DAPA 10MG + INS

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Concomitant Initiation of Dapagliflozin and Prolonged-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. Randomisation was stratified by HbA1c at

baseline (<9.0% or ≥9.0%).

The primary endpoint was the change in HbA1c from baseline to Week 28 (Fig 6).

Compared

dapagliflozin

10 mg

alone

prolonged-release

exenatide

alone,

concomitant initiation of dapagliflozin 10 mg and prolonged-release exenatide resulted in

statistically significant reductions in HbA1c from baseline at Week 28 (Table 7).

Figure 6:

Change in HbA1c over Time, LS Mean (SE) – 28-Week Treatment Period

(Intent-to-Treat Analysis Set)

CFB=change from baseline; EQW=exenatide 2 mg once weekly; Dapa=dapagliflozin 10 mg once daily.

Baseline is defined as Week 0.

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Table 8.

Results of a 28-Week Active-Controlled Trial of Dapagliflozin 10 mg and

prolonged-Release Exenatide 2 mg Concomitant Add-On to Metformin

Dapagliflozin

10 mg QD

+

Extended release

exenatide 2 mg

QW

Dapagliflozin

10 mg QD

+

Placebo QW

Prolonged-release

exenatide 2 mg QW

+

Placebo QD

Intent-to-Treat population

(N)

c

228

230

227

HbA1c (%)

Baseline (mean)

a

9.29

9.25

9.26

Change from baseline

-1.98

-1.39

-1.60

Mean difference in change

from baseline vs.

dapagliflozin (95% CI)

-0.59*

(-0.84 -0.34)

Mean difference in change

from baseline vs. Extended

release exenatide QW

(95% CI)

-0.38**

(-0.63 -0.13)

Percent of patients

achieving HbA1c

7.0%

44.7%

19.1%

26.9%

Body weight (kg)

Baseline (mean)

92.13

90.87

89.12

Change from baseline

-3.55

-2.22

-1.56

Mean difference in change

from baseline vs.

dapagliflozin (95% CI)

-1.33 **

(-2.12 -0.55)

Mean difference in change

from baseline vs. Extended

release exenatide (95% CI)

-2.00*

(-2.79 -1.20)

FPG (mmol/L)

Baseline (mean)

10.9

10.5

10.5

Change from baseline

-3.7

-2.7

-2.5

Mean difference in change

from baseline vs.

dapagliflozin (95% CI)

-0.92*

(-1.36 -0.49)

Mean difference in change

from baseline vs. Extended

release exenatide (95% CI)

-1.12*

(-1.55 -0.68)

2-hour PPG (mg/dL)

Standard meal test

population (n)

Baseline (mean)

14.9

14.5

14.8

Change from baseline

-4.9

-3.4

-3.3

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Table 8.

Results of a 28-Week Active-Controlled Trial of Dapagliflozin 10 mg and

prolonged-Release Exenatide 2 mg Concomitant Add-On to Metformin

Mean difference in change

from baseline vs.

dapagliflozin (95% CI)

-1.49*

(-2.04 -0.93)

Mean difference in change

from baseline vs. Extended

release exenatide (95% CI)

-1.54*

(-2.10 -0.98)

Seated systolic blood pressure (mmHg)

Baseline (mean)

130.7

129.5

129.3

Change from baseline

-4.3

-1.8

-1.2

Mean difference in change

from baseline vs.

dapagliflozin (95% CI)

-2.4

(-4.5 -0.4)

Mean difference in change

from baseline vs. Extended

release exenatide (95% CI)

-3.0**

(-5.2 -0.9)

QD=once daily, QW=once weekly, N=number of patients in treatment group, CI=confidence interval, FPG=

fasting plasma glucose, PPG= postprandial glucose.

Adjusted least squares means (LS Means) and treatment group difference(s) in the change from baseline

values at Week 28 are modeled using a mixed model with repeated measures (MMRM) including

treatment, region, baseline HbA1c stratum (< 9.0% or ≥ 9.0%), week, and treatment by week interaction

as fixed factors, and baseline value as a covariate.

Categories are derived from continuous measurements. All patients with missing endpoint data are imputed

as non-responders. Treatment comparison is based on Cochran-Mantel-Haenszel (CMH) test stratified by

baseline HbA1c (< 9.0% or ≥ 9.0%). P-values are from the general association statistics.

Patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.

*p < 0.001, **p < 0.01,

p < 0.05.

P values are all adjusted p values for multiplicity.

Analyses exclude measurements post rescue therapy and post premature discontinuation of study medication

discontinuation, except for systolic blood pressure analysis, which includes measurements post rescue

therapy but excludes data post premature discontinuation of study medication discontinuation.

