Consumer medicine information

Jardiamet

Empagliflozin; Metformin hydrochloride

BRAND INFORMATION

Brand name

Jardiamet

Active ingredient

Empagliflozin; Metformin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Jardiamet.

What is in this leaflet

This leaflet answers some common questions about Jardiamet.

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 Jardiamet 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.medicines.org.au 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 Jardiamet is used for

Jardiamet 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:
    - sulfonylurea
    - pioglitazone
    - insulin
    - linagliptin.

If you have type 2 diabetes mellitus and cardiovascular disease, empagliflozin (one of the active ingredients in Jardiamet) 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 Jardiamet works

Jardiamet contains two different active ingredients:

  • empagliflozin, which belongs to a group of medicines called SGLT2 (sodium-glucose co-transporter 2) inhibitors, and
  • metformin, which belongs to a class of medicines called biguanides.

Both medicines work together to control blood sugar levels in patients with type 2 diabetes mellitus by increasing the amount of glucose expelled in urine, and lowering the amount of sugar made by your body.

Lowering and controlling blood sugar may help prevent or delay complications of diabetes, such as heart disease, kidney disease, blindness and foot amputation.

Along with diet and exercise, this medicine helps lower your blood sugar.

Your doctor may have prescribed Jardiamet to replace the anti-diabetic medicine(s) you are currently taking. It is important that you continue to follow the diet and/or exercises recommended for you while you are on treatment with Jardiamet.

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.

This medicine is available only with a doctor's prescription. It is not addictive.

Before you take Jardiamet

When you must not take it

Do not take Jardiamet if you have an allergy to:

  • any medicine containing empagliflozin or metformin (the active ingredients in Jardiamet)
  • any of the other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

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

Do not take Jardiamet if you:

  • have any type of metabolic acidosis such as lactic acidosis, diabetic ketoacidosis (a symptom of uncontrolled diabetes, in which substances called ketone bodies build up in the blood - you may notice this as an unusual fruity odour on your breath, difficulty breathing, confusion and frequent urination).
  • have had a diabetic pre-coma
  • have problems with your kidneys
  • have problems with your liver
  • have a severe infection
  • are dehydrated
  • are treated for acute heart failure or have recently had a heart attack
  • have severe problems with your circulation (such as shock)
  • have severe breathing difficulties
  • have blood clots in the lungs (symptoms include coughing, shortness of breath, chest pain and a fast heart rate)
  • have significant blood loss
  • have gangrene
  • have inflammation of the pancreas (pancreatitis), symptoms include severe upper stomach pain, often with nausea and vomiting
  • drink excessive alcohol (all the time or “binge” drinking).

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

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

Do not take this medicine if you are pregnant or intending to become pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine. Metformin, one of the active ingredients in Jardiamet passes into human breast milk and could affect your baby. It is not known whether the active ingredient, empagliflozin passes into human breast milk.

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

Discard any other medicines containing metformin or empagliflozin that your doctor might have prescribed to you in the past and that you may still have in your possession. Jardiamet contains empagliflozin and metformin. If you have more than one metformin-containing medicine in your possession you may accidentally take too much (overdose). Accidentally taking too much metformin can cause a very serious side effect called lactic acidosis.

ACCIDENTAL METFORMIN OVERDOSING IS A SIGNIFICANT SAFETY RISK.

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

Metformin is sold under many different brand names in Australia.

Your doctor or pharmacist will know which other medicines also contain metformin.

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

Tell your doctor if you have type 1 diabetes, a condition where your body does not produce insulin. Jardiamet should not be used to treat type 1 diabetes.

Tell your doctor if you are sick, have diarrhoea or fever, or if you are not able to eat or drink. These conditions can cause dehydration. Your doctor may ask you to stop taking Jardiamet until you recover to prevent loss of too much body fluid.

Tell your doctor if you have a serious infection of the kidney or the urinary tract with fever. Your doctor may ask you to stop taking Jardiamet until you have recovered.

Tell your doctor if you have heart problems, 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 Jardiamet 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 Jardiamet.

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 Jardiamet may interfere with each other. These include:

  • an antibiotic medicine used to treat certain infections such as tuberculosis (rifampicin)
  • a medicine used to treat reflux and ulcers (cimetidine)
  • medicines used to treat diseases that involve inflammation, like asthma and arthritis (corticosteroids)
  • specific medicines for the treatment of high blood pressure (ACE inhibitors, calcium channel blockers, beta blockers)
  • medicines used to prevent blood clots, such as warfarin
  • medicines which increase urine production (diuretics)
  • some medicines used to treat asthma (salbutamol or terbutaline)
  • medicines used to relieve pain, swelling and other symptoms of inflammation, called NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin, diclofenac, ibuprofen, meloxicam, naproxen or piroxicam
  • iodinated contrast agents (which you may receive while having an X-ray)
  • alcohol-containing medicines
  • a medicine used in people with multiple sclerosis, and in young children to treat some types of seizures (fits) (tetracosactrin)
  • a medicine used to treat endometriosis (danazol)
  • a medicine used to treat schizophrenia and other mental illnesses (chlorpromazine)
  • medicines used in the treatment of HIV and chronic hepatitis C infections (dolutegravir, daclatasvir)
  • medicines used in the treatment of certain cancers (crizotinib, olaparib, vandetanib)
  • medicines used to control fits (seizures), chronic pain or glaucoma (topiramate, zonisamide, acetazolamide, dichlorphenamide).

These medicines may be affected by Jardiamet or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor, pharmacist or diabetes educator can tell you what to do if you are taking any of these medicines. They also have more information on medicines to be careful with or avoid while taking this medicine.

How to take Jardiamet

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

Your doctor will tell you how many Jardiamet tablets to take and how often you should take them.

The usual dose is one Jardiamet tablet twice daily.

Take Jardiamet exactly as your doctor or pharmacist has told you.

How to take it

Swallow the tablets whole with a full glass of water during or after meals. This will lessen the chance of a stomach upset.

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.

How long to take it

It is important that you take Jardiamet every day.

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does 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 almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

Do not take a double dose to make up for the dose that you missed. 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 Poisons Information Centre (telephone 13 11 26) for advice, or go to Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Jardiamet. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Jardiamet

Things you must do

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

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Talk to your doctor about when to stop taking Jardiamet and when to start taking it again if you are about to have surgery or an examination such as an X-ray or scan requiring an injection of iodinated contrast (dye).

If you are intending to become pregnant or are pregnant talk to your doctor about alternative medications to control your blood glucose level. It is important your blood glucose levels are as close to normal as possible at this time.

If you are about to have any blood 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 want to perform blood tests to check your kidneys and vitamin B12 levels while you are taking Jardiamet.

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 Jardiamet.

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.

Tell your doctor if you become ill or dehydrated, or experience stress, injury, fever, infection, or need surgery. Your blood glucose may become difficult to control at these times. You may also be at greater risk of developing a serious condition called lactic acidosis or diabetic ketoacidosis. During these times, your doctor may temporarily replace Jardiamet with insulin.

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

HYPOGLYCAEMIA

Jardiamet does not normally cause hypoglycaemia, although you may experience it if you take certain other medicines.

Signs of hypoglycaemia may include:

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

If not treated quickly, these symptoms may progress to:

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

At the first signs of hypoglycaemia, you need to raise your blood glucose quickly.

