Jardiance

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Empagliflozin 25 mg;  
Available from:
Boehringer Ingelheim (NZ) Ltd
INN (International Name):
Empagliflozin 25 mg
Dosage:
25 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Empagliflozin 25 mg   Excipient: Colloidal silicon dioxide Croscarmellose sodium Hyprolose Lactose monohydrate Magnesium stearate Microcrystalline cellulose Opadry yellow 02B38190
Prescription type:
Prescription
Manufactured by:
Boehringer Ingelheim Bidachem SpA
Therapeutic indications:
Glycaemic control Jardiance is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults as: Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance. Add-on combination therapy In combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/Al - 10 tablets - 36 months from date of manufacture stored at or below 30°C protect from light - Blister pack, PVC/Al - 30 tablets - 36 months from date of manufacture stored at or below 30°C protect from light
Authorization number:
TT50-9580a
Authorization date:
2014-06-27

Read the complete document

JARDIANCE NZ CMI V01

Jardiance

®

Film-coated tablets

empagliflozin

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about Jardiance.

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 Jardiance

against the benefits they expect it

will have for you.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

This leaflet was last updated on the

date at the end of this leaflet. More

recent information may be available.

The latest Consumer Medicine

Information is available from your

pharmacist, doctor, or from

www.medsafe.govt.nz/

Consumers/cmi/CMIForm.asp (New

Zealand) and may contain important

information about the medicine and

its use of which you should be aware.

Keep this leaflet with the medicine.

You may need to read it again.

What Jardiance is

used for

Jardiance is used to lower blood

sugar levels in patients with type 2

diabetes mellitus.

It may be used when diet plus

exercise do not provide adequate

blood sugar level control either:

alone as a single medicine, or

in combination with certain other

anti-diabetic medicines such as:

metformin, or

sulfonylurea medicines such

as glimepiride and

glibenclamide, or

pioglitazone, or

insulin, or

dipeptidyl peptidase-4

inhibitor medicines such as

linagliptin.

If you have type 2 diabetes mellitus

and cardiovascular disease, Jardiance

can be used to reduce your risk of

dying from your cardiovascular

disease.

Type 2 diabetes mellitus is also

called non-insulin-dependent

diabetes mellitus or NIDDM. Type 2

diabetes develops if the body does

not make enough insulin, or if the

insulin that your body makes does

not work as well as it should.

Insulin is a substance which helps to

lower the level of sugar in your

blood, especially after meals.

When the level of sugar builds up in

your blood, this can cause damage to

the body's cells and lead to serious

problems with your heart, eyes,

circulation or kidneys.

How Jardiance works

Jardiance contains the active

ingredient, empagliflozin, which

belongs to a group of medicines

called SGLT2 (sodium-glucose co-

transporter 2) inhibitors.

Jardiance works by blocking a

protein in the kidneys called SGLT2.

Jardiance removes blood sugar,

which is too high because of your

type 2 diabetes mellitus, via the

urine. As a result, the levels of

glucose in your blood are reduced.

Ask your doctor if you have any

questions about why this medicine

has been prescribed for you.

Your doctor may have prescribed it

for another reason.

Jardiance is available only with a

doctor's prescription.

Before you take

Jardiance

When you must not take it

Do not take Jardiance if you have

an allergy to:

any medicine containing

empagliflozin (the active

ingredient in Jardiance)

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

JARDIANCE NZ CMI V01

wheezing or difficulty breathing

swelling of the face, lips, tongue

or other parts of the body

rash, itching or hives on the skin.

Do not take Jardiance if you have

severe problems with your kidneys.

Do not take this medicine if you

are pregnant.

It may affect your developing baby if

you take it during pregnancy.

Do not breastfeed if you are taking

this medicine.

It is not known if the active

ingredient in Jardiance passes into

human breast milk and there is a

possibility that your baby may be

affected.

Do not give this medicine to a child

under the age of 18 years.

Safety and effectiveness in children

younger than 18 years has not been

established.

Do not take this medicine after the

expiry date printed on the pack or

if the packaging is torn or shows

signs of tampering.

If it has expired or is damaged, return

it to your pharmacist for disposal.

If you are not sure whether you

should start taking this medicine,

talk to your doctor.

Before you start to take it

Tell your doctor if you have

allergies to any other medicines,

foods, preservatives or dyes.

Tell your doctor if you have or

have had any of the following

medical conditions:

type 1 diabetes, a condition where

your body does not produce

insulin

diabetic ketoacidosis, a condition

in which substances called

'ketone bodies' accumulate in the

blood and which can lead to

diabetic pre-coma. Symptoms

include: rapid weight loss, feeling

sick or being sick, stomach pain,

excessive thirst, fast and deep

breathing, unusual sleepiness or

tiredness, a sweet smell to your

breath, a sweet or metallic taste in

your mouth, or a different odour

to your urine or sweat

kidney problems

galactosaemia, a rare hereditary

condition of galactose intolerance

frequent genital or urinary tract

infections (infections of the

bladder, kidney, or tubes that

carry urine)

illnesses that will make you

dehydrated (e.g. diarrhoea or a

severe infection)

increased urine loss which may

affect the fluid balance in your

body.

Tell your doctor if you have heart

problems, a history of low blood

pressure or are 75 years of age or

older.

Increased passing of urine due to the

medicine may affect fluid balance in

your body and increase your risk of

dehydration.

Tell your doctor if you are 85 years

of age or older.

You should not start taking Jardiance

if you are over 85 years of age.

If you have not told your doctor

about any of the above, tell

him/her before you start taking

Jardiance.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including any that you

get without a prescription from

your pharmacy, supermarket or

health food shop.

Some medicines and Jardiance may

interfere with each other. These

include medicines used to treat high

blood pressure known as water pills

(diuretics).

Your doctor and pharmacist have

more information on medicines to be

careful with or avoid while taking

this medicine.

How to take Jardiance

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 box, ask your

doctor or pharmacist for help.

How much to take

The recommended dose is one 10 mg

tablet once a day.

Your doctor may increase your dose

to 25 mg once a day if your blood

glucose levels remain high after

starting treatment on 10 mg.

Your doctor will prescribe Jardiance

alone, or in combination with another

anti-diabetic medicine if that

medicine alone is not sufficient to

control your blood sugar level.

How to take it

Swallow the tablet whole with a

full glass of water.

When to take it

Take your medicine at about the

same time each day.

Taking it at the same time each day

will have the best effect. It will also

help you remember when to take it.

It does not matter if you take this

medicine before or after food.

How long to take it

Continue taking your medicine for

as long as your doctor tells you.

This medicine helps to control your

condition, but will not cure it. It is

important to keep taking your

medicine even if you feel well.

If you forget to take it

If it is less than 12 hours before

your next dose, skip the dose you

missed and take your next dose

when you are meant to.

JARDIANCE NZ CMI V01

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.

This may increase the chance of you

getting an unwanted side effect.

If you are not sure what to do, ask

your doctor or pharmacist.

If you have trouble remembering

to take your medicine, ask your

pharmacist for some hints.

If you take too much

(overdose)

Immediately telephone your doctor

or the National Poisons Centre

(telephone 0800 764 766) for

advice, or go to Emergency if you

think that you or anyone else may

have taken too much Jardiance. Do

this even if there are no signs of

discomfort or poisoning.

You may need urgent medical

attention.

While you are taking

Jardiance

Things you must do

If you are about to be started on

any new medicine, remind your

doctor and pharmacist that you

are taking Jardiance.

Tell any other doctors and

pharmacists who treat you that

you are taking this medicine.

If you become pregnant while

taking this medicine, tell your

doctor immediately.

If you are about to have any blood

or urine tests, tell your doctor that

you are taking this medicine.

It may interfere with the results of

some tests.

Keep all of your doctor's

appointments so that your progress

can be checked.

Your doctor may do some tests from

time to time to make sure the

medicine is working and to prevent

unwanted side effects.

Follow your doctor's and/or

dietician's advice on diet, drinking

alcohol and exercise.

Diet and exercise can help your body

use its blood sugar better. It is

important to stay on the diet and

exercise program recommended by

your doctor while taking Jardiance.

Make sure you check your blood

glucose regularly.

This is the best way to tell if your

diabetes is being controlled properly.

Your doctor or diabetes educator will

show you how and when to do this.

Check your feet regularly and see

your doctor if you notice any

problems. Follow any other advice

regarding foot care given by your

doctor.

If you are going to have a

procedure (surgery), tell the doctor

that you are taking this medicine.

Your doctor may decide to

temporarily stop your treatment with

Jardiance.

Your doctor will tell you when to

stop taking Jardiance and when to

start taking it again.

Things you must not do

Do not take Jardiance to treat any

other complaints unless your

doctor tells you to.

Do not give your medicine to

anyone else, even if they have the

same condition as you.

Do not stop taking your medicine

or lower the dosage without

checking with your doctor.

Things to be careful of

Be careful driving or operating

machinery until you know how

Jardiance affects you.

When taken with other anti-diabetic

medicines, such as sulfonylurea or

insulin, your risk of getting low

blood sugar is higher.

This may cause dizziness, light-

headedness, tiredness, drowsiness in

some people. Low blood glucose

levels may also slow your reaction

time and affect your ability to drive

or operate machinery.

If you have any of these symptoms,

do not drive, operate machinery or do

anything else that could be

dangerous.

Be careful when doing any of the

following things, which may

increase the risk of your blood

glucose becoming too low:

drinking alcohol

not eating enough

doing unexpected or vigorous

exercise.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are taking

Jardiance.

This medicine helps most people

with type 2 diabetes mellitus, but it

may have unwanted side effects in a

few people. All medicines can have

side effects. Sometimes they are

serious, most of the time they are not.

You may need medical attention if

you get some of the side effects.

Do not be alarmed by the following

lists of side effects. You may not

experience any of them.

Ask your doctor or pharmacist to

answer any questions you may

have.

Tell your doctor or pharmacist if

you notice any of the following and

they worry you:

genital burning, redness, pain and

discharge which may be signs of

a genital yeast infection

passing more urine than normal

itching

JARDIANCE NZ CMI V01

thirst.

The above list includes the more

common side effects of your

medicine. They are usually mild and

short-lived.

Tell your doctor as soon as possible

if you notice any of the symptoms

of low blood sugar such as:

sweating

weakness

hunger

dizziness

trembling

headache

flushing or paleness

numbness

a fast pounding heartbeat.

Low blood sugar may occur in

patients who already take another

medication to treat diabetes, such as

a sulfonylurea or insulin. The dose of

your sulfonylurea or insulin medicine

may need to be reduced while taking

Jardiance.

Tell your doctor as soon as possible

if you notice any of the following:

burning sensation when passing

urine

urine that appears cloudy

pain in the pelvis, or mid-back

pain

straining or pain when passing

urine

unusual thirst

light-headedness, or dizziness

upon standing

fainting or loss of consciousness.

The above list includes serious side

effects that may require medical

attention. Serious side effects are

rare.

Tell your doctor immediately if

you experience pain or tenderness,

itching, swelling in the genital or

back passage area, fever or are

generally feeling unwell.

These may be symptoms of a serious

and life-threatening infection called

Fournier’s gangrene. Your doctor

may tell you to stop taking Jardiance.

Tell your doctor immediately or go

to Emergency if you notice any of

the following:

swelling of the face, lips, mouth,

tongue or throat which may cause

difficulty in swallowing or

breathing

severe and sudden onset of itchy

or raised skin rash, hives or nettle

rash.

Tell your doctor immediately or go

to Emergency if you notice any of

the symptoms of diabetic

ketoacidosis such as:

rapid weight loss

feeling sick or being sick

stomach pain

excessive thirst

fast and deep breathing

confusion

unusual sleepiness or tiredness

a sweet smell to your breath, a

sweet or metallic taste in your

mouth or a different odour to

your urine or sweat.

In rare cases, empagliflozin, the

active substance in Jardiance, can

cause a serious side effect called

diabetic ketoacidosis.

The above list includes very serious

side effects. You may need urgent

medical attention or hospitalisation.

These side effects are very rare.

Tell your doctor or pharmacist if

you notice anything that is making

you feel unwell.

Other side effects not listed above

may also occur in some people.

Some of these side effects can only

be found when your doctor does tests

from time to time to check your

progress.

After using Jardiance

Storage

Keep your tablets in the pack until

it is time to take them.

If you take the tablets out of the pack

they may not keep well.

Keep your tablets in a cool dry

place where the temperature stays

below 30°C.

Do not store Jardiance or any

other medicine in the bathroom or

near a sink. Do not leave it on a

window sill or in the car.

Heat and dampness can destroy some

medicines.

Keep it where children cannot

reach it.

A locked cupboard at least one-and-

a-half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

taking this medicine or the expiry

date has passed, ask your

pharmacist what to do with any

medicine that is left over.

Product description

What it looks like

Jardiance is the brand name of your

medicine.

Jardiance is available in two

strengths:

Jardiance 10 mg tablets are pale

yellow, round, biconvex and

bevel-edged, marked with the BI

company logo on one side and

'S10' on the other side.

Jardiance 25 mg tablets are pale

yellow, oval and biconvex,

marked with the BI company logo

on one side and 'S25' on the other

side.

JARDIANCE NZ CMI V01

Jardiance tablets are available in

PVC/Aluminium blister packs of 10

(sample) or 30 tablets.

Not all pack sizes may be available.

Ingredients

Active ingredient:

Jardiance 10 mg - 10 mg of

empagliflozin.

Jardiance 25 mg - 25 mg of

empagliflozin.

Inactive ingredients:

lactose monohydrate

microcrystalline cellulose

hyprolose

croscarmellose sodium

colloidal silicon dioxide

magnesium stearate.

Tablet coating:

hypromellose

titanium dioxide (E171)

talc

macrogol 400

iron oxide yellow (E172).

This medicine does not contain

sucrose, gluten, tartrazine or any

other azo dyes.

Supplier

Jardiance tablets are supplied in New

Zealand by:

Boehringer Ingelheim (N.Z.) Limited

Auckland.

This Consumer Medicine

Information was updated in

September 2019.