Concomitant initiation therapy of dapagliflozin 10 mg and prolonged-release exenatide

resulted in a greater proportion of patients achieving HbA1c ≤6.5% at Week 28 (30.3%)

compared to dapagliflozin alone (10.4%) and prolonged-release exenatide alone (18.5%).

The mean baseline HbA1c was 9.3%.

Post prandial glucose

Treatment with dapagliflozin 10 mg as an add on to sitagliptin (with or without metformin)

resulted in reductions in 2 hour post prandial 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 sulphonylurea, sitagliptin

(with metformin) or insulin resulted in a statistically significant body weight reduction at 24

weeks (Tables 3, 5 and 6) with placebo-corrected reductions of 1.97 kg (2.43 %), 2.07 kg

(2.25 %) and 1.68 kg (1.83 %), respectively. These effects were sustained in longer-term

trials (see Figure 7 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 and -2.88 kg, respectively.

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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 (Table 4) , that was sustained at 104 and 208 weeks (-5.06 kg and -4.38 kg

respectively) (see Figure 8).

Figure 7:

Total Body Weight (kg) Adjusted Mean Change from Baseline Over Time

in a Placebo-controlled Study of Dapagliflozin in Combination with Insulin

with or without up to 2 Oral Anti-diabetic Therapies Short-term and Long-

term Treatment Period Including Data After Insulin Up-titration

Error bars represent 95% confidence intervals for the adjusted mean change from baseline

-2.4

-2.0

-1.6

-1.2

-0.8

-0.4

Total Body Weight (kg) Adjusted Mean Change from Baseline

Study Week

Treatment Group

PLA + INS

DAPA 2.5MG + INS

DAPA 5/10MG + INS

DAPA 10MG + INS

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Figure 8:

Adjusted Mean Change from Baseline Over Time in Body Weight (kg) in a 208-

Week Active-Controlled Study Comparing Dapagliflozin to Glipizide as Add-on

to Metformin (Longitudinal Repeated Measures Analysis, Excluding Data after

Rescue)

Cardiovascular and renal outcomes

Dapagliflozin

Effect

Cardiovascular

Events

(DECLARE)

international,

multicenter,

randomized,

double-blind,

placebo-controlled

clinical

study

conducted

determine the effect of dapagliflozin compared with placebo on 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). DECLARE was designed to ensure inclusion of a broad population.

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Of 17160 randomized patients, 6974 (40.6%) had established CV disease and 10186

(59.4%)

have

established

disease.

8582

patients

were

randomized

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/m

baseline,

10.0%

patients

history

heart

failure.

Mean

eGFR

85.2 mL/min/1.73 m

, 7.4% of patients had eGFR <60mL/min/1.73 m

and 30.3% of patients

micro-

macroalbuminuria

(urine

albumin

creatinine

ration

[UACR]

≥30

≤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 sulphonylurea,

16.8% with a DPP4 inhibitor, and 4.4% with a GLP-1 agonist.

Approximately 81.3% of patients were treated with ACEi or 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 Figures 9 and 10.

Figure 9:

Treatment

effects

for

the

primary

composite

endpoints

and

their

components and the secondary endpoints and components

p-values are two-sided p-values for primary endpoints and nominal p-values for secondary endpoints and single

components. Time to first event was analyzed in a Cox proportional hazards model. The number of first events

for the single components are the actual number of first events for each component and does not add up to the

number of events in the composite endpoint.

Renal composite endpoint is defined as sustained confirmed ≥40% decrease in eGFR to eGFR <60 mL/min/1.73

and/or ESRD (dialysis ≥90 days or kidney transplantation, sustained confirmed eGFR <15 mL/min/1.73 m

and/or renal or CV death.

CI=confidence interval.

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Figure 10: Treatment effects for the primary and secondary endpoints in patients

with and without established CV disease

Renal composite defined as: sustained confirmed ≥40% decrease in eGFR to eGFR <60 mL/min/1.73 m

and/or

ESRD (dialysis ≥90 days or kidney transplantation, sustained confirmed eGFR <15 mL/min/1.73 m

) and/or

renal or CV death. Time to first event was analyzed in a Cox proportional hazards model.

CI=confidence interval

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 11).

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

9), with no clear difference in CV death (HR 0.98 [95% CI 0.82 to 1.17]).

The treatment benefit of dapagliflozin over placebo was observed both in patients with and

without established CV disease (Figure 10), with and without heart failure at baseline, and

was consistent across key subgroups, including age, gender, renal function (eGFR), and

region.

