Synjardy - patient leaflet, side effects, dosage

B. PACKAGE LEAFLET

Package leaflet: Information for the patient

Synjardy 5 mg/850 mg film-coated tablets Synjardy 5 mg/1,000 mg film-coated tablets Synjardy 12.5 mg/850 mg film-coated tablets Synjardy 12.5 mg/1,000 mg film-coated tablets empagliflozin/met­formin hydrochloride

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, pharmacist or nurse.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Synjardy is and what it is used for

• 2. What you need to know before you take Synjardy

• 3. How to take Synjardy

• 4. Possible side effects

• 5. How to store Synjardy

• 6. Contents of the pack and other information

1. What Synjardy is and what it is used for

What Synjardy is

Synjardy contains two active substances empagliflozin and metformin. Each belongs to a group of medicines called “oral anti-diabetics”. These are medicines taken by mouth to treat type 2 diabetes.

What is type 2 diabetes?

Type 2 diabetes is a disease that comes from both your genes and your lifestyle. If you have type 2 diabetes, your pancreas does not make enough insulin to control the level of glucose in your blood, and your body is unable to use its own insulin effectively. This results in high levels of glucose in your blood which can lead to medical problems like heart disease, kidney disease, blindness, and poor circulation in your limbs.

How Synjardy works

Empagliflozin belongs to a group of medicines called sodium glucose co-transporter-2 (SGLT2) inhibitors. It works by blocking the SGLT2 protein in your kidneys. This causes blood sugar (glucose) to be removed in your urine. Metformin works in a different way to lower blood sugar levels, mainly by blocking glucose production in the liver.

Thereby Synjardy lowers the amount of sugar in your blood. This medicine can also help prevent heart disease.

What Synjardy is used for

• Synjardy is added to diet and exercise to treat type 2 diabetes in adult patients (aged 18 years and older) whose diabetes cannot be controlled by adding metformin alone or metformin with other medicines for diabetes.
• Synjardy can also be combined with other medicines for the treatment of diabetes. These may be medicines taken by mouth or given by injection such as insulin.
• In addition, Synjardy can be used as an alternative to taking both empagliflozin and metformin as single tablets. To avoid overdose, do not continue taking empagliflozin and metformin tablets separately, if you are taking this medicine.

It is important that you continue with your diet and exercise plan as told by your doctor, pharmacist or nurse.

2. What you need to know before you take Synjardy

Do not take Synjardy

• if you are allergic to empagliflozin, metformin or any of the other ingredients of this medicine (listed in section 6);
• if you have uncontrolled diabetes, with, for example, severe hyperglycaemia (very high blood glucose), nausea, vomiting, diarrhoea, rapid weight loss, lactic acidosis (see ‘Risk of lactic acidosis’ below) or ketoacidosis. Ketoacidosis is a condition in which substances called ‘ketone bodies’ accumulate in the blood and which can lead to diabetic pre-coma. Symptoms include stomach pain, fast and deep breathing, sleepiness or your breath developing an unusual fruity smell;
• if you have had a diabetic pre-coma;
• if you have serious kidney problems. Your doctor may limit your daily dose or ask you to take a different medicine (see also section 3, ‘How to take Synjardy’).
• if you have a severe infection such as an infection affecting your lung or bronchial system or your kidney. Severe infections may lead to kidney problems, which can put you at risk for lactic acidosis (see ‚Warnings and precautions‘);
• if you have lost a lot of water from your body (dehydration), e.g. due to long-lasting or severe diarrhoea, or if you have vomited several times in a row. Dehydration may lead to kidney problems, which can put you at risk for lactic acidosis (see ‚Warnings and precautions‘);
• if you are treated for acute heart failure or have recently had a heart attack, have severe problems with your circulation (such as shock) or have breathing difficulties. This may lead to a lack in oxygen supply to tissue which can put you at risk for lactic acidosis (see section ‘Warnings and precautions');
• if you have problems with your liver;
• if you drink large amounts of alcohol, either every day or only from time to time (see section “Synjardy with alcohol”).

Warnings and precautions

Risk of lactic acidosis

Synjardy may cause a very rare, but very serious side effect called lactic acidosis, particularly if your kidneys are not working properly. The risk of developing lactic acidosis is also increased with uncontrolled diabetes, serious infections, prolonged fasting or alcohol intake, dehydration (see further information below), liver problems and any medical conditions in which a part of the body has a reduced supply of oxygen (such as acute severe heart diseases).

If any of the above apply to you, talk to your doctor for further instructions.