You can do this by taking one of the following:

  • 5-7 jelly beans
  • 3 teaspoons of sugar or honey
  • half a can of non-diet soft drink
  • 2-3 concentrated glucose tablets.

Unless you are within 10 to 15 minutes of your next meal or snack, follow up with extra carbohydrates such as plain biscuits, fruit or milk. Taking this extra carbohydrate will prevent a second drop in your blood glucose level.

HYPERGLYCAEMIA

If you notice the return of any signs of hyperglycaemia, contact your doctor immediately. The risk of hyperglycaemia is increased in the following situations:

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

Things you must not do

Do not take Jardiamet 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 Jardiamet 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, lightheadedness, 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 Jardiamet.

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.

If you take Jardiamet, you may be at a greater risk of genital infections and urinary tract infections.

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
  • loss in appetite
  • loss of taste
  • thirst
  • diarrhoea or stomach ache
  • feeling sick (nausea), vomiting.

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 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 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 Jardiamet.

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 Jardiamet.

Tell your doctor immediately if you experience swelling of the penis that makes it difficult to pull back the skin around the tip of the penis (uncircumcised men).

Tell your doctor immediately or go to Emergency if you notice any of the following:

  • sudden onset of hives, itching or skin rash
  • swelling of the face, lips or tongue which may lead to difficulty swallowing or breathing.

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, one of the active substances in Jardiamet can cause a serious side effect called diabetic ketoacidosis.

Stop taking Jardiamet if you get any of the following symptoms of lactic acidosis and go to Emergency immediately:

  • feeling cold (especially in your arms and legs)
  • feeling very weak, tired
  • feeling light-headed, dizzy
  • severe nausea or vomiting
  • feeling uncomfortable
  • muscle pain
  • drowsiness
  • abdominal pain
  • unexplained weight loss
  • irregular heartbeat
  • rapid or difficult breathing.

In rare cases, metformin, one of the active substances in Jardiamet can cause a serious side effect called lactic acidosis.

This is a medical emergency that can cause death. It is caused by build-up of lactic acid in your blood.

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 Jardiamet

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 Jardiamet 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

  • Jardiamet 5 mg/500 mg tablets are orange yellow, oval, biconvex film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol and "S5" the other side is debossed with "500".
  • Jardiamet 5 mg/850 mg tablets are yellowish white, oval, biconvex film-coated tablets. One side is debossed with Boehringer Ingelheim company symbol and "S5", the other side is debossed with "850".*
  • Jardiamet 5 mg/1000 mg tablets are brownish yellow, oval, biconvex film-coated tablets. One side is debossed with Boehringer Ingelheim company symbol and "S5", the other side is debossed with "1000".
  • Jardiamet 12.5 mg/500 mg tablets pale brownish purple, oval, biconvex film-coated tablets. One side is debossed with Boehringer Ingelheim company symbol and "S12", the other side is debossed with "500".
  • Jardiamet 12.5 mg/850 mg tablets are pinkish white, oval, biconvex film-coated tablets. One side is debossed with Boehringer Ingelheim company symbol and "S12", the other side is debossed with "850".*
  • Jardiamet 12.5 mg/1000 mg tablets are dark brownish purple, oval, biconvex film-coated tablets. One side is debossed with Boehringer Ingelheim company symbol and "S12", the other side is debossed with "1000".

Jardiamet is available in blister packs containing 14 (sample) and 60 tablets.

* Not distributed in Australia.

Ingredients

Each Jardiamet 5 mg/500 mg tablet contains 5 mg empagliflozin and 500 mg metformin hydrochloride.

Each Jardiamet 5 mg/850 mg tablet contains 5 mg empagliflozin and 850 mg metformin hydrochloride.

Each Jardiamet 5 mg/1000 mg tablet contains 5 mg empagliflozin and 1000 mg metformin hydrochloride.

Each Jardiamet 12.5 mg/500 mg tablet contains 12.5 mg empagliflozin and 500 mg metformin hydrochloride.

Each Jardiamet 12.5 mg/850 mg tablet contains 12.5 mg empagliflozin and 850 mg metformin hydrochloride.

Each Jardiamet 12.5 mg/1000 mg tablet contains 12.5 mg empagliflozin and 1000 mg metformin hydrochloride.

Inactive ingredients:

  • copovidone
  • maize starch
  • colloidal anhydrous silica
  • magnesium stearate.

Tablet coating:

  • hypromellose
  • titanium dioxide
  • macrogol 400
  • purified talc
  • iron oxide yellow (5 mg/500 mg, 5 mg/850 mg, 5 mg/1000 mg tablets)
  • iron oxide black (12.5 mg/500 mg, 12.5 mg/850 mg, 12.5 mg/1000 mg tablets)
  • iron oxide red (12.5 mg/500 mg, 12.5 mg/850 mg, 12.5 mg/1000 mg tablets).

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Jardiamet is supplied in Australia by:

Boehringer Ingelheim Pty Limited
ABN 52 000 452 308
Sydney NSW
www.boehringer-ingelheim.com.au

This Consumer Medicine Information was updated in March 2020.

® Jardiamet is a registered trade mark of Boehringer Ingelheim.

© Boehringer Ingelheim Pty Limited 2020.

Australian Registration Numbers

Jardiamet 5 mg/500 mg
(AUST R 229815)

Jardiamet 5 mg/850 mg
(AUST R 229816)

Jardiamet 5 mg/1000 mg
(AUST R 229817)

Jardiamet 12.5 mg/500 mg
(AUST R 229818)

Jardiamet 12.5 mg/850 mg
(AUST R 229819)

Jardiamet 12.5 mg/1000 mg
(AUST R 229820)

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Jardiamet

Active ingredient

Empagliflozin; Metformin hydrochloride

Schedule

S4

 

1 Name of Medicine

Empagliflozin and metformin hydrochloride.

6.7 Physicochemical Properties

Empagliflozin is a white to yellowish powder. It is very slightly soluble in water, slightly soluble in acetonitrile and ethanol, sparingly soluble in methanol and practically insoluble in toluene. Empagliflozin is not hygroscopic and no polymorphism has been observed. It is neither a hydrate nor a solvate. Partition coefficient: log P = log D (pH 7.4): 1.7.
Metformin hydrochloride is a white to off-white crystalline compound. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Chemical structure.

Jardiamet contains two oral antihyperglycaemic drugs used in the management of type 2 diabetes mellitus: empagliflozin (a SGLT2 inhibitor) and metformin hydrochloride.

Empagliflozin.

Chemical name: (1S)-1,5-anhydro-1-(4-chloro-3- {4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}phenyl)-D-glucitol.
Molecular formula: C23H27ClO7.
Molecular weight: 450.91.
Structural formula:

Metformin hydrochloride.

Chemical name: 1,1-dimethylbiguanide hydrochloride.
Molecular formula: C4H11N5.HCl.
Molecular weight: 165.63.
Structural formula:

CAS number.

Empagliflozin.

864070-44-0.

Metformin hydrochloride.

1115-70-4.