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Figure 11: Time

to

first

occurrence

of

hospitalization

for

heart

failure

or

cardiovascular death

Patients at risk is the number of patients at risk at the beginning of the period.

CI Confidence interval, HR Hazard ratio

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).

There were numerically fewer MACE events in the dapagliflozin group compared with the

placebo group (HR 0.93 [95% CI 0.84, 1.03]; p=0.172) (Figures 9 and 10).

Nephropathy

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]; nominal p<0.001,

Figure 12). The difference between groups was driven by reductions in events of the renal

components; sustained eGFR decrease, ESRD and renal death (Figure 9), and was

observed both in patients with and without CV disease (Figure 10).

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Figure 12: Time to first occurrence of sustained eGFR decrease, ESRD, renal or CV

death

Patients at risk is the number of patients at risk at the beginning of the period.

Renal composite endpoint defined as sustained confirmed eGFR decrease ≥40% to eGFR <60 mL/min/1.73m

and/or ESRD and/or renal or CV death.

CI Confidence interval; HR Hazard ratio.

When evaluating the renal components, there were 127 and 238 events of new or worsening

nephropathy

(sustained

eGFR

decrease,

ESRD

renal

death)

patients

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], nominal p<0.001).

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], nominal p<0.001).

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], nominal p<0.001).

The treatment benefit of dapagliflozin over placebo was observed both in patients with and

without existing renal impairment.

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Supportive Studies

Dual Energy X-ray Absorptiometry in Diabetic Patients

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 v. -0.88 kg); waist circumference (mean change from baseline: -2.51 cm

v. -0.99 cm), and body fat mass as measured by DXA (mean change from baseline -2.22

kg v. -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 cm

vs. -8.7 cm

) 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

Use in patients with renal impairment

Patients with mild renal impairment (eGFR

60 to <90 mL/min/1.73 m

In the clinical trial program over 3000 patients with mild renal impairment were treated with

dapagliflozin. Efficacy was assessed in a pooled analysis across 9 dapagliflozin clinical

studies consisting of 2226 patients with mild renal impairment. The mean change from

baseline in hemoglobin A1c (HbA1c) and the placebo-corrected mean HbA1c change at

24 weeks was −1.03% and −0.54%, respectively, for dapagliflozin 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 m

The glycemic efficacy and safety of dapagliflozin was evaluated in two dedicated studies of

patients with moderate renal impairment and in two subgroup analyses of pooled clinical

studies.

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 m

(moderate renal impairment

subgroup CKD 3A), with inadequate glycemic 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) (Table 16). 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.

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Table 9

Results

at

Week

24

in

a

Placebo-Controlled

Study

of

dapagliflozin

Treatment in Diabetic Patients with Moderate Renal Impairment (Class 3A,

eGFR

45 to <60 mL/min/1.73 m

2

)

Efficacy Parameter

Dapagliflozin

10 mg

N=159

Placebo

N=161

HbA1c (%)

Baseline (mean)

8.35

8.03

Change from baseline (adjusted mean

-0.37

-0.03

Difference from placebo (adjusted mean

(95% CI)

-0.34

(-0.53, -0.15)

FPG (mmol/L)

Baseline (mean)

10.16

9.62

Change from baseline (adjusted mean

-1.19

-0.27

Difference from placebo (adjusted mean

(95% CI)

-0.92

(-1.48, -0.36)

Body Weight (percentage)

Baseline (mean)

92.51

88.30

% Change from baseline (adjusted mean

-3.42

-2.02

Difference from placebo (adjusted mean

(95% CI)

-1.43

(-2.15, -0.69)

Seated Systolic Blood Pressure (mmHg)

Baseline (mean)

135.7

135.0

Change from baseline (adjusted mean

-4.8

-1.7

Difference from placebo (adjusted mean

(95% CI)

-3.1

(-6.3, 0.0)

* Least squares mean adjusted for baseline value.

p-value <0.001.

p-value <0.05.

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

placebo: -0.90 mL/min/1.73 m

). At 3 weeks after termination of dapagliflozin, the mean

change from baseline in eGFR in the dapagliflozin group was similar to the mean change

placebo

group

(dapagliflozin:

0.57

mL/min/1.73 m

placebo:

-0.04

mL/min/1.73 m

Efficacy in patients with moderate renal impairment was assessed in a pooled analysis

across 9 clinical studies (366 patients, 87% with eGFR

45 to <60 mL/min/1.73 m

); this

pool did not include the two dedicated studies of diabetic patients with moderate renal

impairment. The mean change from baseline in HbA1c and the placebo-corrected mean

HbA1c change at 24 weeks was −0.87% and −0.39%, respectively, for dapagliflozin 10 mg

(n=85).