Stop taking Synjardy for a short time if you have a condition that may be associated with dehydration (significant loss of body fluids) such as severe vomiting, diarrhoea, fever, exposure to heat or if you drink less fluid than normal. Talk to your doctor for further instructions.

Stop taking Synjardy and contact a doctor or the nearest hospital immediately if you experience some of the symptoms of lactic acidosis , as this condition may lead to coma.

Symptoms of lactic acidosis include:

• vomiting
• stomach ache (abdominal pain)
• muscle cramps
• a general feeling of not being well with severe tiredness
• difficulty in breathing
• reduced body temperature and heartbeat

Lactic acidosis is a medical emergency and must be treated in a hospital.

Talk to your doctor, pharmacist or nurse before taking this medicine, and during treatment:

• if you experience 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, contact a doctor or the nearest hospital straight away. These symptoms could be a sign of “diabetic ketoacidosis” – a rare, but serious, sometines life-threatening problem you can get with diabetes because of increased levels of “ketone bodies” in your urine or blood, seen in tests. The risk of developing diabetic ketoacidosis may be increased with prolonged fasting, excessive alcohol consumption, dehydration, sudden reductions in insulin dose, or a higher need of insulin due to major surgery or serious illness;
• if you have “type 1 diabetes” – this type usually starts when you are young and your body does not produce any insulin. Synjardy should not be used to treat patients with type 1 diabetes;
• might be at risk of dehydration, for example:

o if you are being sick, have diarrhoea or fever, or if you are not able to eat or drink

o if you are taking medicines that increase urine production [diuretics] or lower blood

pressure

o if you are over 75 years old

Possible signs are listed in section 4 under ‘dehydration’. Your doctor may ask you to stop taking Synjardy until you recover to prevent loss of too much body fluid. Ask about ways to prevent dehydration.

• if you are 85 years old or older as you should not start taking Synjardy due to limited therapeutic experience;
• if you have a serious infection of the kidney or the urinary tract with fever. Your doctor may ask

you to stop taking Synjardy until you have recovered;

• if you need to undergo an examination with iodination contrast agents (such as X-ray or scan). More information is given below in “Other medicines and Synjardy”.

Talk to your doctor immediately if you develop a combination of symptoms of pain, tenderness, redness, or swelling of the genitals or the area between the genitals and the anus with fever or feeling generally unwell. These symptoms could be a sign of a rare but serious or even life-threatening infection, called necrotising fasciitis of the perineum or Fournier's gangrene which destroys the tissue under the skin. Fournier’s gangrene has to be treated immediately.

Surgery

If you need to have major surgery you must stop taking Synjardy during and for some time after the procedure. Your doctor will decide when you must stop and when to restart your treatment with Synjardy.

Kidney function

During treatment with Synjardy, your doctor will check your kidney function at least once a year or more frequently if you are elderly and/or if you have worsening kidney function.

Foot care

Like for all diabetic patients it is important to check your feet regularly and adhere to any other advice regarding foot care given by your health care professional.

Urine glucose

Because of how this medicine works, your urine will test positive for sugar while you are taking this medicine.

Children and adolescents

This medicine is not recommended for use in children and adolescents under 18 years, because it has not been studied in these patients.

Other medicines and Synjardy

If you need to have an injection of a contrast medium that contains iodine into your bloodstream, for example in the context of an X-ray or scan, you must stop taking Synjardy before or at the time of the injection. Your doctor will decide when you must stop and when to restart your treatment with Synjardy.

Tell your doctor if you are taking, have recently taken or might take any other medicines. You may need more frequent blood glucose and kidney function tests, or your doctor may need to adjust the dosage of Synjardy. It is especially important to mention the following:

• medicines which increase urine production (diuretics), as Synjardy may increase the risk of

losing too much fluid. Your doctor may ask you to stop taking Synjardy. Possible signs of losing too much fluid from your body are listed in section 4.

• other medicines that lower the amount of sugar in your blood such as insulin or a “sulphonylurea” medicine. Your doctor may want to lower the dose of these other medicines, to prevent your blood sugar levels from getting too low (hypoglycaemia).
• medicines that may change the amount of metformin in your blood, especially if you have reduced kidney function (such as verapamil, rifampicin, cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole, crizotinib, olaparib).
• bronchodilators (beta-2 agonists) which are used to treat asthma.
• corticosteroids (given by mouth, as an injection, or inhaled), which are used to treat inflammation in diseases like asthma and arthritis.
• medicines used to treat pain and inflammation (NSAID and COX-2-inhibitors, such as ibuprofen and celecoxib).
• certain medicines for the treatment of high blood pressure (ACE inhibitors and angiotensin II

receptor antagonists).