® Jardiance is a registered trade

mark of Boehringer Ingelheim.

© Boehringer Ingelheim Pty Limited

2019.

Read the complete document

JARDIANCE NZ DS v05

NEW ZEALAND DATA SHEET

1. PRODUCT NAME

JARDIANCE 10 mg film coated tablets

JARDIANCE 25 mg film coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

JARDIANCE 10 mg film coated tablets

Each film coated tablet contains 10 mg empagliflozin.

Excipient with known effect

Each tablet contains lactose monohydrate equivalent to 154.3 mg lactose anhydrous.

JARDIANCE 25 mg film coated tablets

Each film coated tablet contains 25 mg empagliflozin.

Excipient with known effect

Each tablet contains lactose monohydrate equivalent to 107.4 mg lactose anhydrous.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film coated tablet (tablet).

JARDIANCE 10 mg film-coated tablets

Pale yellow, round, biconvex and bevel-edged tablets. One side is debossed with the code

‘S10’, the other side is debossed with the Boehringer Ingelheim company symbol.

JARDIANCE 25 mg film-coated tablets

Pale yellow, oval, biconvex tablets. One side is debossed with the code ‘S25’, the other side

is debossed with the Boehringer Ingelheim company symbol.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Glycaemic control:

JARDIANCE is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic

control in adults as:

Monotherapy

When diet and exercise alone do not provide adequate glycaemic control in patients for whom

use of metformin is considered inappropriate due to intolerance.

Add-on combination therapy

In combination with other glucose–lowering medicinal products including insulin, when these,

together with diet and exercise, do not provide adequate glycaemic control (see Further

Information section 5.1).

Prevention of cardiovascular events:

JARDIANCE

indicated

patients

with

type

diabetes

mellitus

established

cardiovascular disease to reduce the risk of cardiovascular death (see section 5.1).

To prevent cardiovascular deaths, JARDIANCE should be used in conjunction with other

measures to reduce cardiovascular risk in line with the current standard of care.

JARDIANCE NZ DS v05

4.2. Dose and method of administration

Dose

The recommended starting dose of JARDIANCE is 10 mg once daily. In patients tolerating

empagliflozin 10 mg once daily and requiring additional glycaemic control, the dose can be

increased to 25 mg once daily.

When JARDIANCE is used in combination with a sulfonylurea or with insulin, a lower dose of

the sulfonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see

sections 4.5 and 4.8).

Special populations

Renal impairment

JARDIANCE is not recommended for use in patients with eGFR < 30 mL/min/1.73 m

(see

sections 4.3 and 4.4). No dose adjustment is required for patients with eGFR ≥ 30 mL/min/1.73

Hepatic impairment

No dose adjustment is recommended for patients with hepatic impairment.

Elderly Patients

No dosage adjustment is recommended based on age. Therapeutic experience in patients

aged 85 years and older is limited. Initiation of empagliflozin therapy in this population is not

recommended (see sections 4.3 and 4.4). Patients aged 75 years and older should be

prescribed with caution (see sections 4.3 and 4.4).

Paediatric population

Safety and effectiveness of JARDIANCE in children under 18 years of age have not been

established.

Method of administration

JARDIANCE can be taken with or without food.

If a dose is missed, it should be taken as soon as the patient remembers. A double dose should

not be taken on the same day.

4.3. Contraindications

Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE (see section 6.1).

Patients with CKD stage 4 or 5 (severely impaired renal function including patients receiving

dialysis; eGFR < 30mL/min/1.73 m

or CrCl < 30mL/min). The efficacy of JARDIANCE is

dependent on renal function (see section 4.4).

4.4 Special warnings and precautions for use

General

JARDIANCE should not be used in patients with type 1 diabetes.

Diabetic ketoacidosis

Cases of diabetic ketoacidosis (DKA), a serious life-threatening condition requiring urgent

hospitalisation, have been reported in patients treated with empagliflozin, including fatal cases.

In a number of reported cases, the presentation of the condition was atypical with only

moderately increased blood glucose values, below 14 mmol/L.

The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms

such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing,

confusion, unusual fatigue or sleepiness.

JARDIANCE NZ DS v05

Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless

of blood glucose level. If ketoacidosis is suspected, JARDIANCE should be discontinued, the

patient should be evaluated, and prompt treatment should be instituted.

Patients who may be at higher risk of ketoacidosis while taking JARDIANCE include patients

on a very low carbohydrate diet (as the combination may further increase ketone body

production), patients with an acute illness, pancreatic disorders suggesting insulin deficiency

(e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), insulin dose reduction

(including insulin pump failure), alcohol abuse, severe dehydration, and patients with a history

of ketoacidosis. JARDIANCE should be used with caution in these patients. When reducing

insulin

dose

(see

section

4.2),

caution

should

taken.

patients

treated

with

JARDIANCE consider monitoring for ketoacidosis and temporarily discontinuing JARDIANCE

in clinical situations known to predispose to ketoacidosis (e.g. prolonged fasting due to acute

illness or surgery). In these situations, consider monitoring of ketones, even if JARDIANCE

treatment has been interrupted.

Necrotising fasciitis of the perineum (Fournier’s gangrene)

Postmarketing cases of necrotising fasciitis of the perineum (also known as Fournier’s

gangrene), a rare, but serious and life-threatening necrotising infection, have been reported in

female and male patients with diabetes mellitus treated with SGLT2 inhibitors, including

empagliflozin. Serious outcomes have included hospitalisation, multiple surgeries, and death.

Patients treated with JARDIANCE who present with pain or tenderness, erythema, swelling in

the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If

suspected, JARDIANCE should be discontinued and prompt treatment should be instituted

(including broad-spectrum antibiotics and surgical debridement if necessary).

Use in patients with renal impairment

JARDIANCE is contraindicated for use in patients with eGFR < 30 mL/min/1.73 m

(see

sections 4.2 and 4.3).

Monitoring of renal function

Due to the mechanism of action, the efficacy of empagliflozin is dependent on renal function.

Therefore assessment of renal function is recommended:

prior to JARDIANCE initiation and periodically during treatment, i.e. at least yearly;

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

periodically thereafter.

Risk for volume depletion

Based on the mode of action of SGLT2 inhibitors, osmotic diuresis accompanying therapeutic

glucosuria may lead to a modest decrease in BP. Therefore, caution should be exercised in

patients for whom an empagliflozin-induced drop in BP could pose a risk, such as patients with

known

cardiovascular

disease,

patients

anti-hypertensive

therapy

with

history

hypotension or patients aged 75 years and older.

In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring

of volume status (e.g. physical examination, BP measurements, laboratory tests including

haematocrit) and electrolytes is recommended for patients receiving empagliflozin. Temporary

interruption of treatment with JARDIANCE should be considered until the fluid loss is corrected.

Urinary tract infections

In the pooled placebo-controlled double-blind trials of 18 to 24 weeks duration, the overall

frequency of urinary tract infection reported as adverse event was higher than placebo in

patients treated with empagliflozin 10 mg and similar to placebo in patients treated with

empagliflozin 25 mg (see section 4.8). Postmarketing cases of complicated urinary tract

infections including pyelonephritis and urosepsis have been reported in patients treated with

empagliflozin. Temporary interruption of JARDIANCE should be considered in patients with

complicated urinary tract infections.

JARDIANCE NZ DS v05

Combination with glucagon like peptide (GLP-1) analogues

Empagliflozin has not been studied in combination with glucagon like peptide 1 (GLP-1)

analogues.

Elderly

Patients aged 75 years and older may be at increased risk of volume depletion, therefore,

JARDIANCE should be prescribed with caution in these patients (see section 4.8).

Therapeutic experience in patients aged 85 years and older is limited. Initiation of JARDIANCE

therapy in this population is not recommended.

Urine laboratory assessments

Urine will test positive for glucose while patients are taking JARDIANCE due to the nature of

the mechanism of action of the SGLT2 inhibitors (see section 5.1).

Lactose

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance,

the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal

product.

4.5. Interaction with other medicines and other forms of interaction

Pharmacodynamic Interactions

Diuretics

Empagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase

the risk of dehydration and hypotension.

Insulin and Insulin Secretagogues

Insulin

insulin

secretagogues,

such

sulfonylureas,

increase

risk

hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required

to reduce the risk of hypoglycaemia when used in combination with empagliflozin (see sections

4.2 and 4.8).

Interference with 1,5-anhydroglucitol (1,5-AG) Assay

Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-

AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use

alternative methods to monitor glycemic control.

Pharmacokinetic Interactions

In vitro assessment of drug interactions

Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest

that the primary route of metabolism of empagliflozin in humans is glucuronidation by the

uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.

Empagliflozin

does

inhibit

UGT1A1,

UGT1A3,

UGT1A8,

UGT1A9,

UGT2B7.

therapeutic doses, the potential for empagliflozin to reversibly inhibit or inactivate the major

CYP450 and UGT isoforms is remote. Drug-drug interactions involving the major CYP450 and

UGT isoforms with empagliflozin and concomitantly administered substrates of these enzymes

are therefore considered unlikely.

Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein, but

it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies,

empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates.

Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and

OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake

transporters at clinically relevant plasma concentrations and, as such, drug-drug interactions

with substrates of these uptake transporters are considered unlikely.

JARDIANCE NZ DS v05

In vivo assessment of drug interactions

No clinically meaningful pharmacokinetic interactions were observed when empagliflozin was

co-administered

with

other

commonly

used

medicinal

products.

Based

results

pharmacokinetic studies no dose adjustment of JARDIANCE is recommended when co-

administered with commonly prescribed medicinal products.

Empagliflozin pharmacokinetics were similar with and without co-administration of metformin,

glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin in

healthy volunteers and with or without co-administration of torasemide and hydrochlorothiazide

in patients with T2DM. Increases in overall exposure (AUC) of empagliflozin were seen

following co-administration with gemfibrozil (59%), rifampicin (35%), or probenecid (53%).

These changes were not considered to be clinically meaningful.

Empagliflozin

clinically

relevant

effect

pharmacokinetics

metformin,

glimepiride,

pioglitazone,

sitagliptin,

linagliptin,

warfarin,

digoxin,

ramipril,

simvastatin,

hydrochlorothiazide, and oral contraceptives when co-administered in healthy volunteers.

4.6. Fertility, pregnancy and lactation

Pregnancy (Category D)

There are limited data from the use of JARDIANCE in pregnant women. It is recommended to

avoid the use of JARDIANCE during pregnancy unless clearly needed.

Empagliflozin administered to female rats from gestation day 6 to lactation day 20 resulted in

reduced weight gain in offspring at >30 mg/kg/day (maternal exposures approximately 4- and

11- times those seen with a clinical dose of 25 mg and 10 mg, respectively). No adverse effects

on postnatal development were noted at 10 mg/kg/day (maternal exposures approximately

equivalent to those seen with a clinical dose of 25 mg).

Specialised studies in rats with other members of the pharmacological class have shown

toxicity to the developing kidney in the time period corresponding to the second and third

trimesters of human pregnancy. Similar effects have not been excluded for empagliflozin.

JARDIANCE should be used in pregnancy only if the expected benefit to the patients justifies

the potential risk to the foetus.

Breast-feeding

No data in humans are available on excretion of empagliflozin into milk. Available nonclinical

data in animals have shown excretion of empagliflozin in milk. Reduced body weight was

observed in rats exposed to empagliflozin in utero and through the consumption of maternal

milk (see section 4.6). Adverse effects on renal development have been observed in juvenile

rats

treated

with

other

members

this

pharmacological

class.

risk

human

newborns/infants cannot be excluded. It is recommended to discontinue breast feeding during

treatment with JARDIANCE.

Effects on fertility

No studies on the effect on human fertility have been conducted for JARDIANCE. Studies in

rats at doses up to 700 mg/kg/day, do not indicate direct or indirect harmful effects with respect

to fertility. In female rats this dose was 90- and 155-fold the systemic AUC exposure anticipated

with a human dose of 10 and 25 mg.

4.7. Effects on ability to drive and use machines

JARDIANCE has a minor influence on the ability to drive and use machines. Patients should

be advised to take precautions to avoid hypoglycaemia while driving and using machines, in

particular when JARDIANCE is used in combination with a sulfonylurea and/or insulin.

4.8. Undesirable effects

a. Summary of the safety profile

A total of 15,582 patients with T2DM were treated in clinical studies to evaluate the safety of

empagliflozin, of which 10,004 patients were treated with empagliflozin, either alone or in

JARDIANCE NZ DS v05

combination with metformin, a sulfonylurea, a PPAR

agonist, DPP4 inhibitors, or insulin. This

pool includes the EMPA-REG OUTCOME study involving 7,020 patients at high cardiovascular

risk (mean age 63.1 years, 9.3% patients at least 75 years old, 28.5% women) treated with

JARDIANCE 10 mg/day (n=2345), JARDIANCE 25 mg/day (n=2342), or placebo (n=2333) up

to 4.5 years. The overall safety profile of empagliflozin in this study was comparable to the

previously known safety profile. In these trials, the frequency of adverse effects leading to

discontinuation was similar by treatment groups for placebo, JARDIANCE 10 mg and

JARDIANCE 25 mg.

Placebo controlled double-blind trials of 18 to 24 weeks of exposure included 3534 patients,

of which 1183 were treated with placebo, 1185 were treated with JARDIANCE 10 mg and 1166

were treated with JARDIANCE 25 mg. The overall incidence of adverse events in patients

treated with empagliflozin was similar to placebo. The most frequent adverse drug reaction

was hypoglycaemia, which depended on the type of background therapy used in the respective

studies.

b. Tabulated list of adverse reactions

Adverse reactions classified by system organ class and MedDRA preferred terms reported in

patients

received

empagliflozin

placebo-controlled

studies

derived

from

postmarketing experience are presented in Table 1 below. Frequency categories are defined

as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare

(≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the

available data).

Table 1 Adverse reactions reported in patients who received JARDIANCE in placebo-

controlled double-blind studies and derived from postmarketing experience.