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Safety in patients with moderate renal impairment was assessed in a pooled analysis of 12

clinical studies (384 patients, 88% with eGFR

45 to <60 mL/min/1.73 m

); this pool did not

include the two dedicated studies of diabetic patients with moderate renal impairment. At

Week 24, safety was similar to that seen in the overall program of clinical studies except for

a higher proportion of patients reporting at least one event related to renal impairment or

failure (7.9% dapagliflozin 10 mg

versus

5.6% placebo). Of these events, increased serum

creatinine was the most frequently reported (6.7% dapagliflozin 10 mg

versus

2.8%

placebo). Increases in mean parathyroid hormone (PTH) and serum phosphorus observed

with dapagliflozin in the overall program of clinical studies were also seen in the pooled

analysis. In the short-term plus long-term safety pool up to 102 weeks, the safety profile

remained similar.

The efficacy and safety of dapagliflozin was also assessed in a study of 252 diabetic

patients with eGFR

30 to <60 mL/min/1.73 m

(moderate renal impairment subgroup CKD

3A and CKD 3B). 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. In an additional analysis of the subgroup CKD 3A, dapagliflozin 10 mg (n=32)

provided a placebo-corrected mean HbA1c change at 24 weeks of −0.33%. At Week 52,

dapagliflozin was associated with changes from baseline in mean eGFR (dapagliflozin 10

mg −4.46 mL/min/1.73 m

and placebo −2.58 mL/min/1.73 m

). At Week 104, these

changes

persisted

(eGFR:

dapagliflozin

10 mg

−3.50 mL/min/1.73 m

placebo

−2.38 mL/min/1.73 m

). 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 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 5 mg and 10 mg

(4.8% for both groups) 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 groups (6.9% and 6.7% for

the 5 mg and 10 mg groups, respectively). Overall, there were 13 patients with an adverse

event of bone fracture reported in this study up to Week 104 of which 8 occurred in the

dapagliflozin 10 mg group, 5 occurred in the dapagliflozin 5 mg group, and none occurred

in the placebo group. Eight (8) of these 13 fractures were in patients who had eGFR 30 to

45 mL/min/1.73 m

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 imbalance in bone fractures

was observed in the safety analysis of the 12-study pool data and no bone fractures were

reported in the dedicated study of patients with eGFR ≥45 to <60 mL/min/1.73 m

(CKD 3A).

Blood Pressure

In the pre specified pooled analysis of 13 placebo-controlled studies (see section 4.8),

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

both

studies,

dapagliflozin

plus

usual

antidiabetic

treatment

provided

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improvement in HbA1c and decreased the placebo-corrected systolic blood pressure on

average by 3.1 and 4.3 mmHg, respectively

Clinical Safety

Volume depletion

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, in the 13-study, short-term, placebo-controlled pool. Serious

events occurred in

0.2% of patients across 21 active- and placebo-controlled studies

(dapagliflozin as monotherapy or in combination with other antidiabetic therapies) and were

balanced between dapagliflozin 10 mg and comparator.

In the CV 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 ACEi/ARB use. In patients with eGFR <60 mL/min/1.73 m

at baseline, there

were 19 events of SAEs suggestive of volume depletion in the dapagliflozin group and 13

events in the placebo group.

Hypoglycaemia

The incidence of hypoglycemia as seen in controlled clinical studies with dapagliflozin in

different combinations is shown in Table 10.

Table 10:

Incidence

of

Major

a

and

Minor

b

Hypoglycemia

in

Controlled

Clinical

Studies

Placebo/

Active control

Dapagliflozin

10 mg

CV Outcomes Trial (48 months median exposure)

N=8569

N=8574

Major [n(%)]

83 (1.0)

58 (0.7)

Patients treated with insulin

N=4606

N=4177

Major [n(%)]

64 (1.4)

52 (1.2)

Patients treated with a sulphonylurea

N=4521

N=4118

Major [n(%)]

23 (0.5)

14 (0.3)

Monotherapy* (24 weeks)

N=75

N=70

Major [n (%)]

Minor [n (%)]

Add-on to Metformin* (24 weeks)

N=137

N=135

Major [n (%)]

Minor [n (%)]

1 (0.7)

Active Control Add-on to Metformin versus Glipizide (52

weeks)

N=408

N=406

Major [n (%)]

3 (0.7)

Minor [n (%)]

147 (36.0)

7 (1.7)

Add-on to Glimepiride (24 weeks)

N=146

N=151

Major [n (%)]