• medicines that contain alcohol (see section ‘Synjardy with alcohol’).
• iodinated contrast agents (medicines used during an X-ray, see section ‘Warnings and precautions’.
• if you are taking lithium because Synjardy can lower the amount of lithium in your blood.

Synjardy with alcohol

Avoid excessive alcohol intake while taking Synjardy since this may increase the risk of lactic acidosis (see section ‘Warnings and precautions’).

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Do not take Synjardy if you are pregnant. It is unknown if this medicine is harmful to the unborn child.

Metformin passes into human milk in small amounts. It is not known whether empagliflozin passes into human breast milk. Do not take Synjardy if you are breast-feeding.

Driving and using machines

Synjardy has minor influence on the ability to drive and use machines.

Taking this medicine in combination with medicines called sulphonylureas or with insulin can cause blood sugar levels to drop too low (hypoglycaemia), which may cause symptoms such as shaking, sweating and change in vision, and may affect your ability to drive and use machines. Do not drive or use any tools or machines if you feel dizzy while taking Synjardy.

3. How to take Synjardy

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

How much to take

The dose of Synjardy varies depending on your condition and the doses of diabetes medicines you currently take. Your doctor will adjust your dose as necessary and tell you exactly which strength of the medicine to take.

The recommended dose is one tablet twice a day. Your doctor will normally start Synjardy treatment by prescribing the strength of tablet that supplies the same dose of metformin you are already taking (850 mg or 1,000 mg twice a day), and the lowest dose of empagliflozin (5 mg twice a day). If you are already taking both medicines separately, your doctor will start treatment with tablets of Synjardy that will supply the same amount of both. If you have reduced kidney function, your doctor may prescribe a lower dose or decide to use an alternative medicine.

Taking this medicine

• Swallow the tablet whole with water.
• Take the tablets with meals to lower your chance of an upset stomach.
• Take the tablet twice daily by mouth.

Your doctor may prescribe Synjardy together with another diabetes medicine. Remember to take all medicines as directed by your doctor to achieve the best results for your health. Your doctor may need to adjust your doses to control your blood sugar.

Appropriate diet and exercise 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 Synjardy.

If you take more Synjardy than you should

If you take more Synjardy tablets than you should have, you may experience lactic acidosis. Symptoms of lactic acidosis are non-specific such as feeling or being very sick, vomiting, stomach ache with muscle cramps, a general feeling of not being well with severe tiredness, and difficulty in breathing. Further symptoms are reduced body temperature and heartbeat. If this happens to you, you may need immediate hospital treatment, as lactic acidosis can lead to coma. Stop taking this medicine immediately and contact a doctor or the nearest hospital straight away (see section 2). Take the medicine pack with you.

If you forget to take Synjardy

If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take a double dose of this medicine.

If you stop taking Synjardy

Do not stop taking Synjardy without first consulting your doctor. Your blood sugar levels may increase when you stop taking Synjardy.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Contact a doctor or the nearest hospital straight away if you have any of the following side effects:

Severe allergic reaction, seen with unknown frequency (frequency cannot be estimated from the available data )

Possible signs of severe allergic reaction may include:

• swelling of the face, lips, mouth, tongue, or throat that may lead to difficulty breathing or swallowing)

Lactic acidosis, seen very rarely (may affect up to 1 in 10,000 people)

Synjardy may cause a very rare but very serious side effect called lactic acidosis (see section 2). If this happens you must stop taking Synjardy and contact a doctor or the nearest hospital immediately, as lactic acidosis may lead to coma.

Diabetic ketoacidosis, seen rarely (may affect up to 1 in 1,000 people)

These are the signs of diabetic ketoacidosis (see section 2):

• increased levels of “ketone bodies” in your urine or blood
• 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.

This may occur regardless of blood glucose level. Your doctor may decide to temporarily or permanently stop your treatment with Synjardy.

Contact your doctor as soon as possible if you notice the following side effects:

Low blood sugar (hypoglycaemia), seen very commonly (may affect more than 1 in 10 people)

If you take Synjardy with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is increased. The signs of low blood sugar may include:

• shaking, sweating, feeling very anxious or confused, fast heart beat
• excessive hunger, headache

Your doctor will tell you how to treat low blood sugar levels and what to do if you get any of the signs above. If you have symptoms of low blood sugar, eat glucose tablets, a high sugar snack or drink fruit juice. Measure your blood sugar if possible and rest.