System Organ class

Very Common

Common

Uncommon

Not known

Infections and

infestations

Vaginal moniliasis,

vulvovaginitis,

balanitis and other

genital infections

Urinary tract

infection

(including

pyelonephritis and

urosepsis)

Necrotising

fasciitis of the

perineum

(Fournier´s

gangrene)

Metabolism and

nutrition disorders

Hypoglycaemia

(when used with

sulfonylurea or

insulin)

Ketoacidosis

Skin and

subcutaneous tissue

disorders

Pruritus

Allergic skin

reactions (e.g.,

rash, urticaria)

Angioedema

Vascular disorders

Volume

depletion

Renal and urinary

disorders

Increased

urination

Dysuria

General disorders

and administration

site conditions

Thirst

JARDIANCE NZ DS v05

System Organ class

Very Common

Common

Uncommon

Not known

Investigations

Serum lipids

increased

Glomerular

filtration rate

decreased

Blood

creatinine

increased

Haematocrit

increased

see subsections below for additional information

derived from postmarketing experience

see section 5.1 for additional information

c. Description of selected adverse reactions

The frequencies below are calculated for adverse reactions regardless of causality.

Hypoglycaemia

The frequency of hypoglycaemia depended on the background therapy in the respective

studies and was similar for JARDIANCE and placebo as monotherapy, as add-on to metformin,

as add-on to pioglitazone +/- metformin, and as add-on to linagliptin + metformin. The

frequency of patients with hypoglycaemia was increased in patients treated with JARDIANCE

compared to placebo when given as add-on to metformin plus sulfonylurea, and as add-on to

insulin +/- metformin and +/-sulfonylurea (see section 4.2; Table 2).

Major hypoglycaemia (events requiring assistance)

The frequency of patients with major hypoglycaemic events was low (<1%) and similar for

JARDIANCE and placebo as monotherapy, as add-on to metformin ± sulfonylurea, as add-on

to pioglitazone +/- metformin, and as add-on to linagliptin + metformin.

The frequency of patients with major hypoglycaemic events was increased in patients treated

with JARDIANCE compared to placebo when given as add-on to insulin +/- metformin and +/-

sulfonylurea.

Table 2 Frequency of patients with confirmed hypoglycaemic events per trial (1245.19,

1245.20, 1245.23

(met)

, 1245.23

(met+SU)

, 1245.33, 1245.49 and 1275.9

(lina+met)

and 1245.25 –

Treated Set

Placebo

Empagliflozin

10 mg

25 mg

Monotherapy (1245.20) (24 weeks)

n=229

n=224

n=223

Overall confirmed (%)

0.4%

0.4%

0.4%

Major (%)

In Combination with Metformin (1245.23 (met))

(24 weeks)

n=206

n=217

n=214

Overall confirmed (%)

0.5%

1.8%

1.4%

Major (%)

In Combination with Metformin + Sulfonylurea

(1245.23 (met + SU)) (24 weeks)

n=225

n=224

n=217

Overall confirmed (%)

8.4%

16.1%

11.5%

Major (%)

In Combination with Pioglitazone +/-

Metformin (1245.19) (24 weeks)

n=165

n=165

n=168

Overall confirmed (%)

1.8%

1.2%

2.4%

Major (%)

In Combination with Basal Insulin (1245.33)

(18 weeks

2

/ 78 weeks)

n=170

n=169

n=155

Overall confirmed (%)

20.6%/ 35.3%

19.5%/ 36.1%

28.4%/ 36.1%

Major (%)

0%/ 0%

0%/ 0%

1.3%/ 1.3%

JARDIANCE NZ DS v05

Placebo

Empagliflozin

10 mg

25 mg

In Combination with MDI Insulin +/-Metformin

(1245.49) (18 weeks

2

/ 52 weeks)

n=188

n=186

n=189

Overall confirmed (%)

37.2%/ 58.0%

39.8%/ 51.1%

41.3%/ 57.7%

Major (%)

0.5%/ 1.6%

0.5%/ 1.6%

0.5%/ 0.5%

In Combination with Metformin and Linagliptin

(1275.9) (24 weeks

3

)

n=110

n=112

n=110

Overall confirmed (%)

0.9%

0.0%

2.7%

Major (%)

0.9%

EMPA-REG OUTCOME (1245.25)

n=2333

n=2345

n=2342

Overall confirmed (%)

27.9%

27.6%

Major (%)

1.5%

1.4%

1.3%

Confirmed: blood glucose ≤3.9 mmol/L or required assistance

Major: required assistance

1. i.e. patients who had received at least one dose of study drug

2 The dose of insulin as background medication was to be stable for the first 18 weeks

3 This was a fixed-dose combination of empagliflozin with linagliptin 5 mg with a background treatment with metformin (see section 5.1).

MDI = multiple daily injections

Urinary tract infection

The overall frequency of urinary tract infection was similar in patients treated with JARDIANCE

25 mg and placebo (7.0% and 7.2%) and higher in patients treated with JARDIANCE 10 mg

(8.8%). Similar to placebo, urinary tract infection was reported more frequently for JARDIANCE

in patients with a history of chronic or recurrent urinary tract infections. The intensity of urinary

tract infections was similar to placebo for mild, moderate, and severe intensity reports. Urinary

tract infection events were reported more frequently for empagliflozin compared to placebo in

female patients, but not in male patients.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more

frequently for JARDIANCE 10 mg (4.0%) and JARDIANCE 25 mg (3.9%) compared to placebo

(1.0%) and were reported more frequently for empagliflozin compared to placebo in female

patients, and the difference in frequency was less pronounced in male patients. The genital

tract infections were mild and moderate in intensity, none was severe in intensity.

Increased urination

As expected via its mechanism of action, increased urination (as assessed by preferred term

search including pollakiuria, polyuria, nocturia) was observed at higher frequencies in patients

treated with JARDIANCE 10 mg (3.5%) and JARDIANCE 25 mg (3.3%) compared to placebo

(1.4%). Increased urination was mostly mild or moderate in intensity. The frequency of reported

nocturia was comparable between placebo and JARDIANCE (<1%).

Volume depletion

The overall frequency of volume depletion (including the predefined terms BP (ambulatory)

decreased, SBP decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension

and syncope) was similar to placebo (JARDIANCE 10 mg 0.6%, JARDIANCE 25 mg 0.4% and

placebo 0.3%). The effect of empagliflozin on urinary glucose excretion is associated with

osmotic diuresis, which could affect hydration status of patients aged 75 years and older. In

patients ≥ 75 years of age (pooling of all patients with diabetes, n=13, 402) the frequency of

volume depletion events was similar for JARDIANCE 10 mg (2.3%) compared to placebo

(2.1%), but it increased with JARDIANCE 25 mg (4.3%).

Blood creatinine increased and glomerular filtration rate decreased

The overall frequency of patients with increased blood creatinine and decreased glomerular

filtration rate was similar between empagliflozin and placebo (blood creatinine increased:

empagliflozin 10 mg 0.6%, empagliflozin 25 mg 0.1%, placebo 0.5%; glomerular filtration rate

decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.3%).

In placebo-controlled, double-blind studies up to 76 weeks, initial transient increases in

creatinine (mean change from baseline after 12 weeks: empagliflozin 10 mg 0.0011 mmol/L,

JARDIANCE NZ DS v05

empagliflozin 25 mg 0.0006 mmol/L) and initial transient decreases in estimated glomerular

filtration rates (mean change from baseline after 12 weeks: empagliflozin 10 mg -1.34

mL/min/1.73m

, empagliflozin 25 mg -1.37 mL/min/1.73m

) have been observed. These

changes were generally reversible during continuous treatment or after drug discontinuation

(see section 5.1, Figure 6 for the eGFR course in the EMPA-REG OUTCOME study).

Reporting of suspected adverse reactions

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

allows

continued

monitoring

benefit/risk

balance

medicine.

Healthcare

professionals

asked

report

suspected

adverse

reactions

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

4.9 Overdose

For advice on the management of overdose, please contact the National Poisons Centre on

0800 POISON (0800 764766).

During controlled clinical trials in healthy subjects, single doses of up to 800 mg empagliflozin,

equivalent to 32 times the maximum recommended daily dose, were well tolerated.

Treatment

In the event of an overdose, supportive treatment should be initiated as appropriate to the

patient’s clinical status. The removal of empagliflozin by haemodialysis has not been studied.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: SGLT2 Inhibitor, ATC code: A10BK03.

Mechanism of action

Empagliflozin is a reversible competitive inhibitor of SGLT2 with an IC

of 1.3 nM. It has a

5000-fold selectivity over human SGLT1 (IC

of 6278 nM), responsible for glucose absorption

in the gut.

SGLT2 is highly expressed in the kidney, whereas expression in other tissues is absent or very

low. It is responsible as the predominant transporter for re-absorption of glucose from the

glomerular filtrate back into the circulation. In patients with type 2 diabetes mellitus (T2DM)

and hyperglycaemia a higher amount of glucose is filtered and reabsorbed.

Empagliflozin improves glycaemic control in patients with T2DM by reducing renal glucose re-

absorption. The amount of glucose removed by the kidney through this glucuretic mechanism

is dependent upon the blood glucose concentration and glomerular filtration rate (GFR).

Through inhibition of SGLT2 in patients with T2DM and hyperglycaemia, excess glucose is

excreted in the urine.

In patients with T2DM, urinary glucose excretion increased immediately following the first dose

of empagliflozin and is continuous over the 24 hour dosing interval. Increased urinary glucose

excretion was maintained at the end of 4-week treatment period, averaging approximately

78 g/day with empagliflozin 25 mg once daily. Increased urinary glucose excretion resulted in

an immediate reduction in plasma glucose levels in patients with T2DM.

Empagliflozin (10 mg and 25 mg) improves both fasting and post-prandial plasma glucose

levels.

The mechanism of action of empagliflozin is independent of beta cell function and insulin

pathway, and this contributes to a low risk of hypoglycaemia. Improvement of surrogate

markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) and

proinsulin to insulin ratio were noted. In addition urinary glucose excretion triggers calorie loss,

associated with body fat loss and body weight reduction.

The glucosuria observed with empagliflozin is accompanied by mild diuresis which may

contribute to sustained and moderate reduction of blood pressure (BP).

JARDIANCE NZ DS v05

Clinical efficacy and safety

A total of 17331 patients with T2DM were evaluated in 15 double-blind, placebo- and active-

controlled clinical studies, of which 4603 patients received empagliflozin 10 mg and 5567

received empagliflozin 25 mg. Six studies had a treatment duration of 24 weeks; in extensions

of applicable studies, and other trials, patients were exposed to JARDIANCE for up to 102

weeks.

Treatment with empagliflozin (10 mg and 25 mg) as monotherapy and in combination with

metformin, pioglitazone, sulfonylurea, dipeptidyl peptidase 4 (DPP-4) inhibitors, and insulin

lead to clinically relevant improvements in glycated haemoglobin (HbA

), fasting plasma

glucose (FPG), body weight, systolic BP (SBP) and diastolic BP (DBP). Administration of

empagliflozin 25 mg resulted in a higher proportion of patients achieving an HbA

goal of less

than 7% and fewer patients needing glycaemic rescue compared to empagliflozin 10 mg and

placebo. There was a clinically meaningful improvement in HbA

in all subgroups of gender,

race, geographic region, time since diagnosis of T2DM, BMI, insulin resistance based on

HOMA-IR, and beta cell function based on HOMA-β. Higher baseline HbA

was associated

with a greater reduction in HbA

. Clinically meaningful HbA

reduction was seen in patients

with

eGFR > 30 mL/min/1.73

(see

Dosage

Administration,

Patients

with

Renal

impairment). In patients aged 75 years and older, reduced efficacy of JARDIANCE was

observed.

Empagliflozin as monotherapy

The efficacy and safety of empagliflozin (10 mg and 25 mg) as monotherapy was evaluated in

a double-blind, placebo- and active-controlled study of 24 weeks duration in treatment-naïve

patients. The primary endpoint was the change from baseline in HbA

after 24 weeks of

treatment. The key secondary endpoints were the change from baseline in body weight and

blood pressure (SBP and DBP) after 24 weeks of treatment.

Treatment with JARDIANCE resulted in statistically significant reductions in HbA

, body

weight and SBP compared to placebo (Table 3) and a clinically meaningful decrease in FPG.

A numerical decrease in DBP was seen but did not reach statistical significance versus placebo

(-1.0 mmHg for empagliflozin 10 mg, -1.9 mmHg for empagliflozin 25 mg, -0.5 mmHg for

placebo, and +0.7 mmHg for sitagliptin).

In a prespecified analysis of patients (n=201) with a baseline HbA

≥ 8.5% to ≤ 10%

empagliflozin resulted in a reduction in HbA

from baseline of -1.44% for empagliflozin 10 mg,

-1.43% for empagliflozin 25 mg, +0.01% for placebo, and -1.04% for sitagliptin.

In the double-blind placebo-controlled extension of this study, reductions of HbA

(change

from baseline of -0.65% for empagliflozin 10 mg, -0.76% for empagliflozin 25 mg, +0.13% for

placebo, and -0.53% for sitagliptin), body weight (change from baseline of -2.24 kg for

empagliflozin 10 mg, -2.45 kg for empagliflozin 25 mg, -0.43 kg for placebo, and +0.10 kg for

sitagliptin) and BP (SBP: change from baseline of -4.1 mmHg for empagliflozin 10 mg, -4.2

mmHg for empagliflozin 25 mg, -0.7 mmHg for placebo, and -0.3 mmHg for sitagliptin, DBP:

change from baseline of -1.6 mmHg for empagliflozin 10 mg, -1.6 mmHg for empagliflozin 25

mg, +0.6 mmHg for placebo, and -0.1 mmHg for sitagliptin) were sustained up to 76 weeks of

treatment.

Treatment with JARDIANCE daily significantly improved marker of beta cell function HOMA-β.