2 Qualitative and Quantitative Composition

Jardiamet 5 mg/500 mg contains 5 mg empagliflozin and 500 mg metformin hydrochloride;
Jardiamet 5 mg/850 mg contains 5 mg empagliflozin and 850 mg metformin hydrochloride;
Jardiamet 5 mg/1000 mg contains 5 mg empagliflozin and 1000 mg metformin hydrochloride;
Jardiamet 12.5 mg/500 mg contains 12.5 mg empagliflozin and 500 mg metformin hydrochloride;
Jardiamet 12.5 mg/850 mg contains 12.5 mg empagliflozin and 850 mg metformin hydrochloride;
Jardiamet 12.5 mg/1000 mg contains 12.5 mg empagliflozin and 1000 mg metformin hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Jardiamet are film-coated tablets for oral administration and are available in six strengths:
Jardiamet 5 mg/500 mg - orange yellow, oval, biconvex film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol and "S5" the other side is debossed with "500".
Jardiamet 5 mg/850 mg* - yellowish white, oval, biconvex film-coated tablets. One side is debossed with Boehringer Ingelheim company symbol and "S5", the other side is debossed with "850".
Jardiamet 5 mg/1000 mg - brownish yellow, oval, biconvex film-coated tablets. One side is debossed with Boehringer Ingelheim company symbol and "S5", the other side is debossed with "1000".
Jardiamet 12.5 mg/500 mg - pale brownish purple, oval, biconvex film-coated tablets. One side is debossed with Boehringer Ingelheim company symbol and "S12", the other side is debossed with "500".
Jardiamet 12.5 mg/850 mg* - pinkish white, oval, biconvex film-coated tablets. One side is debossed with Boehringer Ingelheim company symbol and "S12", the other side is debossed with "850".
Jardiamet 12.5 mg/1000 mg - dark brownish purple, oval, biconvex film-coated tablets. One side is debossed with Boehringer Ingelheim company symbol and "S12", the other side is debossed with "1000".
* Not currently distributed in Australia.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Combinations of oral blood glucose lowering drugs, ATC code: A10BD20.

Mechanism of action.

Empagliflozin.

Empagliflozin is a reversible competitive inhibitor of SGLT2 with an IC50 of 1.3 nanoM. It has a 5000-fold selectivity over human SGLT1 (IC50 of 6278 nanoM), 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 25 mg empagliflozin once daily. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with T2DM.
Empagliflozin improves both fasting and post-prandial plasma glucose levels.
The insulin independent mechanism of action of empagliflozin contributes to a low risk of hypoglycaemia.
The effect of empagliflozin in lowering blood glucose is independent of beta cell function and insulin pathway. 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).

Metformin hydrochloride.

Metformin hydrochloride is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin hydrochloride may act via 3 mechanisms:
1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis;
2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation;
3) and delay of intestinal glucose absorption.
Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin hydrochloride increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.
In humans, independently of its action on glycaemia, metformin hydrochloride has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium or long-term clinical studies: metformin hydrochloride reduces total cholesterol, LDL cholesterol and triglyceride levels.

Clinical trials.

A total of 10,224 patients with type 2 diabetes were treated in 9 double-blind, placebo or active-controlled clinical studies, of at least 24 weeks duration, of which 2947 patients received empagliflozin 10 mg and 3703 received empagliflozin 25 mg as add-on to metformin therapy.
Treatment with empagliflozin in combination with metformin with or without other background (pioglitazone, sulfonylurea, DPP-4 inhibitors, and insulin) led to clinically relevant improvements in HbA1c, fasting plasma glucose (FPG), body weight, systolic and diastolic blood pressure (BP). Administration of empagliflozin 25 mg resulted in a higher proportion of patients achieving HbA1c goal of < 7% and fewer patients needing glycaemic rescue compared to empagliflozin 10 mg and placebo. There was a clinically meaningful improvement in HbA1c in all subgroups of gender, race, geographic region, time since diagnosis of type 2 diabetes mellitus (T2DM) and body mass index (BMI). In patients aged 75 years and older, numerically lower reductions in HbA1c were observed with empagliflozin treatment. Higher baseline HbA1c was associated with a greater reduction in HbA1c. Empagliflozin in combination with metformin in drug-naïve patients led to clinically meaningful reductions in HbA1c, FPG, body weight and BP.

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 not sufficiently treated with metformin.
Treatment with empagliflozin resulted in statistically significant improvements in HbA1c and body weight, and clinically meaningful reductions in FPG and BP compared to placebo (Table 3).
In the double-blind placebo-controlled extension of this study, reductions of HbA1c (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 (systolic BP: change from baseline of -5.2 mmHg for empagliflozin 10 mg, -4.5 mmHg for empagliflozin 25 mg and -0.8 mmHg for placebo, diastolic BP: 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 Week 76.

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. The majority of patients had been diagnosed with diabetes for up to a year (55.8%) or for between one and five years (28.6%). Their mean age was 52.6 years and mean BMI was 30.37 kg/m2. 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 HbA1c and led to significantly greater reductions in FPG and body weight compared to the individual components. A greater proportion of patients with a baseline HbA1c ≥ 7.0% and treated with empagliflozin in combination with metformin achieved a target HbA1c < 7% compared to the individual components (Tables 4 and 5).

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. Treatment with empagliflozin resulted in statistically significant improvements in HbA1c and body weight and clinically meaningful reductions in FPG and BP compared to placebo (Table 6).
In the double-blind placebo-controlled extension of this study, reductions of HbA1c (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 25 mg and -0.63 kg for placebo) and BP (systolic BP: change from baseline of -3.8 mmHg for empagliflozin 10 mg, -3.7 mmHg for empagliflozin 25 mg and -1.6 mmHg for placebo, diastolic BP: 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 Week 76.

2 hour post-prandial glucose.

Treatment with empagliflozin 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), -2.48 mmol/L for empagliflozin 25 mg (n=58), 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), -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 in combination with pioglitazone, with or without metformin (75.5% of all patients were on metformin background) was evaluated in a double-blind, placebo-controlled study of 24 weeks duration. Empagliflozin in combination with pioglitazone (mean dose ≥ 30 mg) with or without metformin resulted in statistically significant reductions in HbA1c, fasting plasma glucose, and body weight and clinically meaningful reductions in BP compared to placebo (Table 7).
In the double-blind placebo-controlled extension of this study, reductions of HbA1c (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 (systolic BP: change from baseline of -1.7 mmHg for empagliflozin 10 mg, -3.4 mmHg for empagliflozin 25 mg and +0.3 mmHg for placebo, diastolic BP: change from baseline of -1.43 mmHg for empagliflozin 10 mg, -2.0 mmHg for empagliflozin 25 mg and +0.2 mmHg for placebo) were sustained up to Week 76.

Empagliflozin and linagliptin as add on therapy to metformin.

In a factorial design study, patients inadequately controlled on metformin, 24 weeks treatment with both doses of empagliflozin 10 mg and 25 mg administered together with linagliptin 5 mg provided statistically significant improvements in HbA1c and FPG compared to linagliptin 5 mg and also compared to empagliflozin 10 or 25 mg. Compared to linagliptin 5 mg, both doses of empagliflozin plus linagliptin 5 mg provided statistically significant reductions in body weight and blood pressure. A greater proportion of patients with a baseline HbA1c ≥ 7.0% and treated with empagliflozin plus linagliptin achieved a target HbA1c of < 7% compared to linagliptin 5 mg (Table 8).
After 24 weeks' treatment with empagliflozin + linagliptin, both systolic and diastolic blood pressures were reduced, -5.6/-3.6 mmHg (p < 0.001 versus linagliptin 5 mg for SBP and DBP) for empagliflozin 25 mg + linagliptin 5 mg and -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 blood pressure were maintained for 52 weeks, -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.
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.