Urinary tract infection, seen commonly (may affect up to 1 in 10 people)

The signs of urinary tract infection are:

• burning sensation when passing urine
• urine that appears cloudy
• pain in the pelvis, or mid-back pain (when kidneys are infected)

An urge to pass urine or more frequent urination may be due to the way Synjardy works, but they can also be signs of urinary tract infection. If you note an increase in such symptoms, you should also contact your doctor.

Dehydration, seen uncommonly (may affect up to 1 in 100 people)

The signs of dehydration are not specific, but may include:

• unusual thirst
• lightheadedness or dizziness upon standing
• fainting or loss of consciousness

Other side effects while taking Synjardy:

Very common

• feeling sick (nausea), vomiting
• diarrhoea or stomach ache
• loss of appetite

Common

• genital yeast infection (thrush)
• passing more urine than usual or needing to pass urine more often
• itching
• rash or red skin – this may be itchy and include raised bumps, oozing fluid or blisters
• changes to the way things taste
• thirst
• blood tests may show an increase in blood fat (cholesterol) levels in your blood

Uncommon

• hives
• straining or pain when emptying the bladder
• blood tests may show a decrease in kidney function (creatinine or urea)
• blood tests may show increases in the amount of red blood cells in your blood (haematocrit)

Very rare

• decreased vitamin B12 levels in the blood
• abnormalities in liver function tests, inflammation of the liver (hepatitis)
• redness of the skin (erythema)
• inflammation of the kidneys (tubulointerstitial nephritis)

Not known

• necrotising fasciitis of the perineum or Fournier's gan­grene, a serious soft tissue infection of the

genitals or the area between the genitals and the anus

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Synjardy

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and the carton after ‘EXP’. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not use this medicine if you notice that the packaging is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Synjardy contains

The active substances are empagliflozin and metformin.

Each Synjardy 5 mg/850 mg film-coated tablet (tablet) contains 5 mg empagliflozin and

850 mg metformin hydrochloride.

Each Synjardy 5 mg/1,000 mg film-coated tablet (tablet) contains 5 mg empagliflozin and 1,000 mg metformin hydrochloride.

Each Synjardy 12.5 mg/850 mg film-coated tablet (tablet) contains 12.5 mg empagliflozin and 850 mg metformin hydrochloride.

Each Synjardy 12.5 mg/1,000 mg film-coated tablet (tablet) contains 12.5 mg empagliflozin and 1,000 mg metformin hydrochloride.

The other ingredient(s) are:

• - Tablet core : maize starch, copovidone, colloidal anhydrous silica, magnesium stearate.

• - Film coating : hypromellose, macrogol 400, titanium dioxide (E171), talc.

What Synjardy looks like and contents of the pack

Synjardy 5 mg/850 mg film-coated tablets are yellowish white, oval, biconvex. They have “S5” and the Boehringer Ingelheim logo on one side and “850” on the other. The tablet is 19.2 mm long and has a width of 9.4 mm.

Synjardy 5 mg/1,000 mg film-coated tablets are brownish yellow, oval, biconvex. They have “S5” and the Boehringer Ingelheim logo on one side and “1000” on the other. The tablet is 21.1 mm long and has a width of 9.7 mm.

Synjardy 12.5 mg/850 mg film-coated tablets are pinkish white, oval, biconvex. They have “S12” and the Boehringer Ingelheim logo on one side and “850” on the other. The tablet is 19.2 mm long and has a width of 9.4 mm.

Synjardy 12.5 mg/1,000 mg film-coated tablets are dark brownish purple, oval, biconvex. They have “S12” and the Boehringer Ingelheim logo on one side and “1000” on the other. The tablet is 21.1 mm long and has a width of 9.7 mm.

The tablets are available in PVC/PVDC/aluminium perforated unit dose blisters. The pack sizes are 10 × 1, 14 × 1, 30 × 1, 56 × 1, 60 × 1, 90 × 1 and 100 × 1 film-coated tablets and multipacks containing 120 (2 packs of 60 × 1), 180 (2 packs of 90 × 1) and 200 (2 packs of 100 × 1) film-coated tablets.

Not all pack sizes may be marketed in your country.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH

Binger Strasse 173

55216 Ingelheim am Rhein

Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG

Binger Strasse 173

55216 Ingelheim am Rhein

Germany

Boehringer Ingelheim Hellas Single Member S.A.

5th km Paiania – Markopoulo

Koropi Attiki, 19441

Greece

Patheon France

40 boulevard de Champaret Bourgoin Jallieu, 38300 France

Boehringer Ingelheim France 100–104 Avenue de France 75013 Paris

France

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgiqu­e/Belgien SCS Boehringer Ingelheim Comm.V Tél/Tel: +32 2 773 33 11	Lietuva Boehringer Ingelheim RCV GmbH & Co KG Lietuvos filialas Tel.: +370 5 2595942
Efc^rapufl EbopuHrep HHrenxaňM PUB R-ioX u Ko Kr -K.TOH Ebnrapua	Luxembourg/Lu­xemburg SCS Boehringer Ingelheim Comm.V Tel/Tel: +32 2 773 33 11

Ten: +359 2 958 79 98

Česká republika Boehringer Ingelheim spol. s r.o. Tel: +420 234 655 111	Magyarorszag Boehringer Ingelheim RCV GmbH & Co KG Magyarorszagi Fioktelepe Tel.: +36 1 299 89 00
Danmark Boehringer Ingelheim Danmark A/S Tlf: +45 39 15 88 88	Malta Boehringer Ingelheim Ireland Ltd. Tel: +353 1 295 9620
Deutschland Boehringer Ingelheim Pharma GmbH & Co. KG Tel: +49 (0) 800 77 90 900	Nederland Boehringer Ingelheim b.v. Tel: +31 (0) 800 22 55 889

Lilly Deutschland GmbH

Tel. +49 (0) 6172 273 2222

Eesti Boehringer Ingelheim RCV GmbH & Co KG Eesti filiaal

Norge Boehringer Ingelheim Norway KS Tlf: +47 66 76 13 00

Tel: +372 612 8000

EXXáSa Boehringer Ingelheim Ellas A.E. Tql: +30 2 10 89 06 300	Österreich Boehringer Ingelheim RCV GmbH & Co KG Tel: +43 1 80 105–7870
España Boehringer Ingelheim España, S.A. Tel: +34 93 404 51 00	Polska Boehringer Ingelheim Sp.zo.o. Tel.: +48 22 699 0 699

Lilly S.A.

Tel: +34 91 663 50 00

France Boehringer Ingelheim France S.A.S. Tel: +33 3 26 50 45 33	Portugal Boehringer Ingelheim Portugal, Lda. Tel: +351 21 313 53 00
Lilly France SAS Tel: +33 1 55 49 34 34	Lilly Portugal Produtos Farmacéuticos, Lda Tel: +351 21 412 66 00
Hrvatska Boehringer Ingelheim Zagreb d.o.o. Tel: +385 1 2444 600	Romania Boehringer Ingelheim RCV GmbH & Co KG Viena – Sucursala Bucuresti Tel: +40 21 302 28 00

Slovenija

Boehringer Ingelheim RCV GmbH & Co KG

Podružnica Ljubljana

Tel: +386 1 586 40 00

This leaflet was last revised in {MM/YYYY }.

Detailed information on this medicine is available on the European Medicines Agency web site:.

ANNEX IV

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)

Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for empagliflozin, empagliflozin/met­formin, the scientific conclusions of CHMP are as follows:

In view of available data on tubulointerstitial nephritis from the literature and spontaneous reports highly suggestive of causality association including a close temporal relationship and a positive dechallenge, the PRAC considers a causal relationship between empagliflozin, empagliflozin/met­formin and tubulointerstitial nephritis is at least a reasonable possibility. The PRAC concluded that the product information of products containing empagliflozin, empagliflozin/met­formin should be amended accordingly.

In view of available data on the drug-drug interaction between empagliflozin and lithium from clinical trials and the literature suggestive for causal association, including in some cases a close temporal relationship and positive dechallenge/recha­llenge and in view of a plausible mechanism of interaction, the PRAC considers a causal relationship between empagliflozin, empagliflozin/met­formin and drugdrug interaction with lithium is at least a reasonable possibility. The PRAC concluded that the product information of products containing empagliflozin, empagliflozin/met­formin should be amended accordingly.

The CHMP agrees with the scientific conclusions made by the PRAC.

Grounds for the variation to the terms of the marketing authorisation(s)

On the basis of the scientific conclusions for empagliflozin, empagliflozin/met­formin the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing empagliflozin, empagliflozin/met­formin is unchanged subject to the proposed changes to the product information.

The CHMP recommends that the terms of the marketing authorisation(s) should be varied.

79

See subsections below for additional information

Identified adverse reactions of empagliflozin monotherapy

Identified adverse reactions of metformin monotherapy

Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia)

Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.

a See section 4.4

b 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%.

c 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.