Minor [n (%)]

3 (2.1)

9 (6.0)

Add-on to Metformin and a Sulphonylurea (24 Weeks)

N=109

N=109

Major [n (%)]

Minor [n (%)]

4 (3.7)

14 (12.8)

Add-on to Pioglitazone (24 weeks)

N=139

N=140

Major [n (%)]

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Placebo/

Active control

Dapagliflozin

10 mg

Minor [n (%)]

Add-on to DPP4 inhibitor (24 weeks)

N=226

N=225

Major [n (%)]

1 (0.4)

Minor [n (%)]

3 (1.3)

4 (1.8)

Add-on to Insulin with or without other OADs

c

(24 weeks)

N=197

N=196

Major [n (%)]

1 (0.5)

1 (0.5)

Minor [n (%)]

67 (34.0)

79 (40.3)

Major episodes of hypoglycemia were defined as symptomatic episodes requiring external (third party)

assistance due to severe impairment in consciousness or behavior with a capillary or plasma glucose value

<54 mg/dL and prompt recovery after glucose or glucagon administration.

Minor episodes of hypoglycemia were defined as either a symptomatic episode with a capillary or plasma

glucose measurement <63 mg/dL regardless of need for external assistance, or an asymptomatic capillary

or plasma glucose measurement <63 mg/dL that does not qualify as a major episode.

OAD = oral antidibetic therapy.

Events Related to Decreased Renal Function

13-study,

short-term,

placebo-controlled

pool,

mean

serum

creatinine

levels

increased

small

amount

Week

(mean

change

from

baseline:

0.041

mg/dL

dapagliflozin 10mg

vs.

-0.008 mg/dL placebo) and decreased toward baseline by Week 24

(mean change from baseline: 0.019 mg/dL dapagliflozin 10 mg

vs.

0.008 mg/dL placebo).

There were no further changes through Week 102.

In the CV outcomes study, there were fewer patients with marked laboratory abnormalities

of creatinine, creatinine clearance, eGFR, and 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.

Laboratory findings - dapagliflozin

Hematocrit

In the pool of 13 placebo-controlled studies, increases from baseline in mean hematocrit

values were observed in dapagliflozin-treated patients starting at Week 1 and continuing up

to Week 16, when the maximum mean difference from baseline was observed. At Week

24, the mean changes from baseline in hematocrit were 2.30% in the dapagliflozin 10 mg

group

versus

−0.33% in the placebo group. At Week 102, the mean changes were 2.68%

versus

−0.46%, respectively. By Week 24, hematocrit values >55% were reported in 1.3%

of dapagliflozin 10-mg–treated patients

versus

0.4% of placebo-treated patients. Results

were similar during the short-term plus long-term phase (the majority of patients were

exposed to treatment for more than one year).

Serum Inorganic Phosphorus

In the pool of 13 placebo-controlled studies, increases from baseline in mean serum

phosphorus levels were reported at Week 24 in dapagliflozin 10-mg-treated patients

compared with placebo-treated patients (mean increases of 0.13 mg/dL

vs.

−0.04 mg/dL,

respectively). Similar results were seen at Week 102. Higher proportions of patients with

marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL if age 17-65 or ≥5.1

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mg/dL if age ≥66) were reported in dapagliflozin 10 mg group

versus

placebo at Week 24

(1.7%

vs.

0.9%, respectively) and during the short-term plus long-term phase (3.0%

vs.

1.6%, respectively). The clinical relevance of these findings is unknown.

Lipids

In the pool of 13 placebo-controlled studies, small changes from baseline in mean lipid

values were reported at Week 24 in dapagliflozin-10-mg−treated patients compared with

placebo-treated patients. Mean percent change from baseline at Week 24 for dapagliflozin

10 mg

versus

placebo, respectively, was as follows: total cholesterol, 2.5%

versus

0.0%;

HDL cholesterol, 6.0%

versus

2.7%; LDL cholesterol, 2.9%

versus

−1.0%; triglycerides,

−2.7%

versus

−0.7%. Mean percent change from baseline at Week 102 for dapagliflozin

10 mg

versus

placebo, respectively, was as follows: total cholesterol, 2.1%

versus

−1.5%;

HDL cholesterol, 6.6%

versus

2.1%; LDL cholesterol, 2.9%

versus

−2.2%; triglycerides,

−1.8%

versus

−1.8%. The ratio between LDL cholesterol and HDL cholesterol decreased

for both treatment groups at Week 24.

In the CV outcomes study, no clinical important differences in total cholesterol, HDL

cholesterol, LDL cholesterol or triglycerides were seen.