Empagliflozin in patients inadequately controlled on metformin and linagliptin.

In patients inadequately controlled on metformin and linagliptin 5 mg, 24 weeks treatment with both empagliflozin/linagliptin 10 mg/5 mg and empagliflozin/linagliptin 25 mg/5 mg provided statistically significant improvements in HbA1c, FPG and body weight compared to placebo + linagliptin 5 mg. A statistically significantly greater number of patients with a baseline HbA1c ≥ 7.0% and treated with both doses of empagliflozin achieved a target HbA1c of < 7% compared to placebo + linagliptin 5 mg (Table 9). After 24 weeks' treatment with empagliflozin, both systolic and diastolic blood pressures were reduced, -2.6/-1.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 25 mg + linagliptin 5 mg and -1.3/-0.1 mmHg (n.s. versus placebo for SBP and 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 + linagliptin 5 mg.
In a prespecified subgroup of patients with baseline HbA1c greater or equal than 8.5% the reduction from baseline in HbA1c with empagliflozin 25 mg + linagliptin 5 mg was -1.3% at 24 weeks (p < 0.0001 versus placebo + linagliptin 5 mg) and with empagliflozin 10 mg + linagliptin 5 mg -1.3% at 24 weeks (p < 0.0001 versus placebo + 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 daily resulted in superior reduction in HbA1c, and a clinically meaningful reduction in FPG, compared to glimepiride (Table 10). Empagliflozin daily resulted in a statistically significant reduction in body weight, systolic and diastolic BP (change from baseline in diastolic BP of -1.8 mmHg for empagliflozin and +0.9 mmHg for glimepiride, p < 0.0001).
Treatment with empagliflozin resulted in statistically significantly lower proportion of patients with hypoglycaemic events compared to glimepiride (2.5% for empagliflozin, 24.2% for glimepiride, p < 0.0001).

Empagliflozin as add on to basal insulin therapy.

The efficacy and safety of empagliflozin as add-on to basal insulin with or without concomitant metformin and/or sulfonylurea therapy (79.8% of all patients were on metformin background) was evaluated in a double-blind, placebo-controlled trial of 78 weeks duration. 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 provided statistically significant improvement in HbA1c compared to placebo. A greater proportion of patients with a baseline HbA1c ≥ 7.0% achieved a target HbA1c of < 7% compared to placebo. At 78 weeks, empagliflozin resulted in a statistically significant decrease in HbA1c and insulin sparing compared to placebo (Table 11).
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 (systolic BP: -4.1 mmHg for empagliflozin 10 mg, -2.4 mmHg for empagliflozin 25 mg and 0.1 mmHg for placebo, diastolic BP: -2.9 mmHg for empagliflozin 10 mg, -1.5 mmHg for empagliflozin 25 mg and -0.3 mmHg for placebo).

Empagliflozin as add on to MDI 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 kept stable, but was adjusted to achieve preprandial 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 HbA1c compared with placebo (Table 12). A greater proportion of patients with a baseline HbA1c ≥ 7.0% (19.5% empagliflozin 10 mg, 31.0% empagliflozin 25 mg) achieved a target HbA1c of < 7% compared with placebo (15.1%).
At Week 52, treatment with empagliflozin resulted in a statistically significant decrease in HbA1c 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 BP (systolic BP: change from baseline of -2.6 mmHg for placebo, -3.9 mmHg for empagliflozin 10 mg and -4.0 mmHg for empagliflozin 25 mg, diastolic BP: change from baseline of -1.0 mmHg for placebo, -1.4 mmHg for empagliflozin 10 mg and -2.6 mmHg for empagliflozin 25 mg).

Empagliflozin twice daily versus once daily as add on to metformin therapy.

The efficacy and safety of empagliflozin twice daily versus once daily (daily dose of 10 mg and 25 mg) as add-on therapy in patients with insufficient glycaemic control on metformin monotherapy was evaluated in a double blind placebo-controlled study of 16 weeks duration. All treatments with empagliflozin resulted in significant reductions in HbA1c from baseline (total mean 7.8%) after 16 weeks of treatment compared with placebo. Empagliflozin twice daily dose regimens led to comparable reductions in HbA1c versus once daily dose regimens with a treatment difference in HbA1c reductions from baseline to week 16 of -0.02% (95% CI -0.16, 0.13) for empagliflozin 5 mg twice daily vs. 10 mg once daily, and -0.11% (95% CI -0.26, 0.03) for empagliflozin 12.5 mg twice daily vs. 25 mg once daily.

Patients with baseline HbA1c ≥ 9%.

In a pre-specified analysis of subjects with baseline HbA1c ≥ 9.0%, treatment with empagliflozin 10 mg or 25 mg as add-on to metformin resulted in statistically significant reductions in HbA1c at Week 24 (adjusted mean change from baseline of -1.49% for empagliflozin 25 mg, -1.40% for empagliflozin 10 mg, and -0.44% for placebo).

Body weight.

In a pre-specified pooled analysis of 4 placebo controlled studies, treatment with empagliflozin (68% of all patients were on metformin background) 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).

Blood pressure.

The efficacy and safety of empagliflozin was evaluated in a double-blind, placebo controlled study of 12 weeks duration in patients with type 2 diabetes and high blood pressure on different antidiabetic (67.8% treated with metformin with or without other antidiabetic drugs including insulin) and up to 2 antihypertensive therapies (Table 13). Treatment with empagliflozin once daily resulted in statistically significant improvement in HbA1c, 24 hour mean systolic and diastolic blood pressure as determined by ambulatory BP monitoring. Treatment with empagliflozin provided reductions in seated systolic BP (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 diastolic BP (change from baseline of -1.13 mmHg for placebo, -3.06 mmHg for empagliflozin 10 mg and -3.02 mmHg for empagliflozin 25 mg).
In a pre-specified pooled analysis of 4 placebo-controlled studies, treatment with empagliflozin (68% of all patients were on metformin background) resulted in a reduction in systolic blood pressure (empagliflozin 10 mg -3.9 mmHg, empagliflozin 25 mg -4.3 mmHg) compared with placebo (-0.5 mmHg), and in diastolic blood pressure (empagliflozin 10 mg -1.8 mmHg, empagliflozin 25 mg -2.0 mmHg) compared with placebo (-0.5 mmHg), at week 24, that were maintained up to week 52.

Cardiovascular outcome.

Empagliflozin is indicated in patients with type 2 diabetes mellitus and established cardiovascular disease to reduce the risk of cardiovascular death. However, the effectiveness of Jardiamet on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established. The effect of empagliflozin on cardiovascular risk in adult patients with type 2 diabetes and established cardiovascular disease is presented below.
The EMPA-REG OUTCOME study is a multi-centre, multi-national, randomised, double-blind, placebo-controlled trial investigating the effect of empagliflozin as adjunct to standard care therapy in reducing cardiovascular events in patients with type 2 diabetes and one or more cardiovascular 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, non-fatal MI, or nonfatal 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.
A total of 7020 patients were treated with empagliflozin (empagliflozin 10 mg: 2345, empagliflozin 25 mg: 2342, placebo: 2333) and followed for a median of 3.1 years. Approximately 74% of patients were being treated with metformin at baseline, 48% with insulin and 43% with sulfonylurea.
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.
About half of the patients (52.2%) had an eGFR of 60-90 mL/min/1.73 m2, 17.8% of 45-60 mL/min/1.73 m2 and 7.7% of 30-45 mL/min/1.73 m2. Mean systolic BP was 136 mmHg, diastolic BP 76 mmHg, low density lipoprotein (LDL) 2.2 mmol/L, high density lipoprotein (HDL) 1.1 mmol/L, and urinary albumin to creatinine ratio (UACR) 19.8 mg/mmol at baseline.