Table

Results

week

(LOCF)

placebo-controlled

study

JARDIANCE

monotherapy (Full Analysis Set)

JARDIANCE as monotherapy

Placebo

Empagliflozin

10 mg

Empagliflozin

25 mg

Sitagliptin

100mg

HbA

1c

(%)

Baseline (mean)

7.91

7.87

7.86

7.85

Change from baseline

0.08

-0.66

-0.78

-0.66

Difference from placebo

(97.5% CI)

-0.74*

(-0.90, -0.57)

-0.85*

(-1.01, -0.69)

-0.73

(-0.88, -0.59)

JARDIANCE NZ DS v05

JARDIANCE as monotherapy

Placebo

Empagliflozin

10 mg

Empagliflozin

25 mg

Sitagliptin

100mg

Patients (%) achieving HbA

< 7% with baseline HbA

1c

≥ 7%

4

12.0

35.3

43.6

37.5

Fasting plasma glucose

(mmol/L)

4

Baseline (mean)

8.59

8.48

8.47

8.17

Change from baseline

0.65

-1.08

-1.36

-0.38

Difference from placebo

(95% CI)

-1.73*

(-2.03, -1.43)

-2.01*

(-2.31, -1.71)

-1.04*

(-1.34, -0.73)

Body weight (kg)

Baseline (mean)

78.23

78.35

77.80

79.31

Change from baseline

-0.33

-2.26

-2.48

0.18

Difference from placebo

(97.5% CI)

-1.93*

(-2.48, -1.38)

-2.15*

(-2.70,-1.60)

0.52

(-0.04, 1.00)

Patients(%) achieving weight

loss of >5%

5

22.8

29.0

Systolic blood pressure

(mmHg)

2

Baseline (mean)

130.4

133.0

129.9

132.5

Change from baseline

-0.3

-2.9

-3.7

Difference from placebo

(97.5% CI)

-2.6*

(-5.2, 0.0)

-3.4*

(-6.0, -0.9)

(-1.4, 3.1)

1. Last observation (prior to glycaemic rescue) carried forward (LOCF)

2. Mean adjusted for baseline value and stratification

3. Last observation (prior to glycaemic rescue or antihypertensive rescue) carried forward (LOCF

4. 95% CI

5. Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints

* p value <0.0001

Empagliflozin as add on to metformin therapy

A double-blind, placebo-controlled study of 24 weeks duration was conducted to evaluate the

efficacy and safety of empagliflozin in patients with T2DM not controlled on metformin. The

primary endpoint was the change from baseline in HbA

after 24 weeks of treatment. The key

secondary endpoints were the change from baseline in body weight and mean daily plasma

glucose (MDG) after 24 weeks of treatment.

Treatment with JARDIANCE resulted in statistically significant improvements in HbA

body weight, and clinically meaningful reductions in FPG and BP compared to placebo (Table

In the double-blind placebo-controlled extension of this study, reductions of HbA

(change

from baseline of -0.62% for empagliflozin 10 mg, -0.74% for empagliflozin 25 mg and -0.01%

for placebo), body weight (change from baseline of -2.39 kg for empagliflozin 10 mg, -2.65 kg

for empagliflozin 25 mg and -0.46 kg for placebo) and BP (SBP: change from baseline of -5.2

mmHg for empagliflozin 10 mg, -4.5 mmHg for empagliflozin 25 mg and -0.8 mmHg for

placebo, DBP: change from baseline of -2.5 mmHg for empagliflozin 10 mg, -1.9 mmHg for

empagliflozin 25 mg and -0.5 mmHg for placebo) were sustained up to 76 weeks of treatment.

JARDIANCE NZ DS v05

Table 4 Results of a 24 week (LOCF)

placebo-controlled study of JARDIANCE as add-on to

metformin (Full Analysis Set)

JARDIANCE as add-on to

metformin therapy

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

HbA

1c

(%)

Baseline (mean)

7.90

7.94

7.86

Change from baseline

-0.13

-0.70

-0.77

Difference from placebo

(97.5% CI)

-0.57* (-0.72, -0.42)

-0.64* (-0.79, -0.48)

Patients (%) achieving HbA

1c

< 7%

with baseline HbA

1c

≥ 7%

2

12.5

37.7

38.7

Fasting plasma glucose (mmol/L)

2

Baseline (mean)

8.66

8.58

8.29

Change from baseline

0.35

-1.11

-1.24

Difference from placebo

(95% CI)

-1.47* (-1.74, -1.20)

-1.59* (-1.86, -1.32)

Body weight (kg)

Baseline (mean)

79.73

81.59

82.21

Change from baseline

-0.45

-2.08

-2.46

Difference from placebo

(97.5% CI)

-1.63* (-2.17, -1.08)

-2.01* (-2.56, -1.46)

Patients (%) achieving weight loss

of >5%

2

21.2

23.0

Systolic blood pressure (mmHg)

2

Baseline (mean)

128.6

129.6

130.0

Change from baseline

-0.4

-4.5

-5.2

Difference from placebo

(95% CI)

-4.1* (-6.2, -2.1)

-4.8* (-6.9, -2.7)

1. Mean adjusted for baseline value and stratification

2. Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints

3. Last observation (prior to glycaemic rescue) carried forward (LOCF)

* p-value <0.0001

Empagliflozin and metformin combination therapy in drug-naïve patients

A factorial design study of 24 weeks duration was conducted to evaluate the efficacy and safety

of empagliflozin in drug-naïve patients. Treatment with empagliflozin in combination with

metformin (5 mg and 500 mg; 5 mg and 1000 mg; 12.5 mg and 500 mg, and 12.5 mg and 1000

mg given twice daily) provided statistically significant improvements in HbA

and led to

significantly

greater

reductions

body

weight

compared

individual

components. A greater proportion of patients with a baseline HbA

≥ 7.0% and treated with

empagliflozin in combination with metformin achieved a target HbA

< 7% compared to the

individual components (Tables 5 and 6).

JARDIANCE NZ DS v05

Table 5 Results of a 24 week (OC)

study comparing empagliflozin 10 mg in combination with

metformin to the individual components

Empagliflozin

10 mg + metformin

1000 mg

a

Empagliflozin

10 mg + metformin

2000 mg

a

Empagliflozin

10 mg (qd)

Metformin

1000 mg

a

Metformin

2000 mg

a

HbA

1c

(%)

Baseline (mean)

Change from baseline

-2.0

-2.1

-1.4

-1.2

-1.8

Comparison vs.

empagliflozin (95% CI)

-0.6*

(-0.9, -0.4)

-0.7*

(-1.0, -0.5)

Comparison vs. metformin

(95% CI)

-0.8*

(-1.0, -0.6)

-0.3*

(-0.6, -0.1)

Patients (%) achieving

HbA

1c

<7% with baseline

HbA

1c

≥7%

96 (63%)

112 (70%)

69 (43%)

63 (38%)

92 (58%)

FPG (mmol/L)

Baseline (mean)

Change from baseline

-2.5

-2.7

-1.8

-1.0

-1.8

Comparison vs.

empagliflozin (95% CI)

-0.7**

(-1.1, -0.3)

-0.8**

(-1.2, -0.5)

Comparison vs. metformin

(95% CI)

-1.6**

(-1.9, -1.2)

-0.9**

(-1.2, -0.5)

Body Weight (kg)

Baseline (mean)

82.3

83.0

83.9

82.9

83.8

% Change from baseline

-3.1

-4.1

-2.7

-0.4

-1.2

Comparison vs. metformin

(95% CI)

-2.7**

(-3.6, -1.8)

-2.8**

(-3.8, -1.9)

a Given in two equally divided doses per day

b. Full analysis population (observed case) using MMRM. MMRM model included treatment, renal function, region, visit, visit by

treatment interaction, and baseline HbA

; FPG included baseline FPG in addition; weight included baseline weight in addition.

1. Mean adjusted for baseline value

2. Analyses were performed on the full analysis set (FAS) using an observed cases (OC) approach

* p≤0.0062 for HbA

** Analysis in an exploratory manner: p≤0.0002 for FPG and p<0.0001 for body weight

Table 6 Results of a 24 week (OC)

study comparing empagliflozin 25 mg in combination with

metformin to the individual monotherapy components

Empagliflozin

25 mg + metformin

1000 mg

a

Empagliflozin

25 mg + metformin

2000 mg

a

Empagliflozin

25 mg qd

Metformin

1000 mg

a

Metformin

2000 mg

a

HbA

1c

(%)

Baseline (mean)

Change from baseline

-1.9

-2.1

-1.4

-1.2

-1.8

Comparison vs.

empagliflozin (95% CI)

-0.6*

(-0.8, -0.3)

-0.7*

(-1.0, -0.5)

Comparison vs. metformin

(95% CI)

-0.8*

(-1.0, -0.5)

-0.3*

(-0.6, -0.1)

Patients (%) achieving

HbA

1c

<7% with baseline

HbA

1c

≥7%

91 (57%)

111 (68%)

51 (32%)

63 (38%)

92 (58%)

FPG (mmol/L)

Baseline (mean)

Change from baseline

-2.4

-2.8

-1.6

-1.0

-1.8

Comparison vs.

empagliflozin (95% CI)

-0.9**

(-1.3, -0.5)

-1.3**

(-1.6, -0.9)

Comparison vs. metformin

(95% CI)

-1.5**

(-1.9, -1.1)

-1.0**

(-1.4, -0.7)

JARDIANCE NZ DS v05

Empagliflozin

25 mg + metformin

1000 mg

a

Empagliflozin

25 mg + metformin

2000 mg

a

Empagliflozin

25 mg qd

Metformin

1000 mg

a

Metformin

2000 mg

a

Body Weight (kg)

Baseline (mean)

82.9

83.7

83.4

82.9

83.8

% Change from baseline

-3.6

-4.3

-2.8

-0.4

-1.2

Comparison vs. metformin

(95% CI)

-3.1**

(-4.1, -2.2)

-3.1**

(-4.1, -2.2)

a. Given in two equally divided doses per day

b. Full analysis population (observed case) using MMRM. MMRM model included treatment, renal function, region, visit, visit by

treatment interaction, and baseline HbA

; FPG included baseline FPG in addition; weight included baseline weight in addition.

1. Mean adjusted for baseline value

2. Analyses were performed on the full analysis set (FAS) using an observed cases (OC) approach

* p≤0.0056 for HbA

** Analysis in an exploratory manner: p<0.0001 for FPG and p<0.0001 for body weight

Empagliflozin as add on to a combination of metformin and sulfonylurea therapy

A double-blind, placebo-controlled study of 24 weeks duration was conducted to evaluate the

efficacy and safety of empagliflozin in patients not sufficiently treated with a combination of

metformin and a sulfonylurea. The primary endpoint was the change from baseline in HbA

after 24 weeks of treatment. The key secondary endpoints were the change from baseline in

body weight and mean daily plasma glucose (MDG) after 24 weeks of treatment.

Treatment with JARDIANCE resulted in statistically significant improvements in HbA

body weight and clinically meaningful reductions in FPG and BP compared to placebo (Table

In the double-blind placebo-controlled extension of this study, reductions of HbA

(change

from baseline of -0.74% for empagliflozin 10 mg, -0.72% for empagliflozin 25 mg and -0.03%

for placebo), body weight (change from baseline of -2.44 kg for empagliflozin 10 mg, -2.28 kg

for empagliflozin and -0.63 kg for placebo) and BP (SBP: change from baseline of -3.8 mmHg

for empagliflozin 10 mg, -3.7 mmHg for empagliflozin 25 mg and -1.6 mmHg for placebo, DBP:

change from baseline of -2.6 mmHg for empagliflozin 10 mg, -2.3 mmHg for empagliflozin 25

mg and -1.4 mmHg for placebo) were sustained up to 76 weeks of treatment.

Table 7 Results of a 24 week (LOCF)

placebo-controlled study of JARDIANCE as add-on to

metformin and a sulfonylurea (Full Analysis Set)

JARDIANCE as add-on to

metformin and a sulfonylurea

therapy

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

HbA

1c

(%)

Baseline (mean)

8.15

8.07

8.10

Change from baseline

-0.17

-0.82

-0.77

Difference from placebo

(97.5% CI)

-0.64* (-0.79, -0.49)

-0.59* (-0.74, -0.44)

Patients (%) achieving HbA

1c

< 7%

with baseline HbA

1c

≥ 7%

2

26.3

32.2

Fasting plasma glucose (mmol/L)

Baseline (mean)

8.42

8.38

8.68

Change from baseline

0.31

-1.29

-1.29

Difference from placebo

(95% CI)

-1.60* (-1.90, -1.30)

-1.60* (-1.90, -1.29)

Body weight (kg)

Baseline (mean)

76.23

77.08

77.50

Change from baseline

-0.39

-2.16

-2.39

Difference from placebo

(97.5% CI)

-1.76* (-2.25, -1.28)

-1.99* (-2.48, -1.50)

Patients (%) achieving weight loss

of >5%

2

27.6

23.6

JARDIANCE NZ DS v05

JARDIANCE as add-on to

metformin and a sulfonylurea

therapy

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

Systolic blood pressure (mmHg)

2

Baseline (mean)

128.8

128.7

129.3

Change from baseline

-1.4

-4.1

-3.5

Difference from placebo

(95% CI)

-2.7 (-4.6, -0.8)

-2.1 (-4.0, -0.2)

1. Mean adjusted for baseline value and stratification

2. Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints

3. Last observation (prior to glycaemic rescue) carried forward (LOCF)

* p-value <0.0001

2 hour post-prandial glucose

Treatment with empagliflozin (10 mg or 25 mg) as add-on to metformin or metformin plus

sulfonylurea resulted in clinically meaningful improvement of 2-hour post-prandial glucose

(meal tolerance test) at 24 weeks (add-on to metformin: -2.55 mmol/L for empagliflozin 10 mg

(n=52), -2.47 mmol/L for empagliflozin 25 mg (n=58) and +0.33 mmol/L for placebo (n=57);

add-on to metformin plus sulfonylurea: -1.98 mmol/L for empagliflozin 10 mg (n=44), -2.03

mmol/L for empagliflozin 25 mg (n=46) and -0.13 mmol/L for placebo (n=35)).

Empagliflozin as add on to a combination of pioglitazone therapy (+/- metformin)

The efficacy and safety of empagliflozin was evaluated in a double-blind, placebo-controlled

study of 24 weeks duration in patients with T2DM not controlled on a combination of metformin

and pioglitazone or pioglitazone alone. The primary endpoint was the change from baseline in

after 24 weeks of treatment. The key secondary endpoints were the change from

baseline in FPG and body weight after 24 weeks of treatment.

Empagliflozin in combination with pioglitazone (dose ≥ 30 mg) with or without metformin

resulted in statistically significant reductions in HbA

, FPG, and body weight and clinically

meaningful reductions in BP compared to placebo (Table 8).

In the double-blind placebo-controlled extension of this study, reductions of HbA

(change

from baseline of -0.61% for empagliflozin 10 mg, -0.70% for empagliflozin 25 mg and -0.01%

for placebo), body weight (change from baseline of -1.47 kg for empagliflozin 10 mg, -1.21 kg

for empagliflozin 25 mg and +0.50 kg for placebo) and BP (SBP: change from baseline of

-1.71 mmHg for empagliflozin 10 mg, -3.4 mmHg for empagliflozin 25 mg and +0.3 mmHg for

placebo, DBP: change from baseline of -1.3 mmHg for empagliflozin 10 mg, -2.0 mmHg for

empagliflozin 25 mg and +0.2 mmHg for placebo) were sustained up to 76 weeks of treatment.

Table 8 Results of a 24 week (LOCF)

placebo-controlled study of JARDIANCE as add-on to

pioglitazone with or without metformin (Full Analysis Set)

Pioglitazone +/- metformin add-on

therapy

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

HbA

1c

(%)

Baseline (mean)

8.16

8.07

8.06

Change from baseline

-0.11

-0.59

-0.72

Difference from placebo1 (97.5% CI)

-0.48* (-0.69, -0.27)

-0.61* (-0.82, -0.40)

Patients (%) achieving HbA

<7% with

baseline HbA

≥7%

23.8

30.0

Fasting plasma glucose (mmol/L)

Baseline (mean)

8.43

8.44

8.43

Change from baseline

0.37

-0.94

-1.23

Difference from placebo1 (97.5% CI)

-1.32* (-1.72, -0.91)

-1.61* (-2.04, -1.12)

JARDIANCE NZ DS v05

Pioglitazone +/- metformin add-on

therapy

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

Body Weight (kg)

Baseline (mean)

78.1

77.97

78.93

Change from baseline

0.34

-1.62

-1.47

Difference from placebo1 (97.5% CI)

-1.95* (-2.64, -1.27)

-1.81* (-2.49, -1.13)

Patients(%) achieving weight loss of >5%

18.8

13.7

Systolic blood pressure (mmHg)

2

Baseline (mean)

125.7

126.5

125.9

Change from baseline

-3.1

-4.0

Difference from placebo

(95% CI)

-3.9 (-6.2, -1.5)

-4.7 (-7.1, -2.4)

1. Mean adjusted for baseline value and stratification

2. Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints

3. Last observation (prior to glycaemic rescue) carried forward (LOCF)

* p-value <0.0001

Empagliflozin and linagliptin in treatment naïve patients

After 24-weeks treatment, empagliflozin 25 mg/linagliptin 5 mg in treatment naïve patients

provided statistically significant improvement in A1C compared to linagliptin 5 mg but there

was no statistically significant difference between the FDC empagliflozin 25 mg/linagliptin 5

mg and empagliflozin 25 mg (Table 9). Compared to linagliptin 5 mg both doses of the

empagliflozin/linagliptin FDC provided statistically relevant improvements in body weight. After

24 weeks’ treatment with empagliflozin/linagliptin, both SBP and DBPs were reduced,

-2.9/-1.1 mmHg (n.s. versus linagliptin 5 mg for SBP and DBP) for empagliflozin 25

mg/linagliptin 5 mg and -3.6/-0.7 mmHg (p<0.05 versus linagliptin 5 mg for SBP, n.s. for DBP)

for empagliflozin 10 mg/linagliptin 5 mg. Rescue therapy was used in 2 (1.5%) patients treated

with empagliflozin 25 mg/linagliptin 5 mg and in 1 (0.7%) patient treated with empagliflozin 10

mg /linagliptin 5 mg compared to 11 (8.3%) patients treated with linagliptin 5 mg, 1 (0.8%)

patients treated with empagliflozin 25 mg and 4 (3.0%) patients treated with empagliflozin 10

mg. Clinically meaningful reductions in HbA

(Table 9) and SBPs were observed at week 52,

-2.0 mmHg (n.s. versus linagliptin 5 mg) for empagliflozin 25 mg/linagliptin 5 mg and -1.7

mmHg (n.s. versus linagliptin 5 mg) for empagliflozin 10 mg/linagliptin 5 mg.

Table 9 Results of a 24- and 52-week (LOCF)

randomised, double-blind controlled study of

empagliflozin and linagliptin as a fixed-dose combination in treatment naïve patients

Empagliflozin/linagliptin

Empagliflozin

Linagliptin

25 mg/5 mg

10 mg /5 mg

25 mg

10 mg

5 mg

Primary endpoint: HbA

1c

[%] - 24 weeks

Number of patients analysed

Baseline mean (SE)

7.99 (0.08)

8.04 (0.08)

7.99 (0.08)

8.05 (0.09)

8.05 (0.08)

Adjusted mean (SE) change from

baseline at Week 24

−1.08

(0.07)

−1.24

(0.07)

−0.95

(0.07)

−0.83

(0.07)

−0.67

(0.07)

Comparison vs. empagliflozin

vs. empa 25 mg

vs. empa 10 mg

Adjusted mean (SE)

−0.14 (0.10)

−0.41 (0.10)

95.0% CI

−0.33, 0.06

−0.61, −0.21

p-value

0.1785

not assessed

Comparison vs. linagliptin 5 mg

Adjusted mean (SE)

−0.41 (0.10)

−0.57 (0.10)

95.0% CI

−0.61, −0.22

−0.76, −0.37

p-value

<0.0001

not assessed

HbA

1c

[%] – 52 weeks

4

Baseline mean (SE)

7.99 (0.08)

8.04 (0.08)

7.99 (0.08)

8.05 (0.09)

8.05 (0.08)

Adjusted mean (SE) change from

baseline at Week 52

−1.17

(0.08)

−1.22

(0.08)

−1.01

(0.08)

−0.85

(0.08)

−0.51

(0.08)

Comparison vs. empagliflozin

vs. empa 25 mg

vs. empa 10 mg

Adjusted mean (SE)

−0.16 (0.12)

−0.37 (0.12)

95.0% CI

−0.39, 0.07

−0.60, −0.14

Comparison vs. linagliptin 5 mg

Adjusted mean (SE)

−0.66 (0.12)

−0.71 (0.12)

95.0% CI

−0.90, −0.43

−0.94, −0.48

JARDIANCE NZ DS v05

Empagliflozin/linagliptin

Empagliflozin

Linagliptin

25 mg/5 mg

10 mg /5 mg

25 mg

10 mg

5 mg

Key secondary endpoint: [mmol/L] - 24 weeks

Number of patients analysed

Baseline mean (SE)

8.66 (0.17)

8.27 (0.17)

8.48 (0.19)

8.89 (0.20)

8.66 (0.18)

Adjusted mean (SE) change from

baseline at Week 24

−1.64

(0.15)

−1.57

(0.15)

−1.35

(0.15)

−1.24

(0.15)

−0.33

(0.15)

Comparison vs. empagliflozin

vs. empa 25 mg

vs. empa 10 mg

Adjusted mean (SE)

−0.29 (0.21)

−0.32 (0.21)

95.0% CI

−0.71, 0.12

−0.74, 0.09

p-value

not assessed

not assessed

Comparison vs. linagliptin 5 mg

Adjusted mean (SE)

−1.31 (0.21)

−1.24 (0.21)

95.0% CI

−1.72, −0.90

−1.65, −0.83

p-value

not assessed

not assessed

Key secondary endpoint: body weight [kg] - 24 weeks

Number of patients analysed

Baseline mean (SE)

87.92 (1.57)

87.30 (1.59)

86.73 (1.71)

87.82 (2.08)

89.51 (1.74)

Adjusted mean (SE) change from

baseline at Week 24

−2.00

(0.36)

−2.74

(0.36)

−2.13

(0.36)

−2.27

(0.37)

−0.78

(0.36)

Comparison vs. linagliptin 5 mg

Adjusted mean (SE)

−1.22 (0.51)

−1.96 (0.51)

95.0% CI

−2.23, −0.21

−2.97, −0.95

p-value

not assessed

not assessed

Key secondary endpoint: patients with HbA

1c

<7.0% - 24 weeks

Number of patients, N (%)

121 (100.0)

122 (100.0)

118 (100.0)

121 (100.0)

127 (100.0)

With HbA

<7.0% at Week 24

67 (55.4)

76 (62.3)

49 (41.5)

47 (38.8)

41 (32.3)

Comparison vs. Empagliflozin

vs. empa 25 mg

vs. empa 10 mg

Odds ratio

1.893

2.961

95.0% CI

1.095, 3.274

1.697, 5.169

p-value

not assessed

not assessed

Comparison vs. lina 5 mg

Odds ratio

3.065

4.303

95.0% CI

1.768, 5.314

2.462, 7.522

p-value

not assessed

not assessed

1. Last observation (prior to glycaemic rescue) carried forward (LOCF)

2. Mean adjusted for baseline value and stratification

3. ANCOVA model includes baseline body weight, baseline HbA

, baseline eGFR (MDRD), geographical region, and treatment;

based on FAS (LOCF). The comparisons vs. empa were exploratory and not part of the testing hierarchy (empa 25 mg/lina 5 mg

vs. empa 25 mg: adjusted mean 0.19 (95% CI −0.65, 1.03) kg; empa 10 mg/lina 5 mg vs. empa 10 mg: −0.07 (0.91, 0.77) kg)

4. Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints. Specification

‘not assessed’ means that the previous hierarchical test in the confirmatory sequence failed so no subsequent testing was

performed.

5. Logistic regression includes baseline HbA

, baseline eGFR (MDRD), geographical region, and treatment; based on FAS

(NCF), patients with HbA

of 7% and above at baseline

In a pre-specified subgroup of patients with baseline HbA

greater or equal than 8.5% the

reduction from baseline in HbA

with empagliflozin 25 mg/linagliptin 5 mg was -1.9% at 24

weeks (p<0.0001 versus linagliptin 5 mg, n.s. versus empagliflozin 25 mg) and -2.0% at 52

weeks (p<0.0001 versus linagliptin 5 mg, p<0.05 versus empagliflozin 25 mg) and with

empagliflozin 10 mg/linagliptin 5 mg -1.9% at 24 weeks (p<0.0001 versus linagliptin 5 mg,

p<0.05 versus empagliflozin 10 mg) and -2.0% at 52 weeks (p<0.0001 versus linagliptin 5 mg,

p<0.05 versus empagliflozin 10 mg).

Empagliflozin and linagliptin as add on therapy to metformin

In patients inadequately controlled on metformin 24-weeks treatment with both doses of the

empagliflozin/linagliptin FDC provided statistically significant improvements in HbA

and FPG

compared to linagliptin 5 mg and also compared to empagliflozin 10 or 25 mg. Compared to

linagliptin 5 mg both doses of the empagliflozin/linagliptin FDC provided statistically significant

improvements in body weight. A greater proportion of patients with a baseline HbA

≥7.0%

and treated with the empagliflozin/linagliptin FDC achieved a target HbA

of <7% compared

individual

components

(Table

10).

After

weeks

treatment

with

empagliflozin/linagliptin, both SBPs and DBPs were reduced, -5.6/-3.6 mmHg (p<0.001 versus

linagliptin

DBP)

empagliflozin

mg/linagliptin

-4.1/-2.6 mmHg (p<0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for empagliflozin 10

mg/linagliptin 5 mg. Clinically meaningful reductions in HbA

(Table 10) and both SBPs and

DBPs were observed at week 52, -3.8/-1.6 mmHg (p<0.05 versus linagliptin 5 mg for SBP and

DBP) for empagliflozin 25 mg/linagliptin 5 mg and -3.1/-1.6 mmHg (p<0.05 versus linagliptin 5

mg for SBP, n.s. for DBP) for empagliflozin 10 mg/linagliptin 5 mg.

JARDIANCE NZ DS v05

After 24 weeks, rescue therapy was used in 1 (0.7%) patient treated with empagliflozin 25

mg/linagliptin 5 mg and in 3 (2.2%) patients treated with empagliflozin 10 mg /linagliptin 5 mg,

compared to 4 (3.1%) patients treated with linagliptin 5 mg and 6 (4.3%) patients treated with

empagliflozin 25 mg and 1 (0.7%) patient treated with empagliflozin 10 mg.