5.2

PHARMACOKINETIC PROPERTIES

The results of bioequivalence studies in healthy subjects demonstrated that X

IGDUO

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 X

IGDUO

Interaction with food

The administration of X

IGDUO

XR in healthy subjects after a standard meal compared to the

fasted state results in the same extent of exposure for both dapagliflozin and metformin XR.

Compared to the fasted state, the standard meal results in 35% reduction and a delay of 1

to 2 hours in the peak plasma concentrations of dapagliflozin. This effect of food is not

considered to be clinically meaningful.

Absorption

Dapagliflozin

Dapagliflozin

rapidly

well

absorbed

after

oral

administration

administered with or without food. Maximum dapagliflozin plasma concentrations (C

were usually attained within 2 hours after administration in the fasted state. The C

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%.

Metformin hydrochloride

Following a single oral dose of metformin extended-release, C

is achieved with a median

value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and C

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 µg/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 C

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and T

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. Metformin is negligibly bound

to plasma proteins, in contrast to sulphonylureas, which are more than 90% protein bound.

Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism

Dapagliflozin

Dapagliflozin is a C-linked glucoside, meaning the aglycone component is attached to

glucose

carbon-carbon

bond,

thereby

conferring

stability

against

glucosidase

enzymes. The mean plasma terminal half-life (t

) for dapagliflozin is 12.9 hours following

a single oral dose of dapagliflozin 10 mg to healthy subjects. Dapagliflozin is extensively

metabolized primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite.

Dapagliflozin 3-O-glucuronide accounts for 61% of a 50 mg [14C]-dapagliflozin dose and is

the predominant drug-related component in human plasma, accounting for 42% (based on

AUC[0-12 h]) of total plasma radioactivity, similar to the 39% contribution by parent drug.

Based on AUC, no other metabolite accounts for >5% of the total plasma radioactivity.

Dapagliflozin 3-O-glucuronide or other metabolites do 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.

Metabolism studies with extended-release metformin tablets have not been conducted.

Elimination

Dapagliflozin

Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which

less

than

unchanged

dapagliflozin.

After

oral

administration

[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.

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

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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

Dapagliflozin

For dosing recommendations for patients with moderate to severe renal impairment see

section 4.2. 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.

Metformin hydrochloride

In patients with renal impairment, 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 patients with hepatic impairment compared to

healthy subjects. In patients with mild or moderate hepatic impairment mean C

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 C

and AUC of dapagliflozin were up to 40% and 67% higher than matched

healthy controls, respectively. No dose adjustment is required for patients with severe

hepatic impairment. However, the benefit:risk for the use of dapagliflozin in patients with

severe hepatic impairment should be individually assessed since the safety and efficacy of

dapagliflozin have not been specifically studied in this population.

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Metformin hydrochloride

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

impairment.

Elderly Patients

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 C

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 C

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

basis

gender.

Gender

evaluated

covariate

population

pharmacokinetic model using data from healthy subject and patient studies. The mean

dapagliflozin AUC

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

patients

with

type

diabetes

when

analysed

according

gender

(males=19,

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females=16). 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

patient

studies

used

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 type 2 diabetes mellitus patients

with low body weight (<50 kg) is recommended.

5.3

PRECLINICAL SAFETY DATA

Carcinogenesis, mutagenesis, impairment of fertility

Dapagliflozin

Dapagliflozin did not induce tumours in either mice or rats at any of the doses evaluated in

two-year carcinogenicity studies.

Oral doses in mice consisted of 5, 15, and 40 mg/kg/day

in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and

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10 mg/kg/day for both males and females. The highest doses evaluated in mice were

equivalent to AUC exposure multiples of approximately 72× (males) and 105× (females) the

human AUC at MRHD of 10 mg/day. In rats, AUC exposures were approximately 131×

(males) and 186× (females) the human AUC at the MRHD.

Dapagliflozin was negative in the Ames mutagenicity assay

and was positive in an

in-vitro

clastogenicity assay, but only in the presence of S9 activation and at concentrations ≥

100 μg/mL. Importantly, dapagliflozin was negative for clastogenicity

in vivo

in a series of

studies evaluating micronuclei or DNA repair in rats at exposure multiples >2100× the

human exposure at the MRHD. These studies, along with the absence of tumour findings

in the rat and mouse carcinogenicity studies, support that dapagliflozin does not represent

a genotoxic risk to humans.

Dapagliflozin-related gene transcription changes were evaluated in kidney, liver, adipose,

and skeletal muscle of Zucker Diabetic Fatty (ZDF) rats treated daily with dapagliflozin for

5 weeks. These organs were specifically selected as they represent target organs in the

treatment of diabetes. There was no evidence that dapagliflozin caused transcriptional

changes that are predictive of tumour promoters.

Dapagliflozin and its primary human metabolite (3-O-glucuronide) did not enhance the

in

vitro

growth of six human urinary bladder transitional cell carcinomas (TCC) cell lines at

concentrations ≥100× human C

at the MRHD. In a mouse xenograft study, dapagliflozin

administered daily to male and female nude mice implanted with human TCC tumours did

not significantly enhance the size of tumours at exposures up to 75× and up to 0.9× clinical

exposures at the MRHD for dapagliflozin and its 3-O-glucuronide metabolite, respectively.

These studies provide evidence that dapagliflozin and its primary human metabolite do not

enhance urinary bladder tumour growth.

In a 15-month phenotyping study, there was no evidence of any difference in survival, body

weights, clinical pathology parameters, or histopathologic findings observed between

SGLT2 KO mice and their wild-type (WT) counterparts. SGLT2 KO mice had glucosuria,

unlike the WT mice. Despite a lifetime of glucosuria, there was no evidence of any alteration

of renal function or proliferative changes observed in the kidneys or urinary bladders of

SGLT2 KO mice. These data strongly suggest that high levels of urinary glucose do not

induce urinary tract tumours or accelerate age-related urinary tract pathology.

In a study of fertility and early embryonic development in rats, doses of 15, 75, or

300/210 mg/kg/day dapagliflozin were administered to males (the 300 mg/kg/day dose was

lowered to 210 mg/kg/day after 4 days); and doses of 3, 15, or 75 mg/kg/day were

administered to females. Dapagliflozin had no effects on mating, fertility, or early embryonic

development in treated males or females at any dose tested (at exposure multiples ≤1708×

and 998× the MRHD in males and females, respectively). However, at 300/210 mg/kg/day,

seminal vesicle and epididymal weights were reduced; sperm motility and sperm counts

were reduced; and there were low numbers of morphologically abnormal sperm.

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

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rats. There was, however, an increased incidence of benign stromal uterine polyps in

female rats treated with 900 mg/kg/day.

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.

Fertility of male or female rats was unaffected by metformin when administered at doses as

high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human

daily dose based on body-surface-area comparisons.

Teratogenicity and impairment of early development

Dapagliflozin

Direct administration of dapagliflozin to weanling juvenile rats, and indirect exposure during

late pregnancy and lactation (time periods corresponding to the second and third trimesters

of pregnancy with respect to human renal maturation), are each associated with increased

incidence and/or severity of renal pelvic and tubular dilatations in progeny.

In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from

postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, renal pelvic and

tubular dilatations were reported at all dose levels; pup exposures at the lowest dose tested

were ≥15× the MRHD. These findings were associated with dose-related increases in

kidney weight and macroscopic kidney enlargement observed at all doses. The renal pelvic

and tubular dilatations observed in juvenile animals did not fully reverse within the

approximate 1-month recovery period.

In a separate study of pre-natal and postnatal development, maternal rats were dosed from

gestation day (GD) 6 through PND 21 (also at 1, 15, or 75 mg/kg/day), and pups were

indirectly exposed

in utero

and throughout lactation. (A satellite study was conducted to

assess dapagliflozin exposures in milk and pups.) Increased incidence or severity of renal

pelvic dilatation was again observed in adult offspring of treated dams, although only at 75

mg/kg/day (associated maternal and pup dapagliflozin exposures were 1415× and 137×,

respectively, the human values at the MRHD). Additional developmental toxicity was limited

to dose-related reductions in pup body weights and observed only at doses

15 mg/kg/day

(associated with pup exposures that are

29× the human values at the MRHD). Maternal

toxicity was evident only at 75 mg/kg/day and limited to transient reductions in body weight

and food consumption at dose initiation. The no-adverse-effect level (NOAEL) for

developmental toxicity, 1 mg/kg/day, is associated with a maternal systemic exposure

multiple that is approximately 19× the human value at the MRHD.

In additional studies of embryo-foetal development in rats and rabbits, dapagliflozin was

administered for intervals coinciding with the major periods of organogenesis in each

species. Neither maternal nor developmental toxicities were observed in rabbits at any

dose tested (20, 60, or 180 mg/kg/day); 180 mg/kg/day is associated with a systemic

exposure multiple of approximately 1191× the MRHD. In rats, dapagliflozin was neither

embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441× the MRHD). Doses

mg/kg/day (≥ 2344× the human values at the MRHD) were associated with both maternal

and developmental toxicities. Maternal toxicity included mortality, adverse clinical signs,

and decrements in body weight and food consumption. Developmental toxicity consisted of

increased embryo-foetal lethality, increased incidences of fetal malformations and skeletal

variations, and reduced foetal body weights. Malformations included a low incidence of

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great vessel malformations, fused ribs and vertebral centra, and duplicated manubria and

sternal centra. Variations were primarily reduced ossifications.

Metformin hydrochloride

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This

represents an exposure of about 2 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.

Animal toxicology

A 3-month rat study was conducted with the combination of dapagliflozin and metformin.

No toxicity was observed at AUC exposures 52 and 1.4 times the MRHD for dapagliflozin

and metformin, respectively.

Dapagliflozin

Most of the effects observed in pivotal repeat-dose toxicity studies in both rats and dogs

were considered to be secondary to pharmacologically mediated increases in urinary

glucose and included decreases in body weights and/or body-weight gains, increased food

consumption, and increases in urine volumes due to osmotic diuresis. Dapagliflozin was

well tolerated when given orally to rats for up to 6 months at doses of

25 mg/kg/day

(≥346×the human exposures at the MRHD) and in dogs for up to 12 months at doses of

120 mg/kg/day (≥3200× the human exposures at the MRHD). Also, single-dose studies

with dapagliflozin indicated that the dapagliflozin 3-O-glucuronide metabolite would have

been formed in both rat and dog toxicity studies at exposure levels (AUCs) that are greater

than or approximately equal to anticipated human dapagliflozin 3-O-glucuronide exposures

following administration of dapagliflozin at the MRHD. In rats, the most noteworthy

nonclinical

toxicity

finding

increased

trabecular

bone

tissue

mineralization

(associated with increased serum calcium), was only observed at high-exposure multiples

2100× based on human exposures at the MRHD). Despite achieving exposure multiples

of ≥3200× the human exposure at the MRHD, there was no dose-limiting or target-organ

toxicities identified in the 12-month dog study.

6.

PHARMACEUTICAL PARTICULARS

6.1

LIST OF EXCIPIENTS

Each film-coated tablet of X

IGDUO

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 CI77491 (X

IGDUO

XR 10/500 and X

IGDUO

XR 5/1000 tablets)

iron oxide yellow CI77492 (X

IGDUO

XR 10/1000 tablets).

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6.2

INCOMPATABILITIES

Not applicable.

6.3

SHELF LIFE

36 months

6.4

SPECIAL PRECAUTIONS FOR STORAGE

The tablets should be stored below 30°C.

6.5

NATURE AND CONTENTS OF CONTAINER

IGDUO

XR 10/500: Aluminium/aluminium blisters in pack sizes of 7 (not available in NZ)

and 28 tablets.

IGDUO

XR 10/1000: Aluminium/aluminium blisters in pack sizes of 7 (not available in NZ)

and 28 tablets.

IGDUO

XR 5/1000: Aluminium/aluminium blisters in pack sizes of 14 (not available in NZ)

and 56 tablets.

6.6

SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING

Return unused and expired medicines to your local pharmacy for disposal.

7.

MEDICINE SCHEDULE

Prescription Medicine.

8.

DATE OF FIRST APPROVAL

10 December 2015

9.

SPONSOR

AstraZeneca Limited

PO Box 87453

Meadowbank

Auckland 1742.

Telephone: (09) 306 5650

10.

DATE OF REVISION OF TEXT

18 May 2020

CDS 071218

API 3 January 2019

© AstraZeneca 2020

Xigduo is a registered trademark of the AstraZeneca Group of Companies.

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SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Redundant chemistry text deleted

Extension of indications as per DECLARE study.

Minor editorial changes

Renal Impairment section updated as per DECLARE study

Updated section based on DECLARE data.

Text simplifications

Renal contraindication amended

Metabolic acidosis replaces more specific conditions

Additions / amendments as per DERIVE study

Additions / amendments as per DECLARE study

Modifications to wording to simplify and reduce redundant text

Modifications to clarify / simplify current information

Text simplified

Multiple updates as a result of recent studies

Inclusion of Clinical Trials information for

DERIVE

Study

(patients

with

mild

moderate

renal

impairment)

DECLARE Study (CV outcomes study)

Long term 4 year data for dapagliflozin + sulphonylurea study

DURATION 8 study (use with exenatide)

BP Studies

New section – Clinical Safety. Text is relocated from other sections

and updated in accordance with new data (DECLARE / DERIVE)

Updates to renal information

Minor text updates

Minor updates to headings and text order.

PO Box address amended.

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