Reductions in risk of CV death and overall mortality.

Empagliflozin is 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 reduction in cardiovascular death with no significant change in non-fatal MI, or non-fatal stroke (Table 14 and Figure 1).
Empagliflozin also improved overall survival (Table 14), which was driven by a reduction in cardiovascular death with empagliflozin. There was no statistically significant difference between empagliflozin and placebo in non-cardiovascular mortality.

Reductions in risk of heart failure requiring hospitalisation or CV death.

Empagliflozin is superior in reducing the risk of hospitalisation for heart failure and cardiovascular death or hospitalisation for heart failure compared with placebo (Table 15 and Figure 2).
The cardiovascular benefits (CV death and hospitalisation for heart failure or CV death) of empagliflozin observed were consistent across the major demographic and disease subgroups.
In the subgroup of patients who were on metformin at baseline, the effects on CV outcomes were consistent with the results observed in the entire study population of EMPA-REG OUTCOME.

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 16 and Figure 3).
Empagliflozin 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).
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 4).
In the subgroup of patients who were on metformin at baseline, the effects on these renal outcomes were consistent with the results observed in the entire study population of EMPA-REG OUTCOME.

Thorough QTc study.

In a randomised, placebo-controlled, active comparator, crossover study of 30 healthy subjects no increase in QTc was observed with either 25 mg or 200 mg empagliflozin.

5.2 Pharmacokinetic Properties

The results of bioequivalence studies in healthy subjects demonstrated that Jardiamet (empagliflozin/metformin hydrochloride) 5 mg/500 mg, 5 mg/850 mg, 5 mg/1000 mg, 12.5 mg/500 mg, 12.5 mg/850 mg, and 12.5 mg/1000 mg combination tablets are bioequivalent to co-administration of corresponding doses of empagliflozin and metformin as individual tablets.
Administration of 12.5 mg empagliflozin/1000 mg metformin under fed conditions resulted in a 9% decrease in AUC and a 28% decrease in Cmax for empagliflozin, when compared to fasted conditions. For metformin, AUC decreased by 12% and Cmax decreased by 26% compared to fasting conditions. The observed effect of food on empagliflozin and metformin is not considered to be clinically relevant. However, as metformin is recommended to be given with meals, Jardiamet is also proposed to be given with food.
The following statements reflect the pharmacokinetic properties of the individual active substances of Jardiamet.

Empagliflozin.

Absorption.

The pharmacokinetics of empagliflozin have been extensively characterised in healthy volunteers and patients with T2DM. After oral administration, empagliflozin was rapidly absorbed with peak plasma concentrations occurring at a median tmax 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 AUC and Cmax were 1870 nanomol.h and 259 nanomol/L with empagliflozin 10 mg and 4740 nanomol.h and 687 nanomol/L with empagliflozin 25 mg once daily, respectively. 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.
The pharmacokinetics of 5 mg empagliflozin twice daily and 10 mg empagliflozin once daily were compared in healthy subjects. Overall exposure (AUCss) of empagliflozin over a 24-hour period with 5 mg administered twice daily was similar to 10 mg administered once daily. As expected, empagliflozin 5 mg administered twice daily compared with 10 mg empagliflozin once daily resulted in lower Cmax and higher trough plasma empagliflozin concentrations (Cmin).
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 Cmax decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.

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 [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.

Metabolism.

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

Excretion.

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 the half-life, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state. Following administration of an oral [14C]-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.

Metformin hydrochloride.

Absorption.

After an oral dose of metformin, tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin hydrochloride absorption are non-linear.
At the recommended metformin hydrochloride doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/mL. In controlled clinical trials, maximum metformin hydrochloride plasma levels (Cmax) did not exceed 5 microgram/mL, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.

Distribution.

Plasma protein binding is negligible. Metformin hydrochloride partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 L.

Metabolism.

Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism.

Excretion.

Renal clearance of metformin hydrochloride is > 400 mL/min, indicating that metformin hydrochloride is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin hydrochloride in plasma.

Pharmacokinetics in special patient groups.

Paediatric.

Empagliflozin.

Studies characterising the pharmacokinetics of empagliflozin in paediatric patients have not been performed.

Metformin hydrochloride.

Single dose study: After single doses of metformin 500 mg, paediatric patients have shown a similar pharmacokinetic profile to that observed in healthy adults.
Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg twice daily for 7 days in paediatric patients the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.

Elderly.

Empagliflozin.

Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.

Metformin hydrochloride.

Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin hydrochloride is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin hydrochloride pharmacokinetics with aging is primarily accounted for by a change in renal function.
Jardiamet treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.

Body mass index (BMI).

Empagliflozin.

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.

Empagliflozin.

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.

Metformin hydrochloride.

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

Race.

Empagliflozin.

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/m2 compared to non-Asian patients with a BMI of 25 kg/m2.

Metformin hydrochloride.

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

Renal impairment.

Empagliflozin.

In patients with mild (eGFR: 60 - < 90 mL/min/1.73 m2), moderate (eGFR: 30 - < 60 mL/min/1.73 m2), severe (eGFR: < 30 mL/min/1.73 m2) renal impairment and patients with kidney failure/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, the population pharmacokinetic analysis showed that the apparent oral clearance of 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 impairment.

Metformin hydrochloride.

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

Hepatic impairment.

Empagliflozin.

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 Cmax 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.

Metformin hydrochloride.

No pharmacokinetic studies of metformin hydrochloride have been conducted in subjects with hepatic impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Empagliflozin.

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.

Metformin hydrochloride.

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

Carcinogenicity.

Empagliflozin.

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 12.5 and 5 mg twice daily, respectively). These tumours are likely associated with a metabolic pathway not present in humans, and are considered to be irrelevant to patients given clinical doses of empagliflozin. No drug-related tumours were seen in female mice or female rats 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 5 or 12.5 mg empagliflozin twice daily. 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 dose of 12.5 mg and 5 mg twice daily, respectively). These tumours are common in rats and are unlikely to be relevant to humans.

Metformin hydrochloride.

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

4 Clinical Particulars

4.1 Therapeutic Indications

Jardiamet is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and metformin is appropriate (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials).
Empagliflozin is indicated in adults with type 2 diabetes mellitus and established cardiovascular disease to reduce the risk of cardiovascular death (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
To prevent cardiovascular deaths, empagliflozin should be used in conjunction with other measures to reduce cardiovascular risk in line with the current standard of care.