Table 10 Results of a 24- and 52- week (LOCF)

randomised, double-blind controlled study of

empagliflozin and linagliptin as a fixed dose combination as add-on Therapy in Patients

Inadequately Controlled on Metformin

Empagliflozin/linagliptin

Empagliflozin

Linagliptin

25 mg/5 mg

10 mg /5 mg

25 mg

10 mg

5 mg

Primary endpoint: HbA

1c

[%] - 24 weeks

Number of patients analysed

Baseline mean (SE)

7.90 (0.07)

7.95 (0.07)

8.02 (0.07)

8.00 (0.08)

8.02 (0.08)

Adjusted mean (SE) change

from baseline at Week 24

1, 2

−1.19

(0.06)

−1.08

(0.06)

−0.62 (0.06)

−0.66 (0.06)

−0.70 (0.06)

Comparison vs. empagliflozin

vs. empa 25 mg

vs. empa 10 mg

Adjusted mean (SE)

−0.58 (0.09)

−0.42 (0.09)

95.0% CI

−0.75, −0.41

−0.59, −0.25

p-value

<0.0001

<0.0001

Comparison vs. linagliptin 5 mg

Adjusted mean (SE)

−0.50 (0.09)

−0.39 (0.09)

95.0% CI

−0.67, −0.32

−0.56, −0.21

p-value

<0.0001

<0.0001

HbA

1c

[%] - 52 weeks

4

Baseline mean (SE)

7.90 (0.07)

7.95 (0.07)

8.02 (0.07)

8.00 (0.08)

8.02 (0.08)

Adjusted mean (SE) change

from baseline at Week 52

1, 2

−1.21 (0.07)

−1.05 (0.07)

−0.64 (0.07)

−0.69 (0.07)

−0.48 (0.07)

Comparison vs. empagliflozin

vs. empa 25 mg

vs. empa 10 mg

Adjusted mean (SE)

−0.57 (0.10)

−0.36 (0.10)

95.0% CI

−0.77, −0.37

−0.56, −0.17

Comparison vs. linagliptin 5 mg

Adjusted mean (SE)

−0.73 (0.10)

−0.57 (0.10)

95.0% CI

−0.93, −0.53

−0.77, −0.37

Key secondary endpoint: FPG [mmol/L] - 24 weeks

Number of patients analysed

Baseline mean (SE)

8.58 (0.16)

8.70 (0.17)

8.87 (0.18)

8.97 (0.17)

8.68 (0.15)

Adjusted mean (SE) change

from baseline at Week 24

−1.96 (0.14)

−1.79 (0.14)

−1.05 (0.14)

−1.16 (.014)

−0.72 (0.14)

Comparison vs. empagliflozin

vs. empa 25 mg

vs. empa 10 mg

Adjusted mean (SE)

−0.91 (0.20)

−0.63 (0.20)

95.0% CI

−1.30, −0.53

−1.02, −0.24

p-value

<0.0001

0.0015

Comparison vs. linagliptin 5 mg

Adjusted mean (SE)

−1.23 (0.20)

−1.06 (0.20)

95.0% CI

−1.63, −0.84

−1.45, −0.67

p-value

<0.0001

<0.0001

Key secondary endpoint: body weight [kg] – 24 weeks

Number of patients analysed

Baseline mean (SE)

85.47 (1.76)

86.57 (1.64)

87.68 (1.49)

86.14 (1.55)

85.01 (1.62)

Adjusted mean (SE) change

from baseline at Week 24

1, 2, 3

−2.99 (0.31)

−2.60 (0.30)

−3.18 (0.30)

−2.53 (0.30)

−0.69 (0.31)

Comparison vs. linagliptin 5 mg

Adjusted mean (SE)

−2.30 (0.44)

−1.91 (0.44)

95.0% CI

−3.15, −1.44

−2.77, −1.05

p-value

<0.0001

<0.0001

JARDIANCE NZ DS v05

Empagliflozin/linagliptin

Empagliflozin

Linagliptin

25 mg/5 mg

10 mg /5 mg

25 mg

10 mg

5 mg

Key secondary endpoint: patients with HbA

1c

< 7.0% - 24 weeks

Number of patients, N (%)

123 (100.0)

128 (100.0)

132 (100.0)

125 (100.0)

119 (100.0)

With HbA

<7.0% at Week 24

76 (61.8)

74 (57.8)

43 (32.6)

35 (28.0)

43 (36.1)

Comparison

vs. empagliflozin

vs. empa 25 mg

vs. empa 10 mg

Odds ratio

4.191

4.500

95.0% CI

2.319, 7.573

2.474, 8.184

p-value

<0.0001

<0.0001

Comparison vs. linagliptin 5 mg

Odds ratio

3.495

2.795

95.0% CI

1.920, 6.363

1.562, 5.001

p-value

<0.0001

0.0005

1. Last observation (prior to glycaemic rescue) carried forward (LOCF)

2. Mean adjusted for baseline value and stratification

3. ANCOVA model includes baseline body weight, baseline HbA

, baseline eGFR (MDRD), geographical region, and treatment;

based on FAS (LOCF). The comparisons vs. empagliflozin were exploratory and not part of the testing hierarchy (empa 25/lina

5 vs. empa 25: adjusted mean 0.19 (95% CI −0.65, 1.03) kg; empa 10/lina 5 vs. empa 10: −0.07 (−0.91, 0.77) kg)

4. Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints

5. Logistic regression includes baseline HbA

, baseline eGFR (MDRD), geographical region, and treatment; based on FAS

(NCF), patients with HbA

of 7% and above at baseline

In a pre-specified subgroup of patients with baseline HbA

greater or equal than 8.5% the

reduction from baseline in HbA

with empagliflozin 25 mg/linagliptin 5 mg was -1.8% at 24

weeks (p<0.0001 versus linagliptin 5 mg, p<0.001 versus empagliflozin 25 mg) and -1.8% at

52 weeks (p<0.0001 versus linagliptin 5 mg, p<0.05 versus empagliflozin 25 mg) and with

empagliflozin 10 mg/5 mg linagliptin -1.6% at 24 weeks (p<0.01 versus linagliptin 5 mg, n.s.

versus empagliflozin 10 mg) and -1.5% at 52 weeks (p<0.01 versus linagliptin 5 mg, n.s. versus

empagliflozin 10 mg).

Empagliflozin vs. placebo in patients inadequately controlled on metformin and linagliptin

In patients inadequately controlled on metformin and linagliptin, 24-weeks treatment with both

doses (10 mg and 25 mg) of empagliflozin provided statistically significant improvements in

, FPG and body weight compared to placebo (background linagliptin 5 mg). A statistically

significant

greater

number

patients

with

baseline

≥7.0%

treated

with

empagliflozin achieved a target HbA

of <7% compared to placebo (background linagliptin 5

mg) (Table 11). After 24 weeks’ treatment with empagliflozin, both SBPs and DBPs were

reduced, -2.6/-1.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 25

mg/linagliptin

-1.3/-0.1 mmHg

(n.s.

versus

placebo for

DBP) for

empagliflozin 10 mg/linagliptin 5 mg.

After 24 weeks, rescue therapy was used in 4 (3.6%) patients treated with empagliflozin 25

mg/linagliptin 5 mg and in 2 (1.8%) patients treated with empagliflozin 10 mg/linagliptin 5 mg,

compared to 13 (12.0%) patients treated with placebo (background linagliptin 5 mg).

JARDIANCE NZ DS v05

Table 11 Efficacy Parameters Comparing Empagliflozin to placebo as Add-on Therapy in

Patients Inadequately Controlled on Metformin and Linagliptin 5 mg

1 Patients randomized to the empagliflozin 10 mg group were receiving empagliflozin 10 mg/linagliptin 5 mg or empagliflozin 25

mg/linagliptin 5 mg with background metformin

2 Patients randomized to the placebo group were receiving the placebo plus linagliptin 5 mg with background metformin

3 MMRM model on FAS (OC) includes baseline HbA

, baseline eGFR (MDRD), geographical region, visit, treatment,and visit

by treatment interaction. For FPG, baseline FPG is also included. For weight, baseline weight is also included.

4 not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints

5 Logistic regression on FAS (NCF) includes baseline HbA

, baseline eGFR (MDRD), geographical region, and treatment;

based on patients with HbA

of 7% and above at baseline

In a prespecified subgroup of patients with baseline HbA

1c

greater or equal than 8.5% the

reduction from baseline in HbA

1c

with empagliflozin 25 mg/ linagliptin 5 mg was -1.3% at 24

weeks (p<0.0001 versus placebo [background linagliptin 5 mg]) and with empagliflozin 10

mg/linagliptin 5 mg -1.3% at 24 weeks (p<0.0001 versus placebo [background linagliptin

5 mg]).

Empagliflozin 2-year data, as add on to metformin in comparison to glimepiride

In a study comparing the efficacy and safety of empagliflozin 25 mg versus glimepiride (1-4

mg) in patients with inadequate glycaemic control on metformin alone, treatment with

empagliflozin 25 mg daily resulted in superior reduction in HbA

, and a clinically meaningful

reduction in FPG, compared to glimepiride (Table 12). Empagliflozin 25 mg daily resulted in a

statistically significant reduction in body weight, systolic and diastolic blood pressure (change

from baseline in DBP of -1.8 mmHg for empagliflozin and +0.9 mmHg for glimepiride,

p<0.0001).

Treatment with empagliflozin 25 mg resulted in statistically significantly lower proportion of

patients with hypoglycaemic events compared to glimepiride (2.5% for empagliflozin 25 mg,

24.2% for glimepiride, p<0.0001).

Metformin + Linagliptin 5 mg

Empagliflozin 10 mg

1

Empagliflozin 25 mg

1

Placebo

2

HbA

1c

(%) - 24 weeks

3

Baseline (mean)

7.97

7.97

7.96

Change from baseline (adjusted mean)

-0.65

-0.56

0.14

Comparison vs. placebo (adjusted mean)

(95% CI)

-0.79 (-1.02, -0.55)

p<0.0001

-0.70 (-0.93, -0.46)

p<0.0001

FPG (mmol/L) – 24 weeks

3

N

Baseline (mean)

Change from baseline (adjusted mean)

-1.5

-1.8

Comparison vs. placebo (adjusted mean)

(95% CI)

-1.8 (-2.3, -1.3)

p<0.0001

-2.1 (-2.6, -1.6)

p<0.0001

Body Weight-24 weeks

3

Baseline (mean) in kg

88.4

84.4

82.3

Change from baseline (adjusted mean)

-3.1

-2.5

-0.3

Comparison vs. placebo (adjusted mean)

(95% CI)

-2.8 ( 3.5, 2.1)

p<0.0001

-2.2 ( 2.9, 1.5)

p<0.0001

Patients (%) achieving HbA

1c

<7% with

baseline HbA

1c

≥7% - 24 weeks

4

Patients (%) achieving A1C <7%

37.0

32.7

17.0

Comparison vs. placebo (odds ratio) (95%

4.0 (1.9, 8.7)

2.9 (1.4, 6.1)

JARDIANCE NZ DS v05

Table 12 Results at 104 weeks (LOCF)

in an active controlled study comparing empagliflozin

to glimepiride as add on to metformin (Full Analysis Set)

Empagliflozin as add-on to metformin

therapy in comparison to glimepiride

Empagliflozin 25 mg

Glimepiride

(up to 4 mg)

HbA

1c

(%)

Baseline (mean)

7.92

7.92

Change from baseline

-0.66

-0.55

Difference from glimepiride

(97.5%) CI)

-0.11* (-0.20, -0.01)

Patients (%) achieving HbA

1c

<7% with

baseline HbA

1c

≥7%

2

33.6

30.9

FPG (mmol/L)

Baseline (mean)

8.33

8.32

Change from baseline

-0.85

-0.17

Difference from glimepiride

(95% CI)

-0.69 (-0.86,-0.52)

Body Weight (kg)

Baseline (mean)

82.52

83.03

Change from baseline

-3.12

1.34

Difference from glimepiride

(97.5% CI)

-4.46** (-4.87, -4.05)

Patients(%) achieving weight loss of >5%

2

27.5

SBP (mmHg)

3

Baseline (mean)

133.4

133.5

Change from baseline

-3.1

Difference from glimepiride

(97.5% CI)

-5.6** (-7.0,-4.2)

1. Mean adjusted for baseline value and stratification

2. Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints

3. Last observation (prior glycaemic rescue or to antihypertensive rescue) carried forward (LOCF)

4. Last observation (prior to glycaemic rescue) carried forward (LOCF)

* p-value <0.0001 for non-inferiority, and p-value = 0.0153 for superiority

** p-value <0.0001

Empagliflozin as add on to multiple daily insulin therapy and metformin

The efficacy and safety of empagliflozin as add-on to multiple daily insulin with or without

concomitant metformin therapy (71.0% of all patients were on metformin background) was

evaluated in a double-blind, placebo-controlled trial of 52 weeks duration. During the initial 18

weeks and the last 12 weeks, the insulin dose was to be kept stable, but was adjusted to

achieve pre-prandial glucose levels < 5.5 mmol/L, and post-prandial glucose levels < 7.8

mmol/L between Weeks 19 and 40.

At Week 18, empagliflozin provided statistically significant improvement in HbA

compared

with placebo (Table 13). A greater proportion of patients with a baseline HbA

≥ 7.0% (19.5%

empagliflozin 10 mg, 31.0% empagliflozin 25 mg) achieved a target HbA

of < 7% compared

with placebo (15.1%).

At Week 52, treatment with empagliflozin resulted in a statistically significant decrease in HbA

and insulin sparing compared with placebo and a reduction in FPG (change from baseline of

−0.02 mmol/L for placebo, −1.09 mmol/L for empagliflozin 10 mg, and −1.31 mmol/L for

empagliflozin 25 mg), body weight, and blood pressure (SBP: change from baseline of −2.6

mmHg for placebo, −3.9 mmHg for empagliflozin 10 mg and -4.0 mmHg for empagliflozin 25

mg, DBP: change from baseline of −1.0 mmHg for placebo, -1.4 mmHg for empagliflozin 10

mg and -2.6 mmHg for empagliflozin 25 mg).

JARDIANCE NZ DS v05

Table 13 Results at 18 and 52 (LOCF)

weeks in a placebo-controlled study of empagliflozin

as add on to multiple daily doses of insulin with metformin

Empagliflozin as add-on to insulin

+ metformin therapy

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

HbA

1c

(%) at week 18

Baseline (mean)

8.33

8.39

8.29

Change from baseline

-0.50

-0.94

-1.02

Difference from placebo

(97.5% CI)

-0.44* (-0.61, -0.27)

-0.52* (-0.69, -0.35)

HbA

1c

(%) at week 52

3

Baseline (mean)

8.25

8.40

8.37

Change from baseline

-0.81

-1.18

-1.27

Difference from placebo

(97.5% CI)

-0.38** (-0.62, -0.13)

-0.46* (-0.70, -0.22)

Patients (%) achieving HbA

1c

<7%

with baseline HbA

1c

≥7% at week

52

4

26.5

39.8

45.8

FPG (mmol/L) at week 52

5

Baseline (mean)

8.41

8.83

8.34

Change from baseline

-0.02

-1.09

-1.31

Difference from placebo

(95% CI)

-1.07 (-1.55, -0.06)

-1.30 (-1.77, -0.83)

Insulin dose (IU/day) at week 52

3

Baseline (mean)

89.94

88.57

90.38

Change from baseline

10.16

1.33

-1.06

Difference from placebo

(97.5% CI)

-8.83** (-15.69, -1.97)

-11.22**(-18.09, -4.36)

Body Weight (kg) at week 52

3

Baseline (mean)

96.34

96.47

95.37

Change from baseline

0.44

-1.95

-2.04

Difference from placebo

(97.5% CI)

-2.39* (-3.54, -1.24)

-2.48* (-3.63, -1.33)

N

SBP (mmHg)

6

Baseline (mean)

132.6

134.2

132.9

Change from baseline

-2.6

-3.9

-4.0

Difference from placebo

(95% CI)

-1.4 (-3.6, 0.9)

-1.4 (-3.7, 0.8)

1. Mean adjusted for baseline value and stratification

2. Week 18: FAS; week 52: PPS-Completers-52

3. Week 19-40: treat-to-target regimen for insulin dose adjustment to achieve pre-defined glucose target levels (pre-prandial

<5.5 mmol/L, post-prandial <7.8 mmol/L

4. Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints

5. Last observation (prior to glycaemic rescue) carried forward (LOCF)

6. Week 52: FAS

* p-value <0.0001

** p-value <0.005

Empagliflozin as add on to basal insulin therapy

The efficacy and safety of empagliflozin (10 mg or 25 mg) as add on to basal insulin with or

without concomitant metformin and/or sulfonylurea therapy was evaluated in a double-blind,

placebo-controlled trial of 78 weeks duration. The primary endpoint was the change from

baseline in HbA

after 18 weeks of treatment. The key secondary endpoints were the change

from baseline in dose of basal insulin dose after 78 weeks of treatment and change from

baseline in HbA

after 78 weeks of treatment.

During the initial 18 weeks the insulin dose was to be kept stable, but was adjusted to achieve

a FPG < 6.10 mmol/L in the following 60 weeks.

At week 18, empagliflozin (10 mg or 25 mg) provided statistically significant improvement in

compared to placebo. A greater proportion of patients with a baseline HbA

≥ 7.0%

achieved a target HbA

of <7% compared to placebo. At 78 weeks, empagliflozin resulted in

JARDIANCE NZ DS v05

a statistically significant decrease in HbA

and insulin sparing compared to placebo (Table

14).

At week 78, empagliflozin resulted in a reduction in FPG (-0.58 mmol/L for empagliflozin 10

mg, -0.97 mmol/L for empagliflozin 25 mg and -0.30 mmol/L for placebo), body weight (-2.47

kg for empagliflozin 10 mg, -1.96 kg for empagliflozin 25 mg and +1.16 kg for placebo, p<

0.0001), BP (SBP: -4.1 mmHg for empagliflozin 10 mg, -2.4 mmHg for empagliflozin 25 mg

and +0.1 mmHg for placebo, DBP: -2.9 mmHg for empagliflozin 10 mg, -1.5 mmHg for

empagliflozin 25 mg and -0.3 mmHg for placebo).

Table 14 Results at 18 and 78 weeks (LOCF) in a placebo-controlled study of JARDIANCE as

add on to basal insulin with or without metformin or sulfonylurea (Full Analysis Set -

Completers)

Basal insulin +/- metformin or

sulfonylurea add-on therapy

Placebo

Empagliflozin

10 mg

Empagliflozin

25 mg

HbA

1c

(%) at week 18

Baseline (mean)

8.10

8.26

8.34

Change from baseline

-0.01

-0.57

-0.71

Difference from placebo

(97.5% CI)

-0.56*

(-0.78,-0.33)

-0.70*

(-0.93, -0.47)

HbA

1c

(%) at week 78

Baseline (mean)

8.09

8.27

8.29

Change from baseline

-0.02

-0.48

-0.64

Difference from placebo

(97.5% CI)

-0.46*

(-0.73, -0.19)

-0.62*

(-0.90, -0.34)

Basal insulin dose (IU/day) at

week 78

Baseline (mean)

47.84

45.13

48.43

Change from baseline

5.45

-1.21

-0.47

Difference from placebo

(97.5% CI)

-6.66**

(-11.56, -1.77)

-5.92**

(-11.00, -0.85)

1. Mean adjusted for baseline value and stratification

* p-value ≤0.0001; ** p-value <0.025

Empagliflozin as add on to DPP-4 inhibitor therapy

The efficacy and safety of empagliflozin as add on to DPP-4 inhibitors plus metformin, with or

without one additional oral anti-diabetic drug was evaluated in 160 patients with T2DM and

high cardiovascular risk. Treatment with empagliflozin for 28 weeks reduced Hb1Ac compared

to placebo (change from baseline -0.54% for empagliflozin 10 mg, -0.52% for empagliflozin 25

mg and -0.02% for placebo).

Patients with renal impairment, 52 weeks placebo controlled data

The efficacy and safety of empagliflozin as add on to anti-diabetic therapy was evaluated in

patients with mild and moderate renal impairment in a double-blind, placebo-controlled study

for 52 weeks.

Treatment with JARDIANCE led to statistically significant reduction of HbA

and clinically

meaningful improvement in FPG, body weight and BP compared to placebo at Week 24 (Table

15). The improvement in HbA

, FPG, body weight, and BP was sustained up to 52 weeks.

JARDIANCE NZ DS v05

Table 15 Results at 24 weeks (LOCF) in a placebo-controlled study of JARDIANCE in renally

impaired type 2 diabetes patients (Full Analysis Set)

eGFR ≥ 60 to <90mL/min/1.73m²

eGFR ≥30 to

<60mL/min/1.73m

2

Placebo

Empagliflozin

Placebo

Empagliflozin

25 mg

10 mg

25 mg

HbA

1c

(%)

Baseline (mean)

8.09

8.02

7.96

8.04

8.03

Change from baseline

0.06

-0.46

-0.63

0.05

-0.37

Difference from

placebo

(95% CI)

-0.52*

(-0.72, -0.32)

-0.68*

(-0.88, -0.49)

-0.42*

(-0.56, -0.28)

Patients (%) achieving

HbA

1c

<7% with

baseline HbA

1c

≥7%

17.0

24.2

12.0

Fasting plasma

glucose (mmol/L)

2

Baseline (mean)

8.04

8.10

8.24

7.98

7.92

Change from baseline

0.31

-0.77

-1.00

0.56

-0.51

Difference from

placebo

(95% CI)

-1.09

(-1.62, -0.55)

-1.32

(-1.86, -0.78)

-11.08*

(-1.51, -0.64)

Body Weight (kg)

Baseline (mean)

86.00

92.05

88.06

82.49

83.22

Change from baseline

-0.33

-1.76

-2.33

-0.08

-0.98

Difference from

placebo

(95% CI)

-1.43

(-2.09, -0.77)

-2.00

(-2.66, -1.34)

-0.91

(-1.41, -0.41)

Systolic blood

pressure (mmHg)

Baseline (mean)

134.69

137.37

133.68

136.38

136.64

Change from baseline

0.65

-2.92

-4.47

0.40

-3.88

Difference from

placebo

(95% CI)

-3.57

(-6.86, -0.29)

-5.12

(-8.41, -1.82)

-4.28

(-6.88, -1.68)

1. Mean adjusted for baseline value and stratification

2. Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints

* p<0.0001

Patients with high baseline HbA1c >10%

In a pre-specified pooled analysis of three phase 3 studies, treatment with open-label

empagliflozin 25 mg in patients with severe hyperglycaemia (N=184, mean baseline HbA

11.15%) resulted in a clinically meaningful reduction in HbA

from baseline (-3.27%) at week

Body weight

In a pre-specified pooled analysis of 4 placebo controlled studies, treatment with empagliflozin

resulted in body weight reduction compared to placebo at week 24 (-2.04 kg for empagliflozin

10 mg, -2.26 kg for empagliflozin 25 mg and -0.24 kg for placebo) that was maintained up to

week 52 (-1.96 kg for empagliflozin 10 mg, -2.25 kg for empagliflozin 25 mg and -0.16 kg for

placebo).

Waist circumference

At 24 weeks, treatment with empagliflozin as monotherapy or as add-on to metformin,

pioglitazone,

metformin

plus

sulfonylurea

resulted

sustained

reduction

waist

circumference over the duration of studies in a range of -1.7 cm to -0.9 cm for empagliflozin

and -0.5 cm to +0.2 cm for placebo.

JARDIANCE NZ DS v05

Blood pressure

The efficacy and safety of empagliflozin (10 mg or 25 mg) was evaluated in a double-blind,

placebo controlled study of 12 weeks duration in patients with T2DM and high BP on different

oral anti-diabetic drugs and up to 2 antihypertensive agents (Table 16). Treatment with

empagliflozin once daily resulted in statistically significant improvement in HbA

and reduction

in 24 hour mean SBP and DBP as determined by ambulatory BP monitoring. Treatment with

empagliflozin also provided reductions in seated SBP (change from baseline of -0.67 mmHg

for placebo, -4.60 mmHg for empagliflozin 10 mg and -5.47 mmHg for empagliflozin 25 mg)

and seated DBP (change from baseline of -1.13 mmHg for placebo, -3.06 mmHg for

empagliflozin 10 mg and -3.02 mmHg for empagliflozin 25 mg).

Table 16 Results at 12 weeks (LOCF)

in a placebo-controlled study of JARDIANCE in patients

with type 2 diabetes and uncontrolled blood pressure (Full Analysis Set)

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

HbA

1c

(%)

Baseline (mean)

7.90

7.87

7.92

Change from baseline

0.03

-0.59

-0.62

Difference from placebo

(95% CI)

-0.62* (-0.72, -0.52)

-0.65* (-0.75, -0.55)

24

hour

s

ystolic

blood

pressure

(mmHg)

Baseline (mean)

131.72

131.34

131.18

Change from baseline

0.48

-2.95

-3.68

Difference from placebo

(95% CI)

-3.44* (-4.78, -2.09)

-4.16* (-5.50, -2.83)

24

hour

d

iastolic

blood

pressure

(mmHg)

Baseline (mean)

75.16

75.13

74.64

Change from baseline

0.32

-1.04

-1.40

Difference from placebo

(95% CI)

-1.36** (-2.15, -0.56)

-1.72* (-2.51, -0.93)

1. Mean adjusted for baseline value and stratification

2. Last observation (prior to antihypertensive rescue) carried forward (LOCF)

3. Last observation (prior to glycaemic rescue) carried forward (LOCF)

* p-value <0.0001

** p-value = 0.0008

In a pre-specified pooled analysis of 4 placebo-controlled studies, treatment with empagliflozin

resulted in a reduction in SBP (-3.9 mmHg for empagliflozin 10 mg and -4.3 mmHg for

empagliflozin 25 mg) compared with placebo (-0.5 mmHg), and in DBP (-1.8 mmHg for

empagliflozin 10 mg and -2.0 mmHg for empagliflozin 25 mg) compared with placebo (-0.5

mmHg), at week 24, that were maintained up to week 52.

Laboratory parameters

Haematocrit increased

In a pooled safety analysis (pooling of all patients with diabetes, n=13,402), mean changes

from baseline in haematocrit were 3.4% and 3.6% for empagliflozin 10 mg and 25 mg,

respectively,

compared

-0.1%

placebo.

EMPA-REG

OUTCOME

study,

haematocrit values returned towards baseline values after a follow-up period of 30 days after

treatment stop.

Serum lipids increased

In a pooled safety analysis (pooling of all patients with diabetes, n=13,402), mean percent

increases from baseline for empagliflozin 10 mg and 25 mg versus placebo, respectively, were

total cholesterol 4.9% and 5.7% versus 3.5%; HDL-cholesterol 3.3% and 3.6% versus 0.4%;

LDL-cholesterol 9.5% and 10.0% versus 7.5%; triglycerides 9.2% and 9.9% versus 10.5%.

Cardiovascular outcome

The EMPA-REG OUTCOME study is a multi-centre, multi-national, randomised, double-blind,

placebo-controlled trial investigating the effect of JARDIANCE as adjunct to standard care

JARDIANCE NZ DS v05

therapy in reducing cardiovascular (CV) events in patients with type 2 diabetes and one or

more CV risk factors, including coronary artery disease, peripheral artery disease, history of

myocardial infarction (MI), or history of stroke. The primary endpoint was the time to first event

in the composite of CV death, nonfatal MI, or non-fatal stroke (Major Adverse Cardiovascular

Events (MACE-3)). Additional pre-specified endpoints addressing clinically relevant outcomes

tested in an exploratory manner included CV death, the composite of heart failure requiring

hospitalisation or CV death, all-cause mortality and the composite of new or worsening

nephropathy.

total

7020

patients

were

treated

with

JARDIANCE

(empagliflozin

2345,

empagliflozin 25 mg: 2342, placebo: 2333) and followed for a median of 3.1 years.

The population was 72.4% Caucasian, 21.6% Asian, and 5.1% Black. The mean age was 63

years and 71.5% were male. At baseline, approximately 81% of patients were being treated

with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 89% with

anticoagulants, and 81% with lipid lowering medication. Approximately 74% of patients were

being treated with metformin at baseline, 48% with insulin and 43% with sulfonylurea.

About half of the patients (52.2%) had an eGFR of 60-90 ml/min/1.73 m

, 17.8% of 45-60

mL/min/1.73 m

and 7.7% of 30-45 mL/min/1.73 m

. Mean systolic BP was 136 mmHg,

diastolic BP 76 mmHg, Low Density Lipoprotein 2.2 mmol/L, High Density Lipoprotein

1.1 mmol/L, and urinary albumin to creatinine ratio (UACR) 19.8 mg/mmol at baseline.

Reductions in risk of CV death and all-cause mortality

JARDIANCE was superior in reducing the primary composite endpoint of cardiovascular death,

non-fatal MI, or non-fatal stroke compared to placebo. The treatment effect reflected a

significant reduction in cardiovascular death with no significant change in non-fatal MI, or non-

fatal stroke (Table 17 and Figure 1).

JARDIANCE also improved overall survival (Table 17 and Figure 2), which was driven by a

reduction in cardiovascular death with JARDIANCE. There was no statistically significant

difference between empagliflozin and placebo in non-cardiovascular mortality.

Table 17 Treatment effect for the primary composite endpoint, its components and mortality

(Treated Set*)

Placebo

Empagliflozin

(10 and 25 mg, pooled)

2333

4687

Time to first occurrence of CV death,

nonfatal MI, or non-fatal stroke N (%)

282 (12.1)

490 (10.5)

Hazard ratio vs. placebo (95.02% CI)**

0.86 (0.74, 0.99)

p−value for superiority

0.0382

CV Death N (%)

137 (5.9)

172 (3.7)

Hazard ratio vs. placebo (95% CI)

0.62 (0.49, 0.77)

p-value

<0.0001

Non-fatal MI N (%)

121 (5.2)

213 (4.5)

Hazard ratio vs. placebo (95% CI)

0.87 (0.70, 1.09)

p−value

0.2189

Non-fatal stroke N (%)

60 (2.6)

150 (3.2)

Hazard ratio vs. placebo (95% CI)

1.24 (0.92, 1.67)

p−value

0.1638

All-cause mortality N (%)

194 (8.3)

269 (5.7)

Hazard ratio vs. placebo (95% CI)

0.68 (0.57, 0.82)

p-value

<0.0001

Non-CV mortality N (%)

57 (2.4)

97 (2.1)

Hazard ratio vs. placebo (95% CI)

0.84 (0.60, 1.16)

* i.e. patients who had received at least one dose of study drug

** Since data from the trial were included in an interim analysis, a two-sided 95.02% confidence interval applied which

corresponds to a p value of less than 0.0498 for significance.

JARDIANCE NZ DS v05

Figure 1 Time to occurrence of CV death

Figure 2 Time to occurrence of all-cause mortality*

*Kaplan-Meier estimate of time to all cause-mortality, pooled empagliflozin vs. placebo –treated set

Reductions in risk of heart failure requiring hospitalisation or CV death

JARDIANCE significantly reduced the risk of hospitalisation for heart failure and cardiovascular

death or hospitalisation for heart failure compared with placebo (Table 18 and Figure 3).

JARDIANCE NZ DS v05

Table 18 Treatment effect for hospitalisation for heart failure or cardiovascular death (excluding

fatal stroke) (Treated Set*)

Placebo

Empagliflozin **

(10 and 25 mg, pooled)

2333

4687

Heart failure requiring hospitalisation or CV

death (excluding fatal stroke) N (%)***

198 (8.5)

265 (5.7)

HR (95% CI)

0.66 (0.55, 0.79)

p−value

<0.0001

Heart failure requiring hospitalisation N (%)

95 (4.1)

126 (2.7)

HR (95% CI)

0.65 (0.50, 0.85)

p−value

0.0017

CV death (excluding fatal stroke) N (%)

126 (5.4)

156 (3.3)

HR (95% CI)

0.61 (048, 0.77)

p−value

<0.0001

*i.e. patients who had received at least one dose of study drug

**empagliflozin 10 mg and 25 mg showed consistent results

*** time to first event

Figure 3 Time to first occurrence of first heart failure hospitalisation or CV death*

*Estimated cumulative incidence function for time to first occurrence of first heart failure hospitalisation or CV death, pooled

empagliflozin vs placebo – treated set

The cardiovascular benefits of JARDIANCE observed were consistent across the subgroups

depicted in Figure 4.

JARDIANCE NZ DS v05

Figure 4 Subgroup analyses for CV death and hospitalisation for heart failure or CV death*,**

* Hospitalisation for heart failure or CV death excludes fatal stroke

**p-value is for test of homogeneity of treatment group difference among subgroups (test for group by covariate interaction) with

no adjustment for multiple tests and may not reflect the effect of a particular factor after adjustment for all other factors.

Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Diabetic kidney disease

In the EMPA-REG OUTCOME study population, the risk of new or worsening nephropathy

(defined as onset of macroalbuminuria, doubling of serum creatinine, and initiation of renal

replacement therapy (i.e. haemodialysis)) was significantly reduced in empagliflozin group

compared to placebo (Table 19 and Figure 5).

JARDIANCE compared with placebo showed a significantly higher occurrence of sustained

normo- or microalbuminuria in patients with baseline macroalbuminuria (HR 1.82, 95% CI 1.40,

2.37).

JARDIANCE NZ DS v05

Table 19 Time to first new or worsening of nephropathy (Treated Set*)

Placebo

Empagliflozin

(10 and 25 mg, pooled)

2061

4124

New or worsening nephropathy N (%)

388 (18.8)

525 (12.7)

HR (95% CI)

0.61 (0.53, 0.70)

p−value <0.0001

<0.0001

2323

4645

Doubling of serum creatinine level**N (%)

60 (2.6)

70 (1.5)

HR (95% CI)

0.56 (0.39, 0.79

p−value

0.0009

2033

4091

New onset of macroalbuminuria*** N (%)

330 (16.2)

459 (11.2)

HR (95% CI)

0.62 (0.54, 0.72)

p−value

<0.0001

2333

4687

Initiation of continuous renal replacement

therapy N (%)

14 (0.6)

13 (0.3)

HR (95% CI)

0.45 (0.21, 0.97)

p−value

0.0409

2333

4687

Death due to renal disease N (%)****

3 (0.1)

*i.e. patients who had received at least one dose of study drug

**Accompanied by an eGFR ≤45 mL/min/1.73m

*** Urine Albumin Creatinine Ratio >33.9 mg/mmol

**** Due to low event rate, HR not calculated

Figure 5 Time to first new or worsening of nephropathy

Treatment with empagliflozin preserved eGFR and eGFR increased during the post treatment

4-week follow up. However, the placebo group showed a gradual decline in GFR during the

course of the study with no further change during 4-week follow up (see Figure 6).

JARDIANCE NZ DS v05

Figure 6 eGFR over time*

*eGFR (MDRD) (mL/min/1.73m

) MMRM results over time, unadjusted last value on treatment and follow-up value - treated set

– right side based on patients with available last value on treatment (LVOT) and follow-up (FU).

Thorough QTc study

a randomised,

placebo-controlled,

active-comparator,

crossover

study

healthy

subjects no increase in QTc was observed with either 25 mg or 200 mg empagliflozin.

5.2. Pharmacokinetic properties

Absorption

pharmacokinetics of

empagliflozin

have

been

extensively

characterised

healthy

volunteers and patients with T2DM. After oral administration, empagliflozin was rapidly

absorbed with peak plasma concentrations (C

) with a median time to reach C

) of

1.5 h post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid

distribution phase and a relatively slow terminal phase. The steady state mean plasma area

under the curve (AUC) was 4740 nmol·h/L and C

was 687 nmol/L with 25 mg empagliflozin

once daily. Systemic exposure of empagliflozin increased in a dose-proportional manner. The

single-dose and steady-state pharmacokinetics parameters of empagliflozin were similar

suggesting linear pharmacokinetics with respect to time. There were no clinically relevant

differences in empagliflozin pharmacokinetics between healthy volunteers and patients with

T2DM.

Administration of 25 mg empagliflozin after intake of a high-fat and high calorie meal resulted

in slightly lower exposure; AUC decreased by approximately 16% and C

decreased by

approximately

37%,

compared

fasted

condition.

observed

effect

food

empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may

be administered with or without food.

JARDIANCE NZ DS v05

Distribution

The apparent steady-state volume of distribution was estimated to be 73.8 L, based on a

population pharmacokinetic analysis.

Following administration of an oral [

C]-empagliflozin solution to healthy subjects, the red

blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.

Biotransformation

No major metabolites of empagliflozin were detected in human plasma and the most abundant

metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic

exposure of each metabolite was less than 10% of total drug-related material. In vitro studies

suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation

uridine

5'-diphospho-glucuronosyltransferases

UGT2B7,

UGT1A3,

UGT1A8,

UGT1A9.

Elimination

The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and

apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. The

inter-subject and residual variabilities for empagliflozin oral clearance were 39.1% and 35.8%,

respectively. With once-daily dosing, steady-state plasma concentrations of empagliflozin were

reached by the fifth dose. Consistent with half-life, up to 22% accumulation, with respect to

plasma AUC, was observed at steady-state. Following administration of an oral [

empagliflozin solution to healthy subjects, approximately 95.6% of the drug related radioactivity

was eliminated in faeces (41.2%) or urine (54.4%). The majority of drug related radioactivity

recovered in faeces was unchanged parent drug and approximately half of drug related

radioactivity excreted in urine was unchanged parent drug.

Special populations

Renal impairment

patients

with

mild

(eGFR:

60 - < 90

mL/min/1.73m

moderate

(eGFR:

30 - < 60 mL/min/1.73 m

), severe (eGFR: <30 mL/min/1.73 m

) renal impairment and patients

with kidney failure/end stage renal disease (ESRD) patients, AUC of empagliflozin increased

by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal

renal function. Peak plasma levels of empagliflozin were similar in subjects with moderate renal

impairment and kidney failure/ESRD compared to patients with normal renal function. Peak

plasma levels of empagliflozin were roughly 20% higher in subjects with mild and severe renal

impairment as compared to subjects with normal renal function. In line with the Phase I study,

population

pharmacokinetic

analysis

showed

that

apparent

oral

clearance

empagliflozin decreased with a decrease in eGFR leading to an increase in drug exposure.

Based on pharmacokinetics, no dosage adjustment is recommended in patients with renal

insufficiency.

Hepatic impairment

In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh

classification, AUC of empagliflozin increased approximately by 23%, 47%, and 75% and C

by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic

function. Based on pharmacokinetics, no dosage adjustment is recommended in patients with

hepatic impairment.

Body Mass Index (BMI)

No dosage adjustment is necessary based on BMI. Body mass index had no clinically relevant

effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic

analysis.

Gender

No dosage adjustment is necessary based on gender. Gender had no clinically relevant effect

on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.

JARDIANCE NZ DS v05

Race

No dosage adjustment is necessary based on race. Based on the population pharmacokinetic

analysis, AUC was estimated to be 13.5% higher in Asian patients with a BMI of 25 kg/m

compared to non-Asian patients with a BMI of 25 kg/m

Elderly

Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based

on the population pharmacokinetic analysis.

Paediatric population

Studies characterising the pharmacokinetics of empagliflozin in paediatric patients have not

been performed.

5.3. Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, genotoxicity, fertility and early embryonic development.

Carcinogenicity

Two-year oral carcinogenicity studies were conducted in mice and rats. There was an increase

in renal adenomas and carcinomas in male mice given empagliflozin at 1000 mg/kg/day. No

renal tumours were seen at 300 mg/kg/day (11- and 28-times the exposure at the clinical dose

of 25mg and 10 mg, respectively). These tumours are likely associated with a metabolic

pathway not present in humans, and are considered to be irrelevant to patients given 10 or 25

mg empagliflozin. No drug-related tumours were seen in female mice or female rates at doses

up to 1000 and 700 mg/kg/day, respectively, resulting in exposures at least 60 times that

expected at the clinical dose of 10 or 25 mg empagliflozin. In male rats, treatment-related

benign vascular proliferative lesions (haemangiomas) of the mesenteric lymph node, were

observed at 700 mg/kg/day, but not at 300 mg/kg/day (approximately 26- and 65-times the

exposure at the clinical does of 25 mg and 10 mg, respectively). These tumours are common

in rats and are unlikely to be relevant to humans.

Genotoxicity

Empagliflozin was not mutagenic or clastogenic in a battery of genotoxicity studies, including

the Ames bacterial mutagenicity assay (bacterial reverse mutation), in vitro mouse lymphoma

tk assays and in vivo rat bone marrow micronucleus assays.

Reproduction toxicity

Nonclinical studies show that empagliflozin crosses the placenta during late gestation to a very

limited extent but do not indicate direct or indirect harmful effects with respect to early

embryonic development. Empagliflozin administered during the period of organogenesis was

not teratogenic at doses up to 300 mg/kg in the rat or rabbit, which corresponds to

approximately 48- and 122- times or 128- and 325- times the clinical dose of empagliflozin

based on AUC exposure associated with the 25 mg and 10 mg doses, respectively. Doses of

empagliflozin causing maternal toxicity in the rat also caused the malformation of bent limb

bones at exposures approximately 155- and 393- times the clinical dose associated with the

25 mg and 10 mg doses, respectively. Maternally toxic doses in the rabbit also caused

increased embryo-foetal loss at doses approximately 139- and 353- times the clinical dose

associated with the 25 mg and 10 mg doses, respectively.

In pre- and postnatal toxicity studies in rats, reduced weight gain in offspring was observed at

maternal exposures approximately 4- and 11-times the clinical dose associated with the 25 mg

and 10 mg doses, respectively.

In a juvenile toxicity study in the rat, when empagliflozin was administered from postnatal day

21 until postnatal day 90, non-adverse, minimal to mild renal tubular and pelvic dilation in

juvenile rats was seen only at 100 mg/kg/day, which approximates 11-times the maximum

clinical dose of 25 mg. These findings were absent after a 13 weeks drug-free recovery period.

JARDIANCE NZ DS v05

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Tablet core

Colloidal silicon dioxide

Croscarmellose sodium

Hyprolose

Lactose monohydrate

Magnesium stearate

Microcrystalline cellulose.

Film coating

Hypromellose

Titanium dioxide (E171)

Talc

Macrogol 400

Iron oxide yellow (E172)

6.2. Incompatibilities

Not applicable

6.3. Shelf life

36 months.

6.4. Special precautions for storage

Store at or below 30°C. Protect from light.

6.5. Nature and contents of container

PVC/ aluminium perforated unit dose blisters.

Pack size of 10 (sample) or 30 film coated tablets.

Note: not all pack sizes may be available.

6.6. Special precautions for disposal

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

7. MEDICINE SCHEDULE

Prescription Medicine

8. SPONSOR

Boehringer Ingelheim (N.Z.) Limited

P.O. Box 76-216

Manukau City

Auckland

NEW ZEALAND

Telephone 0800 802 461

JARDIANCE NZ DS v05

9. DATE OF FIRST APPROVAL

23 April 2015

10. DATE OF REVISION OF THE TEXT

04 December 2019

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Update to subsection Diabetic ketoacidosis

Minor editorial changes

Similar products

Search alerts related to this product

View documents history

Share this information