4.3 Contraindications

Hypersensitivity to active ingredients empagliflozin and/or metformin hydrochloride or to any of the excipients.
Any type of metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis).
Diabetic pre-coma.
Renal failure or renal dysfunction (creatinine clearance < 60 mL/min), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicaemia.
Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, intravascular administration of iodinated contrast agents (see Section 4.4 Special Warnings and Precautions for Use).
Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial infarction, shock, pulmonary embolism, acute significant blood loss, sepsis, gangrene, pancreatitis (see Section 4.4 Special Warnings and Precautions for Use).
During or immediately following surgery where insulin is essential, elective major surgery.
Hepatic impairment, acute alcohol intoxication, alcoholism (due to the metformin component).
Lactation.
Jardiamet must be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials because use of such products may result in acute alteration of renal function (see Section 4.4 Special Warnings and Precautions for Use, Administration of iodinated contrast agent).

4.4 Special Warnings and Precautions for Use

General.

Jardiamet should not be used in patients with type 1 diabetes (see Section 4.1 Therapeutic Indications).

Diabetic ketoacidosis.

Jardiamet should not be used for the treatment of diabetic ketoacidosis.
Cases of diabetic ketoacidosis (DKA), a serious life-threatening condition requiring urgent hospitalisation, have been reported in postmarketing surveillance in patients treated with SGLT2 inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin.
Patients treated with Jardiamet who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels as ketoacidosis associated with Jardiamet may be present even if blood glucose levels are less than 13.8 mmol/L.
Signs and symptoms of ketoacidosis may include excessive thirst, nausea, vomiting, abdominal pain, generalised malaise, and shortness of breath. If ketoacidosis is suspected, Jardiamet should be discontinued, the patient should be evaluated and prompt treatment should be instituted. Treatment of ketoacidosis generally requires insulin, fluid, potassium and carbohydrate replacement.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
Before initiating Jardiamet, consider factors in the patient history that may predispose to ketoacidosis.
Factors that predispose patients to ketoacidosis include a low carbohydrate diet, dehydration, acute illness, surgery (see Surgery), a previous ketoacidosis, insulin deficiency from any cause (including insulin pump failure, history of pancreatitis, or pancreatic surgery), malnourishment/reduced caloric intake or increased insulin requirements due to infections, and alcohol abuse. Jardiamet should be used with caution in these patients. Consider monitoring for ketoacidosis and temporarily discontinuing Jardiamet in clinical situations known to predispose to ketoacidosis. When reducing the insulin dose in patients requiring insulin, caution should be taken (see Section 4.2 Dose and Method of Administration). In these situations, consider monitoring of ketones, even if Jardiamet treatment has been interrupted.

Lactic acidosis.

Lactic acidosis is a rare but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic impairment and any condition associated with hypoxia.

Diagnosis.

The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps with digestive disorders such as abdominal pain and severe asthenia.
Lactic acidosis is characterised by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalised immediately (see Section 4.9 Overdose).

Cardiac function.

Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, Jardiamet may be used with a regular monitoring of cardiac and renal function.
For patients with acute and unstable heart failure, Jardiamet is contraindicated due to the metformin component (see Section 4.3 Contraindications).

Use in patients at 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 blood pressure. Therefore, caution should be exercised in patients for whom an empagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of 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, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving empagliflozin. Temporary interruption of treatment with Jardiamet should be considered until the fluid loss is corrected.

Urosepsis and pyelonephritis.

There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (see Section 4.8 Adverse Effects (Undesirable Effects)).
Discontinuation of Jardiamet may be considered in cases of recurrent urinary tract infections.

Genital infections including life threatening necrotising fasciitis.

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 Jardiamet who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, Jardiamet should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).

Lower limb amputations.

An increase in cases of lower limb amputation (primarily of the toe) has been observed in a long-term clinical study with another SGLT2 inhibitor. The medicine in that study is not empagliflozin. However, it is unknown whether this constitutes a class effect. In a pooled safety analysis of 12,620 patients with T2DM the frequency of patients with lower limb amputations was similar between empagliflozin and placebo. In the largest placebo-controlled trial in 7020 patients (EMPA-REG OUTCOME trial), in which 88% of all the cases of amputations were reported, lower limb amputations occurred in 1.8% of patients treated with empagliflozin 10 mg, in 2.0% of patients treated with empagliflozin 25 mg, and in 1.8% of patients in the placebo arm. It is important to regularly examine the feet and counsel all diabetic patients on routine preventative footcare.

Combination with glucagon like peptide (GLP-1) analogues.

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

Administration of iodinated contrast agent.

The intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. Therefore, Jardiamet must be discontinued either 48 hours before the test when renal function is known to be impaired or from the time of the test when renal function is known to be normal. Jardiamet may not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Surgery.

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

Vitamin B12 levels.

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anaemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of haematologic parameters on an annual basis is advised in patients on Jardiamet and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful.

Use in patients with renal impairment.

Empagliflozin increases serum creatinine and decreases eGFR (see Section 4.8 Adverse Effects (Undesirable Effects)). Renal function abnormalities can occur after initiating empagliflozin. Patients with hypovolaemia may be more susceptible to these changes.
There have been postmarketing reports of acute kidney injury, some requiring hospitalisation and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age.
Due to the mechanism of action, decreased renal function will result in reduced efficacy of empagliflozin.
As metformin hydrochloride is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter:
at least annually in patients with normal renal function;
at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects.
Decreased renal function in elderly subjects is frequent and asymptomatic (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special patient groups, Elderly). Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID).
In these cases, it is also recommended to check renal function before initiating treatment with Jardiamet.

Hypoglycaemia.

Jardiamet alone does not cause hypoglycaemia under usual circumstances of use, but hypoglycaemia could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.

Use in the elderly.

Patients aged 75 years and older may be at an increased risk of volume depletion, therefore, Jardiamet should be prescribed with caution in these patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Therapeutic experience in patients aged 85 years and older is limited. Initiation of treatment in this population is not recommended.
As metformin is excreted by the kidney, Jardiamet should be used with caution as age increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in elderly patients.

Paediatric use.

Safety and effectiveness of Jardiamet in paediatric patients under 18 years have not been established.

Effects on laboratory tests.

Urine will test positive for glucose while patients are taking Jardiamet due to the nature of the mechanism of action of the SGLT2 inhibitors (see Section 5.1 Pharmacodynamic Properties).

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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

General.

Co-administration of multiple doses of empagliflozin (50 mg once daily) and metformin hydrochloride (1000 mg twice daily) did not meaningfully alter the pharmacokinetics of either empagliflozin or metformin in healthy volunteers.
Pharmacokinetic drug-drug interaction studies with Jardiamet have not been performed; however, such studies have been conducted with empagliflozin and metformin alone.

Empagliflozin.

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 and insulin secretagogues, such as sulfonylureas, may increase the risk of 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 Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

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 UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not notably inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. At 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 (BCRP), 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.

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 on results of pharmacokinetic studies no dose adjustment of empagliflozin is recommended when co-administered with commonly prescribed medicinal products.
Empagliflozin pharmacokinetics were similar with and without co-administration of 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 had no clinically relevant effect on the pharmacokinetics of glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torasemide and oral contraceptives when co-administered in healthy volunteers.

Metformin hydrochloride.

Contraindicated combinations.

Iodinated contrast materials.

Jardiamet must be discontinued either 48 hours before the test when renal function is known to be impaired, or from the time of the test when renal function is known to be normal (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Administration of iodinated contrast agent).

Inadvisable combinations.

Alcohol.

There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic impairment) due to the metformin component of Jardiamet (see Section 4.4 Special Warnings and Precautions for Use, Lactic acidosis). Consumption of alcohol and medicinal products containing alcohol should be avoided. Alcohol may make the signs of hypoglycaemia less clear, and delayed hypoglycaemia can occur. The CNS depressant effects of alcohol plus hypoglycaemia can make driving or the operation of dangerous machinery much more hazardous.

Combinations requiring precautions for use.

Medicinal products with intrinsic hyperglycaemic activity e.g. glucocorticoids and tetracosactides (systemic and local routes), beta-2-agonists, danazol, chlorpromazine at high dosages of 100 mg per day and diuretics.

More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon discontinuation.

Diuretics, especially loop diuretics.

May increase the risk of lactic acidosis due to their potential to decrease renal function.

ACE-inhibitors.

ACE-inhibitors may decrease the blood glucose levels. Therefore, dose adjustment of Jardiamet may be necessary when such medicinal products are added or discontinued.

Calcium channel blockers.

Calcium channel blockers may affect glucose control in diabetic patients; regular monitoring of glycaemic control is recommended.

Beta-blockers.

Co-administration of metformin and beta-blockers may result in a potentiation of the anti-hyperglycaemic action. In addition, some of the premonitory signs of hypoglycaemia, in particular tachycardia, may be masked. Monitoring of blood glucose should be undertaken during dosage adjustment of either agent.

Cimetidine.

Reduced clearance of metformin has been reported during cimetidine therapy, so a dose reduction should be considered.

Anticoagulants.

Metformin increases the elimination rate of vitamin K antagonists. Consequently, the prothrombin time should be closely monitored in patients in whom metformin and vitamin K antagonists are being co-administered. Cessation of metformin in patients receiving vitamin K antagonists can cause marked increases in the prothrombin time.

Nifedipine.

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

Organic cation transporters (OCT).

Metformin is a substrate of both transporters OCT1 and OCT2.
Co-administration of metformin with:
Substrates/inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.
Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy.
Substrates/inhibitors of OCT2 (such as cimetidine, dolutegravir, crizotinib, olaparib, daclatasvir, vandetanib) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.

Carbonic anhydrase inhibitors.

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride tablet may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

NSAID.

May increase the risk of lactic acidosis and adversely affect renal function.
Therefore, caution is advised when these drugs are co-administered with metformin and a dose adjustment may be considered, particularly in patients with renal impairment.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies on the effect on human fertility have been conducted with Jardiamet or its individual components.
Nonclinical studies in animals with the individual components do not indicate direct or indirect harmful effects with respect to fertility.

Empagliflozin.

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.

Metformin hydrochloride.

Fertility of male or female rats was unaffected by metformin when administered at doses up to 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose based on body surface area comparisons.
(Category D)
There are limited data from the use of Jardiamet or its individual components in pregnant women.
When the patient plans to become pregnant, and during pregnancy, it is recommended that diabetes is not treated with Jardiamet, but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus associated with abnormal blood glucose levels.
A study in pregnant rats did not reveal teratogenicity or other adverse effects on embryofetal development with co-administration of empagliflozin and metformin at oral doses up to 100/200 mg/kg/day, yielding exposures of approximately 35- and 14-times the clinical AUC exposure of empagliflozin associated with the 5 and 12.5 mg twice daily doses, respectively, and 4-times the clinical AUC exposure of metformin associated with the 1000 mg twice daily dose. At a dose of 300/600 mg/kg/day, associated with 49-times the exposure to empagliflozin and 8-times the exposure to metformin in humans at the maximum recommended dose, teratogenicity attributable to the metformin component was observed.

Empagliflozin.

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 12.5 mg and 5 mg twice daily 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 12.5 mg and 5 mg twice daily doses, respectively. Maternally toxic doses in the rabbit also caused increased embryofetal loss at doses approximately 139- and 353-times the clinical dose associated with the 12.5 mg and 5 mg twice daily doses, respectively.
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 yielding maternal exposures approximately 4- and 11-times those in humans associated with 12.5 mg and 5 mg twice daily doses, respectively.
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 been seen for empagliflozin at approximately 11-times the clinical dose of empagliflozin based on AUC exposure associated with the 12.5 mg twice daily dose. These findings were absent after a 13 week drug-free recovery period.

Metformin hydrochloride.

Metformin was not teratogenic in rats at a dose of 200 mg/kg/day associated with a systemic exposure 4 times that in patients at the maximum recommended human dose (2000 mg metformin per day). At higher doses (500 and 1000 mg/kg/day, associated with 11 and 23 times the clinical exposure at the MRHD), teratogenicity of metformin was observed in the rat which was mostly evident as an increase in the incidence of skeletal malformations.
Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. It is unknown whether empagliflozin is excreted in human 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 Use in pregnancy). Adverse effects on renal development have been observed in juvenile rats treated with other members of this pharmacological class. Similar effects were seen with empagliflozin but the findings were absent after a 13 week drug-free recovery. A risk to human newborns/infants cannot be excluded. It is recommended to discontinue breast feeding during treatment with Jardiamet.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

Adverse reactions in clinical trials.

A total of 12,245 patients with type 2 diabetes were treated in clinical studies to evaluate the safety of empagliflozin plus metformin, of which 8199 patients were treated with empagliflozin plus metformin, either alone, or in addition to a sulfonylurea, pioglitazone, DPP4 inhibitors, or insulin. In these trials 2910 patients received treatment with empagliflozin 10 mg plus metformin and 3699 patients treatment with empagliflozin 25 mg plus metformin for at least 24 weeks and 2151 or 2807 patients for at least 76 weeks.
The overall safety profile of empagliflozin plus metformin for patients enrolled in the EMPA-REG OUTCOME study was comparable to the previously known safety profile.
Placebo controlled double-blind trials of 18 to 24 weeks of exposure included 3456 patients, of which 1271 were treated with empagliflozin 10 mg plus metformin and 1259 with empagliflozin 25 mg plus metformin.
The most frequently reported adverse event in clinical trials was hypoglycaemia, which depended on the type of background therapy used in the respective studies (Table 1).
No additional side effects were identified in clinical trials with empagliflozin plus metformin compared to the side effects of the single components.

Tabulated list of adverse reactions.

The adverse reactions are listed by absolute frequency. Frequencies 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), or very rare (< 1/10,000), and not known (cannot be estimated from the available data).

Postmarketing experience.

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

Metabolism and nutrition disorders.

Ketoacidosis.

Infections and infestations.

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

Immune system disorders.

Allergic skin reactions (e.g. rash, urticaria), angioedema.

Reproductive system and breast disorders.

Phimosis.

Hypoglycaemia.

The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar to placebo for empagliflozin as add-on to metformin and as add-on to pioglitazone ± metformin, and as add-on with linagliptin + metformin. The frequency of patients with hypoglycaemia was increased in patients treated with empagliflozin 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 Dose and Method of Administration and Table 2).

Major hypoglycaemia (events requiring assistance).

The overall frequency of patients with major hypoglycaemic events was low (< 1%) and similar for empagliflozin and placebo on a background of metformin. The frequency of major hypoglycaemia depended on the background therapy in the respective studies (see Section 4.2 Dose and Method of Administration and Table 2).

Urinary tract infection.

The overall frequency of urinary tract infection adverse events was higher in patients treated with empagliflozin 10 mg plus metformin (8.8%) as compared to empagliflozin 25 mg plus metformin (6.6%) or placebo plus metformin (7.8%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin plus metformin in patients with a history of chronic or recurrent urinary tract infections. The intensity of urinary tract infections was similar to placebo. Urinary tract infection events were reported more frequently for empagliflozin 10 mg plus metformin compared with placebo in female patients, but not for empagliflozin 25 mg plus metformin. The frequencies of urinary tract infections were low for male patients and were balanced across treatment groups.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently for empagliflozin 10 mg plus metformin (4.0%) and empagliflozin 25 mg plus metformin (3.9%) compared to placebo plus metformin (1.3%), and were reported more frequently for empagliflozin plus metformin compared to placebo in female patients. The difference in frequency was less pronounced in male patients. 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 empagliflozin 10 mg plus metformin (3.0%) and empagliflozin 25 mg plus metformin (2.9%) compared to placebo plus metformin (1.4%). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and empagliflozin, both on a background of metformin (< 1%).

Volume depletion.

The overall frequency of volume depletion (including the predefined terms blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension, and syncope) was low and comparable to placebo (empagliflozin 10 mg plus metformin (0.6%), empagliflozin 25 mg plus metformin (0.3%) and placebo plus metformin (0.1%)). The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect the hydration status of patients age 75 years and older. In patients ≥ 75 years of age volume depletion events have been reported in a single patient treated with empagliflozin 25 mg plus metformin.

Blood creatinine increased and glomerular filtration rate decreased.

Use of empagliflozin was associated with increases in serum creatinine and decreases in eGFR. These changes were observed to reverse after treatment discontinuation, suggesting acute haemodynamic changes play a role in the renal function abnormalities observed with empagliflozin.
Renal-related adverse reactions (e.g. acute kidney injury, renal impairment, acute prerenal failure) may occur in patients treated with empagliflozin.
The overall frequency of patients with increased blood creatinine and decreased glomerular filtration rate was similar between empagliflozin and placebo as add-on to metformin (blood creatinine increased: empagliflozin 10 mg 0.5%, empagliflozin 25 mg 0.1%, placebo 0.4%; glomerular filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.2%).
In these placebo-controlled, double-blind studies up to 24 weeks, initial transient increases in creatinine (mean change from baseline after 12 weeks: empagliflozin 10 mg 0.001 mmol/L, empagliflozin 25 mg 0.001 mmol/L) and initial transient decreases in estimated glomerular filtration rates (mean change from baseline after 12 weeks: empagliflozin 10 mg -1.46 mL/min/1.73 m2, empagliflozin 25 mg -2.05 mL/min/1.73 m2) have been observed. In the long term studies, these changes were generally reversible during continuous treatment or after drug discontinuation (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Figure 4 for the eGFR course in the EMPA-REG OUTCOME study).

Laboratory parameters.

Haematocrit increased.

In a pooled safety analysis of all trials with metformin background treatment, mean changes from baseline in haematocrit were 3.6% and 4.0% for empagliflozin 10 mg and 25 mg, respectively, compared to 0% for placebo. In the 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 of all trials with metformin background treatment, mean percent increases from baseline for empagliflozin 10 mg and 25 mg versus placebo, respectively, were total cholesterol 5.0% and 5.2% versus 3.7%; HDL-cholesterol 4.6% and 2.7% versus -0.5%; LDL-cholesterol 9.1% and 8.7% versus 7.8%; triglycerides 5.4% and 10.8% versus 12.1%.

4.2 Dose and Method of Administration

Life-threatening lactic acidosis can occur due to accumulation of metformin. Risk factors include renal impairment, old age and the use of high doses of metformin above 2000 mg per day.
The recommended dose is one Jardiamet tablet twice daily.
The dosage should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability. The maximum recommended daily dose of Jardiamet is 25 mg of empagliflozin and 2000 mg of metformin.
Jardiamet should be given with meals to reduce the gastrointestinal undesirable effects associated with metformin.

Treatment naïve patients.

The recommended starting dose is 5 mg/500 mg twice daily. If additional glycaemic control is required, adjust dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg empagliflozin and 2000 mg metformin.

Patients switching from separate tablets of empagliflozin and metformin.

Patients switching from separate tablets of empagliflozin (10 mg or 25 mg total daily dose) and metformin to Jardiamet, should receive the same daily dose of empagliflozin and metformin already being taken or the nearest therapeutically appropriate dose of metformin.

Patients not adequately controlled on the maximal tolerated dose of metformin alone or in combination with other products, including insulin.

The recommended starting dose of Jardiamet should provide empagliflozin 5 mg twice daily (10 mg total daily dose) and the dose of metformin similar to the dose already being taken. In patients tolerating a total daily dose of empagliflozin 10 mg, the dose can be increased to a total daily dose of empagliflozin 25 mg.

Combination use.

When Jardiamet is used in combination with a sulfonylurea and/or insulin, a lower dose of sulfonylurea and/or insulin may be required to reduce the risk of hypoglycaemia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)).

Renal impairment.

No dose adjustment is recommended for patients with mild renal impairment. Jardiamet is contraindicated for use in patients with moderate or severe renal impairment (creatinine clearance < 60 mL/min) (see Section 4.3 Contraindications).
Renal function should be assessed before initiation of treatment with Jardiamet and at least annually thereafter.
In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Jardiamet is contraindicated in patients with hepatic impairment due to the metformin component (see Section 4.3 Contraindications).

Elderly patients.

Patients age 75 years and older may be at an increased risk of volume depletion, therefore, Jardiamet should be prescribed with caution in these patients. Therapeutic experience in patients aged 85 years and older is limited. Initiation of treatment in this population is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Paediatric population.

Jardiamet is not recommended for use in children below 18 years due to lack of data on safety and efficacy.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.
Low blood sugar may occur in patients who already take another medication to treat diabetes such as a sulfonylurea or insulin while taking Jardiamet. The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance e.g. driving a car or operating machinery. People should be advised to take precautions to avoid hypoglycaemia whilst driving or operating machinery.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Symptoms.

Empagliflozin.

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. There is no experience with doses above 800 mg in humans.

Metformin hydrochloride.

Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin hydrochloride or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital.

Therapy.

In the event of an overdose, supportive treatment should be initiated as appropriate to the patient's clinical status. The most effective method to remove lactate and metformin hydrochloride is haemodialysis whereas removal of empagliflozin by haemodialysis has not been studied.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each film-coated tablet of Jardiamet contains the following inactive ingredients: copovidone, maize starch, colloidal anhydrous silica, magnesium stearate, hypromellose, titanium dioxide, macrogol 400, purified talc, iron oxide yellow (Jardiamet 5 mg/500 mg, Jardiamet 5 mg/850 mg, Jardiamet 5 mg/1000 mg), iron oxide black (Jardiamet 12.5 mg/500 mg, Jardiamet 12.5 mg/850 mg, Jardiamet 12.5 mg/1000 mg), iron oxide red (Jardiamet 12.5 mg/500 mg, Jardiamet 12.5 mg/850 mg, Jardiamet 12.5 mg/1000 mg).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Jardiamet is available in PVC/PCTFE (Aclar)/ Aluminium blister packs containing 14 or 60 film-coated tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes