Consumer medicine information

Jardiance

Empagliflozin

BRAND INFORMATION

Brand name

Jardiance

Active ingredient

Empagliflozin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Jardiance.

What is in this leaflet

This leaflet answers some common questions about Jardiance.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Jardiance against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet. More recent information may be available. The latest Consumer Medicine Information is available from your pharmacist, doctor, or from www.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 Jardiance is used for

Jardiance is used to lower blood sugar levels in patients with type 2 diabetes mellitus.

It may be used when diet plus exercise do not provide adequate blood sugar level control either:

  • alone as a single medicine, or
  • in combination with certain other anti-diabetic medicines such as:
    - metformin, or
    - sulfonylurea medicines such as glimepiride and glibenclamide, or
    - pioglitazone, or
    - insulin, or
    - dipeptidyl peptidase-4 inhibitor medicines such as linagliptin or sitagliptin.

If you have type 2 diabetes mellitus and cardiovascular disease, Jardiance can be used to reduce your risk of dying from your cardiovascular disease.

Type 2 diabetes mellitus is also called non-insulin-dependent diabetes mellitus or NIDDM. Type 2 diabetes develops if the body does not make enough insulin, or if the insulin that your body makes does not work as well as it should.

Insulin is a substance which helps to lower the level of sugar in your blood, especially after meals.

When the level of sugar builds up in your blood, this can cause damage to the body's cells and lead to serious problems with your heart, eyes, circulation or kidneys.

How Jardiance works

Jardiance contains the active ingredient, empagliflozin, which belongs to a group of medicines called SGLT2 (sodium-glucose co-transporter 2) inhibitors.

Jardiance works by blocking a protein in the kidneys called SGLT2. Jardiance removes blood sugar, which is too high because of your type 2 diabetes mellitus, via the urine. As a result, the levels of glucose in your blood are reduced.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

Jardiance is available only with a doctor's prescription.

Before you take Jardiance

When you must not take it

Do not take Jardiance if you have an allergy to:

  • any medicine containing empagliflozin (the active ingredient in Jardiance)
  • any of the other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

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

Do not take Jardiance if you have severe problems with your kidneys.

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

Do not breastfeed if you are taking this medicine. It is not known if the active ingredient in Jardiance passes into human breast milk and there is a possibility that your baby may be affected.

Do not give this medicine to a child under the age of 18 years. Safety and effectiveness in children younger than 18 years has not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

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

Tell your doctor if you have or have had any of the following medical conditions:

  • type 1 diabetes, a condition where your body does not produce insulin
  • diabetic ketoacidosis, a condition in which substances called 'ketone bodies' accumulate in the blood and which can lead to diabetic pre-coma. Symptoms include: rapid weight loss, feeling sick or being sick, stomach pain, excessive thirst, fast and deep breathing, unusual sleepiness or tiredness, a sweet smell to your breath, a sweet or metallic taste in your mouth, or a different odour to your urine or sweat
  • kidney problems
  • galactosaemia, a rare hereditary condition of galactose intolerance
  • frequent genital or urinary tract infections (infections of the bladder, kidney, or tubes that carry urine)
  • illnesses that will make you dehydrated (e.g. diarrhoea or a severe infection)
  • increased urine loss which may affect the fluid balance in your body.

Tell your doctor if you have heart problems, a history of low blood pressure or are 75 years of age or older.

Increased passing of urine due to the medicine may affect fluid balance in your body and increase your risk of dehydration.

Tell your doctor if you are 85 years of age or older. You should not start taking Jardiance if you are over 85 years of age.

If you have not told your doctor about any of the above, tell him/her before you start taking Jardiance.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Jardiance may interfere with each other. These include medicines used to treat high blood pressure known as water pills (diuretics).

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

How to take Jardiance

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

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

How much to take

The recommended dose is one 10 mg tablet once a day.

Your doctor may increase your dose to 25 mg once a day if your blood glucose levels remain high after starting treatment on 10 mg.

Your doctor will prescribe Jardiance alone, or in combination with another anti-diabetic medicine if that medicine alone is not sufficient to control your blood sugar level.

How to take it

Swallow the tablet whole with a full glass of water.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take it

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

This medicine helps to control your condition, but will not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is less than 12 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

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 Poisons Information Centre (telephone 13 11 26) for advice, or go to Emergency if you think that you or anyone else may have taken too much Jardiance. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Jardiance

Things you must do

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

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

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood or urine tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Follow your doctor's and/or dietician's advice on diet, drinking alcohol and exercise. Diet and exercise can help your body use its blood sugar better. It is important to stay on the diet and exercise program recommended by your doctor while taking Jardiance.

Make sure you check your blood glucose regularly. This is the best way to tell if your diabetes is being controlled properly. Your doctor or diabetes educator will show you how and when to do this.

Check your feet regularly and see your doctor if you notice any problems. Follow any other advice regarding foot care given by your doctor.

Talk to your doctor about when to stop taking Jardiance and when to start taking it again if you are about to have surgery.

Things you must not do

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

Do not give your medicine to anyone else, even if they have the same condition as you.

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

Things to be careful of

Be careful driving or operating machinery until you know how Jardiance affects you.

When taken with other anti-diabetic medicines, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher.

This may cause dizziness, light-headedness, tiredness, drowsiness in some people. Low blood glucose levels may also slow your reaction time and affect your ability to drive or operate machinery.

If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when doing any of the following things, which may increase the risk of your blood glucose becoming too low:

  • drinking alcohol
  • not eating enough
  • doing unexpected or vigorous exercise.

Side effects

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

This medicine helps most people with type 2 diabetes mellitus, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

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

  • genital burning, redness, pain and discharge which may be signs of a genital yeast infection
  • passing more urine than normal
  • itching
  • thirst.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the symptoms of low blood sugar such as:

  • sweating
  • weakness
  • hunger
  • dizziness
  • trembling
  • headache
  • flushing or paleness
  • numbness
  • a fast pounding heartbeat.

Low blood sugar may occur in patients who already take another medication to treat diabetes, such as a sulfonylurea or insulin. The dose of your sulfonylurea or insulin medicine may need to be reduced while taking Jardiance.

Tell your doctor as soon as possible if you notice any of the following:

  • burning sensation when passing urine
  • urine that appears cloudy
  • pain in the pelvis, or mid-back pain
  • straining or pain when passing urine
  • unusual thirst
  • light-headedness, or dizziness upon standing
  • fainting or loss of consciousness.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

Tell your doctor immediately if you experience pain or tenderness, itching, swelling in the genital or back passage area, fever or are generally feeling unwell. These may be symptoms of a serious and life-threatening infection called Fournier's gangrene. Your doctor may tell you to stop taking Jardiance.

Tell your doctor immediately 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:

  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • severe and sudden onset of itchy or raised skin rash, hives or nettle rash.

Tell your doctor immediately or go to Emergency if you notice any of the symptoms of diabetic ketoacidosis such as:

  • rapid weight loss
  • feeling sick or being sick
  • stomach pain
  • excessive thirst
  • fast and deep breathing
  • confusion
  • unusual sleepiness or tiredness
  • a sweet smell to your breath, a sweet or metallic taste in your mouth or a different odour to your urine or sweat.

In rare cases, empagliflozin, the active substance in Jardiance, can cause a serious side effect called diabetic ketoacidosis.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

After using Jardiance

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store Jardiance or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Jardiance is the brand name of your medicine.

Jardiance is available in two strengths:

  • Jardiance 10 mg tablets are pale yellow, round, biconvex and bevel-edged, marked with the BI company logo on one side and 'S10' on the other side.
  • Jardiance 25 mg tablets are pale yellow, oval and biconvex, marked with the BI company logo on one side and 'S25' on the other side.

Jardiance tablets are available in PVC/Aluminium blister packs of 10 (sample) or 30 tablets.

Ingredients

Active ingredient:

  • Jardiance 10 mg - 10 mg of empagliflozin.
  • Jardiance 25 mg - 25 mg of empagliflozin.

Inactive ingredients:

  • lactose monohydrate
  • microcrystalline cellulose
  • hyprolose
  • croscarmellose sodium
  • colloidal anhydrous silica
  • magnesium stearate.

Tablet coating:

  • hypromellose
  • titanium dioxide
  • purified talc
  • macrogol 400
  • iron oxide yellow.

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

Supplier

Jardiance tablets are 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 January 2020.

® Jardiance is a registered trade mark of Boehringer Ingelheim.

© Boehringer Ingelheim Pty Limited 2020.

Australian Registration Numbers:

Jardiance 10 mg (AUST R 208829)

Jardiance 25 mg (AUST R 208827)

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Jardiance

Active ingredient

Empagliflozin

Schedule

S4

 

1 Name of Medicine

Empagliflozin.

2 Qualitative and Quantitative Composition

Jardiance 10 mg film-coated tablets contains 10 mg empagliflozin.
Jardiance 25 mg film-coated tablets contains 25 mg empagliflozin.

Excipients with known effect.

The Jardiance 10 mg tablet contains 162.5 mg of lactose monohydrate and the Jardiance 25 mg tablet contains 113 mg of lactose monohydrate per maximum recommended daily dose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Jardiance are film-coated tablets for oral administration.
Jardiance 10 mg film-coated tablets are pale yellow, round, biconvex and bevel-edged tablets. One side is debossed with the code 'S10', the other side is debossed with the Boehringer Ingelheim company symbol.
Jardiance 25 mg film-coated tablets are pale yellow, oval, biconvex tablets. One side is debossed with the code 'S25', the other side is debossed with the Boehringer Ingelheim company symbol.

4 Clinical Particulars

4.1 Therapeutic Indications

Glycaemic control.

Jardiance is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults as:

Monotherapy.

When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance.

Add-on combination therapy.

In combination with other glucose lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Prevention of cardiovascular death.

Jardiance is indicated in patients 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, Jardiance should be used in conjunction with other measures to reduce cardiovascular risk in line with the current standard of care.

4.2 Dose and Method of Administration

The recommended starting dose of Jardiance is 10 mg once daily. In patients tolerating empagliflozin 10 mg once daily and requiring additional glycaemic control, the dose can be increased to 25 mg once daily. Jardiance can be taken with or without food.

Combination therapy.

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

Patients with renal impairment.

Assess renal function prior to initiation of empagliflozin and periodically thereafter.
Jardiance is contraindicated in patients with eGFR < 30 mL/min/1.73 m2. No dose adjustment is required for patients with eGFR ≥ 30 mL/min/1.73 m2 (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Patients with hepatic impairment.

No dose adjustment is recommended for patients with hepatic impairment.

Elderly patients.

No dosage adjustment is recommended based on age. Therapeutic experience in patients aged 85 years and older is limited. Initiation of empagliflozin therapy in this population is not recommended (see Section 4.4 Special Warnings and Precautions for Use). Patients aged 75 years and older should be prescribed with caution (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric population.

Safety and effectiveness of Jardiance in children under 18 years of age have not been established.

4.3 Contraindications

Hypersensitivity to empagliflozin or any of the excipients in Jardiance.
Patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end-stage renal disease and patients on dialysis. The efficacy of Jardiance is dependent on renal function (see Section 4.4 Special Warnings and Precautions for Use).
In case of rare hereditary conditions that may be incompatible with an excipient of the product, the use of the product is contraindicated. The Jardiance 10 mg tablet contains 162.5 mg of lactose monohydrate and the Jardiance 25 mg tablet contains 113 mg of lactose monohydrate per maximum recommended daily dose. Patients with the rare hereditary conditions of galactose intolerance, e.g. galactosaemia should not take this medicine.

4.4 Special Warnings and Precautions for Use

General.

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

Diabetic ketoacidosis.

Jardiance 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 Jardiance 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 Jardiance 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, Jardiance 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 Jardiance, 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, 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. Jardiance should be used with caution in these patients. When reducing the insulin dose in patients requiring insulin, caution should be taken (see Section 4.2 Dose and Method of Administration). Consider monitoring for ketoacidosis and temporarily discontinuing Jardiance in clinical situations known to predispose ketoacidosis. In these situations, consider monitoring of ketones, even if Jardiance treatment has been interrupted.

Surgery.

Treatment with Jardiance should be ceased prior to major surgery. An increase in other glucose lowering agents may be required during this time.
Patients scheduled for non-urgent surgery who have not ceased empagliflozin should be assessed and consideration should be given to postponing the procedure.
Treatment with Jardiance may be restarted once the patient's condition has stabilised and oral intake is normal.

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 Jardiance. 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)). Patients should be alerted to the symptoms of urinary tract infection, and advised to seek treatment promptly.
Discontinuation of empagliflozin 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 Jardiance who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, Jardiance should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).

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

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.

Use in 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.
Jardiance is contraindicated for use in patients with eGFR < 30 mL/min/1.73 m2 (see Section 4.2 Dose and Method of Administration, Patients with renal impairment; Section 4.3 Contraindications).

Monitoring of renal function.

Due to the mechanism of action, the efficacy of Jardiance is dependent on renal function.
Therefore assessment of renal function is recommended:
prior to empagliflozin initiation and periodically during treatment, i.e. at least yearly;
prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter.
Patients treated with empagliflozin can experience an initial fall in eGFR. More intensive monitoring of renal function is recommended, particularly following treatment initiation, if empagliflozin is used in patients with an eGFR < 60 mL/min/1.73 m2, especially if the eGFR is < 45 mL/min/1.73 m2.
Empagliflozin should be discontinued when the eGFR is below 30 mL/min/1.73 m2 or CrCl < 30 mL/min (see Section 4.3 Contraindications).

Use in the elderly.

Patients aged 75 years and older may be at increased risk of volume depletion, therefore, Jardiance should be prescribed with caution in these patients (see Section 4.8 Adverse Effects (Undesirable Effects)).
Therapeutic experience in patients aged 85 years and older is limited. Initiation of Jardiance therapy in this population is not recommended.

Paediatric use.

Safety and effectiveness of Jardiance in children under 18 years of age have not been established.

Effect on laboratory tests.

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

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

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 UGT2B7, UGT1A3, UGT1A8, and UGT1A9. 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, 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 coadministered with other commonly used medicinal products. Based on results of pharmacokinetic studies no dose adjustment of Jardiance is recommended when coadministered with commonly prescribed medicinal products.
Empagliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, in healthy volunteers and with or without coadministration of torasemide and hydrochlorothiazide in patients with T2DM. Increases in overall exposure (AUC) of empagliflozin were seen following coadministration 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 metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, and oral contraceptives when coadministered in healthy volunteers.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies on the effect on human fertility have been conducted for Jardiance. Studies in rats at doses up to 700 mg/kg/day, do not indicate direct or indirect harmful effects with respect to fertility. In female rats this dose was 90 and 155-fold the systemic AUC exposure anticipated with a human dose of 10 and 25 mg.
(Category D)
There are limited data from the use of Jardiance in pregnant women. It is recommended to avoid the use of Jardiance during pregnancy unless clearly needed.
Empagliflozin administered during the period of organogenesis was not teratogenic at doses up to 300 mg/kg in the rat or rabbit, which corresponds to approximately 48 and 122 times or 128 and 325 times the clinical dose of empagliflozin based on AUC exposure associated with the 25 mg and 10 mg doses, respectively. Doses of empagliflozin causing maternal toxicity in the rat also caused the malformation of bent limb bones at exposures approximately 155 and 393 times the clinical dose associated with the 25 mg and 10 mg doses, respectively. Maternally toxic doses in the rabbit also caused increased embryofetal loss at doses approximately 139 and 353 times the clinical dose associated with the 25 mg and 10 mg 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 (maternal exposures approximately 4 and 11 times those seen with a clinical dose of 25 mg and 10 mg, respectively). No adverse effects on postnatal development were noted at 10 mg/kg/day (maternal exposures approximately equivalent to those seen with a clinical dose of 25 mg).
Specialised studies in rats with other members of the pharmacological class have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy. Similar effects have been seen for empagliflozin at approximately 11 times the clinical AUC exposure associated with the 25 mg dose. These findings were absent after a 13 week drug free recovery period. Jardiance should be used in pregnancy only if the expected benefit to the patient justifies the potential risk to the fetus.
No data in humans are available on excretion of empagliflozin into milk. Available nonclinical data in animals have shown excretion of empagliflozin in milk. Reduced bodyweight 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 breastfeeding during treatment with Jardiance.

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.

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.
A total of 15,582 patients with T2DM were treated in clinical studies to evaluate the safety of empagliflozin, of which 10,004 patients were treated with empagliflozin, either alone or in combination with metformin, a sulfonylurea, a PPARγ agonist, DPP-4 inhibitors, or insulin. This pool includes the EMPA-REG OUTCOME study involving 7020 patients at high cardiovascular risk (mean age 63.1 years, 9.3% patients at least 75 years old, 28.5% women) treated with Jardiance 10 mg/day (n = 2345), Jardiance 25 mg/day (n = 2342), or placebo (n = 2333) up to 4.5 years. The overall safety profile of empagliflozin in this study was comparable to the previously known safety profile.
In the above described trials, the frequency of adverse effects leading to discontinuation was similar by treatment groups for placebo (5.6%), Jardiance 10 mg (5.0%) and Jardiance 25 mg (5.3%).
Placebo controlled double blinded trials of 18 to 24 weeks of exposure included 3534 patients, of which 1183 were treated with placebo, 1185 were treated with Jardiance 10 mg and 1166 were treated with Jardiance 25 mg (Table 1).
The most frequent adverse drug reaction was hypoglycaemia, which depended on the type of background therapy used in the respective studies (Table 2).

Hypoglycaemia.

The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar for Jardiance and placebo as monotherapy, as add-on to metformin, add-on to pioglitazone ± metformin, and as add-on with linagliptin + metformin. The frequency of patients with hypoglycaemia was increased in patients treated with Jardiance compared to placebo when given as add-on to metformin plus sulfonylurea, and as add-on to insulin ± metformin and ± sulfonylurea (Table 2).

Major hypoglycaemia (events requiring assistance).

The frequency of patients with major hypoglycaemic events was low (< 1%) and similar for Jardiance and placebo as monotherapy, as add-on to metformin ± sulfonylurea, as add-on to pioglitazone ± metformin, and as add-on with linagliptin + metformin.
The frequency of patients with major hypoglycaemic events was increased in patients treated with Jardiance compared to placebo when given as add-on to insulin ± metformin and ± sulfonylurea.

Urinary tract infection.

The overall frequency of urinary tract infection adverse events was similar in patients treated with Jardiance 25 mg and placebo (7.0% and 7.2%) and higher in patients treated with Jardiance 10 mg (8.8%). Similar to placebo, urinary tract infection was reported more frequently for Jardiance in patients with a history of chronic or recurrent urinary tract infections. The intensity of urinary tract infections was similar to placebo for mild, moderate, and severe intensity reports. Urinary tract infection events were reported more frequently for empagliflozin compared to placebo in female patients, but not in male patients.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently for Jardiance 10 mg (4.0%) and Jardiance 25 mg (3.9%) compared to placebo (1.0%). These adverse events were reported more frequently for empagliflozin compared to placebo in female patients, and the difference in frequency was less pronounced in male patients. The genital tract infections were mild and moderate in intensity, none was severe in intensity.

Increased urination.

As expected via its mechanism of action, increased urination (as assessed by preferred term search including pollakiuria, polyuria, nocturia) was observed at higher frequencies in patients treated with Jardiance 10 mg (3.5%) and Jardiance 25 mg (3.3%) compared to placebo (1.4%). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and Jardiance (< 1%).

Volume depletion.

The overall frequency of volume depletion (including the predefined terms BP (ambulatory) decreased, SBP decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension and syncope) was similar to placebo (0.6% for Jardiance 10 mg, 0.4% for Jardiance 25 mg and 0.3% for placebo). The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect hydration status of patients aged 75 years and older. In patients ≥ 75 years of age (pooling of all patients with diabetes, n = 13,402) the frequency of volume depletion events was similar for Jardiance 10 mg (2.3%) compared to placebo (2.1%), but it increased with Jardiance 25 mg (4.3%).

Blood creatinine increased and glomerular filtration rate decreased.

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 (blood creatinine increased: Jardiance 10 mg 0.6%, Jardiance 25 mg 0.1%, placebo 0.5%; glomerular filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.3%).
In placebo controlled, double blind studies up to 76 weeks, initial transient increases in creatinine (mean change from baseline after 12 weeks: Jardiance 10 mg 0.0011 mmol/L, Jardiance 25 mg 0.0006 mmol/L) and initial transient decreases in estimated glomerular filtration rates (mean change from baseline after 12 weeks: Jardiance 10 mg -1.34 mL/min/1.73 m2, Jardiance 25 mg -1.37 mL/min/1.73 m2) have been observed. These changes were generally reversible during continuous treatment or after drug discontinuation (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Cardiovascular outcome, Figure 4 for the eGFR course in the EMPA-REG OUTCOME study).

Laboratory parameters.

Haematocrit increased.

In a pooled safety analysis (pooling of all patients with diabetes, n = 13,402), mean changes from baseline in haematocrit were 3.4% and 3.6% for empagliflozin 10 mg and 25 mg, respectively, compared to -0.1% 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 (pooling of all patients with diabetes, n = 13,402), mean percent increases from baseline for empagliflozin 10 mg and 25 mg versus placebo, respectively, were total cholesterol 4.9% and 5.7% versus 3.5%; HDL cholesterol 3.3% and 3.6% versus 0.4%; LDL cholesterol 9.5% and 10.0% versus 7.5%; triglycerides 9.2% and 9.9% versus 10.5%.

Postmarketing experience.

The following postmarketing case reports have been reported during postapproval use of Jardiance. 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.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).
During controlled clinical trials in healthy subjects, single doses of up to 800 mg empagliflozin, equivalent to 32 times the maximum recommended daily dose, were well tolerated.

Treatment.

In the event of an overdose, supportive treatment should be initiated as appropriate to the patient's clinical status. The removal of empagliflozin by haemodialysis has not been studied.

5 Pharmacological Properties

Pharmacotherapeutic group: SGLT2 inhibitor. ATC code: A10BK03.

5.1 Pharmacodynamic Properties

Mechanism of action.

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 reabsorption 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 reabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent upon the blood glucose concentration and glomerular filtration rate (GFR). Through inhibition of SGLT2 in patients with T2DM and hyperglycaemia, excess glucose is excreted in the urine.
In patients with T2DM, urinary glucose excretion increased immediately following the first dose of empagliflozin and is continuous over the 24 hour dosing interval. Increased urinary glucose excretion was maintained at the end of 4 week treatment period, averaging approximately 78 g/day with empagliflozin 25 mg once daily. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with T2DM.
Empagliflozin (10 mg and 25 mg) improves both fasting and postprandial plasma glucose levels.
There is no direct effect on changes in β cell function and insulin secretion/ action, and this contributes to a low risk of hypoglycaemia. Improvement of surrogate markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) and proinsulin to insulin ratio were noted. In addition urinary glucose excretion triggers calorie loss, associated with body fat loss and bodyweight reduction.
The glucosuria observed with empagliflozin is accompanied by mild diuresis which may contribute to sustained and moderate reduction of blood pressure (BP).

Clinical trials.

A total of 17,331 patients with T2DM were evaluated in 15 double blind, placebo and active controlled clinical studies, of which 4603 patients received empagliflozin 10 mg and 5567 received empagliflozin 25 mg. Six studies had a treatment duration of 24 weeks; in extensions of applicable studies, and other trials, patients were exposed to Jardiance for up to 102 weeks.
Treatment with empagliflozin (10 mg and 25 mg) as monotherapy and in combination with metformin, pioglitazone, sulfonylurea, dipeptidyl peptidase 4 (DPP-4) inhibitors, and insulin lead to clinically relevant improvements in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), bodyweight, systolic and diastolic BP (SBP and DBP, respectively). Administration of empagliflozin 25 mg resulted in a higher proportion of patients achieving an 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 T2DM, BMI, insulin resistance based on HOMA-IR, and beta cell function based on HOMA-β. Higher baseline HbA1c was associated with a greater reduction in HbA1c. Clinically meaningful HbA1c reduction was seen in patients with eGFR > 30 mL/min/1.73 m2 (see Section 4.2 Dose and Method of Administration, Patients with renal impairment). In patients aged 75 years and older, reduced efficacy of Jardiance was observed.

Empagliflozin as monotherapy.

The efficacy and safety of empagliflozin (10 mg and 25 mg) as monotherapy was evaluated in a double blind, placebo and active controlled study of 24 weeks duration in treatment naïve patients. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in bodyweight and blood pressure (systolic, SBP and diastolic, DBP) after 24 weeks of treatment.
Treatment with Jardiance resulted in statistically significant reductions in HbA1c, bodyweight and SBP compared to placebo (Table 3) and a clinically meaningful decrease in FPG. A numerical decrease in DBP was seen but did not reach statistical significance versus placebo (-1.0 mmHg for empagliflozin 10 mg, -1.9 mmHg for empagliflozin 25 mg, -0.5 mmHg for placebo, and +0.7 mmHg for sitagliptin).
In a prespecified analysis of patients (n = 201) with a baseline HbA1c ≥ 8.5% to ≤ 10% empagliflozin resulted in a reduction in HbA1c from baseline of -1.44% for empagliflozin 10 mg, -1.43% for empagliflozin 25 mg, +0.01% for placebo, and -1.04% for sitagliptin.
In the double blind placebo controlled extension of this study, reductions of HbA1c (change from baseline of -0.65% for empagliflozin 10 mg, -0.76% for empagliflozin 25 mg, +0.13% for placebo, and -0.53% for sitagliptin), bodyweight (change from baseline of -2.24 kg for empagliflozin 10 mg, -2.45 kg for empagliflozin 25 mg, -0.43 kg for placebo, and +0.10 kg for sitagliptin) and BP (SBP: change from baseline of -4.1 mmHg for empagliflozin 10 mg, -4.2 mmHg for empagliflozin 25 mg, -0.7 mmHg for placebo, and -0.3 mmHg for sitagliptin; DBP: change from baseline of -1.6 mmHg for empagliflozin 10 mg, -1.6 mmHg for empagliflozin 25 mg, -0.6 mmHg for placebo, and -0.1 mmHg for sitagliptin) were sustained up to 76 weeks of treatment.
Treatment with Jardiance daily significantly improved marker of beta cell function, including HOMA-β.

Empagliflozin as add-on to metformin therapy.

A double blind, placebo controlled study of 24 weeks duration was conducted to evaluate the efficacy and safety of empagliflozin in patients with T2DM not controlled on metformin. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in bodyweight and mean daily plasma glucose (MDG) after 24 weeks of treatment.
Treatment with Jardiance resulted in statistically significant improvements in HbA1c and bodyweight, and clinically meaningful reductions in FPG and BP compared to placebo (Table 4).
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), bodyweight (change from baseline of -2.39 kg for empagliflozin 10 mg, -2.65 kg for empagliflozin 25 mg and -0.46 kg for placebo) and BP (SBP: change from baseline of -5.2 mmHg for empagliflozin 10 mg, -4.5 mmHg for empagliflozin 25 mg and -0.8 mmHg for placebo; DBP: change from baseline of -2.5 mmHg for empagliflozin 10 mg, -1.9 mmHg for empagliflozin 25 mg and -0.5 mmHg for placebo) were sustained up to 76 weeks of treatment.

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 bodyweight 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 5 and 6).

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

A double blind, placebo controlled study of 24 weeks duration was conducted to evaluate the efficacy and safety of empagliflozin in patients not sufficiently treated with a combination of metformin and a sulfonylurea. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in bodyweight and mean daily plasma glucose (MDG) after 24 weeks of treatment.
Treatment with Jardiance resulted in statistically significant improvements in HbA1c and bodyweight and clinically meaningful reductions in FPG and BP compared to placebo (Table 7).
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), bodyweight (change from baseline of -2.44 kg for empagliflozin 10 mg, -2.28 kg for empagliflozin and -0.63 kg for placebo) and BP (SBP: change from baseline of -3.8 mmHg for empagliflozin 10 mg, -3.7 mmHg for empagliflozin 25 mg and -1.6 mmHg for placebo; DBP: change from baseline of -2.6 mmHg for empagliflozin 10 mg, -2.3 mmHg for empagliflozin 25 mg and -1.4 mmHg for placebo) were sustained up to 76 weeks of treatment.

2 hour postprandial glucose.

Treatment with empagliflozin as add-on to metformin or metformin plus sulfonylurea resulted in clinically meaningful improvement of 2 hour postprandial glucose (meal tolerance test) at 24 weeks (add-on to metformin: -2.55 mmol/L for empagliflozin 10 mg (n = 52), -2.47 mmol/L for empagliflozin 25 mg (n = 58) and +0.33 mmol/L for placebo (n = 57); add-on to metformin plus sulfonylurea: -1.98 mmol/L for empagliflozin 10 mg (n = 44), -2.03 mmol/L for empagliflozin 25 mg (n = 46) and -0.13 mmol/L for placebo (n = 35)).

Empagliflozin as add-on to a combination of pioglitazone therapy (± metformin).

The efficacy and safety of empagliflozin was evaluated in a double blind, placebo controlled study of 24 weeks duration in patients with T2DM not controlled on a combination of metformin and pioglitazone or pioglitazone alone. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in FPG and bodyweight after 24 weeks of treatment.
Empagliflozin in combination with pioglitazone (dose ≥ 30 mg) with or without metformin resulted in statistically significant reductions in HbA1c, FPG, and bodyweight and clinically meaningful reductions in BP compared to placebo (Table 8).
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), bodyweight (change from baseline of -1.47 kg for empagliflozin 10 mg, -1.21 kg for empagliflozin 25 mg and +0.50 kg for placebo) and BP (SBP: change from baseline of -1.7 mmHg for empagliflozin 10 mg, -3.4 mmHg for empagliflozin 25 mg and +0.3 mmHg for placebo; DBP: change from baseline of -1.3 mmHg for empagliflozin 10 mg, -2.0 mmHg for empagliflozin 25 mg and +0.2 mmHg for placebo) were sustained up to 76 weeks of treatment.

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 (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 9). Empagliflozin daily resulted in a statistically significant reduction in bodyweight, systolic and diastolic blood pressure.
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 (10 mg or 25 mg) as add-on to basal insulin with or without concomitant metformin and/or sulfonylurea therapy was evaluated in a double blind, placebo controlled trial of 78 weeks duration. The primary endpoint was the change from baseline in HbA1c after 18 weeks of treatment. The key secondary endpoints were the change from baseline in dose of basal insulin dose after 78 weeks of treatment and change from baseline in HbA1c after 78 weeks of treatment.
During the initial 18 weeks the insulin dose was to be kept stable, but was adjusted to achieve a FPG < 6.10 mmol/L in the following 60 weeks.
At week 18, empagliflozin (10 mg or 25 mg) provided statistically significant improvement in 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 10).
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), bodyweight (-2.47 kg for empagliflozin 10 mg, -1.96 kg for empagliflozin 25 mg and +1.16 kg for placebo, p < 0.0001), BP (SBP: -4.1 mmHg for empagliflozin 10 mg, -2.4 mmHg for empagliflozin 25 mg and +0.1 mmHg for placebo; DBP: -2.9 mmHg for empagliflozin 10 mg, -1.5 mmHg for empagliflozin 25 mg and -0.3 mmHg for placebo).

Empagliflozin as add-on to multiple daily injection (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 to be kept stable, but was adjusted to achieve preprandial glucose levels < 5.5 mmol/L, and postprandial 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 11). 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), bodyweight, and blood pressure (SBP: change from baseline of -2.6 mmHg for placebo, -3.9 mmHg for empagliflozin 10 mg and -4.0 mmHg for empagliflozin 25 mg, DBP: change from baseline of -1.0 mmHg for placebo, -1.4 mmHg for empagliflozin 10 mg and -2.6 mmHg for empagliflozin 25 mg).

Empagliflozin as add-on to DPP-4 inhibitor therapy.

The efficacy and safety of empagliflozin as add-on to DPP-4 inhibitors plus metformin, with or without one additional oral antidiabetic drug was evaluated in 160 patients with T2DM and high cardiovascular risk. Treatment with empagliflozin for 28 weeks reduced HbA1c compared to placebo (change from baseline -0.54% for empagliflozin 10 mg, -0.52% for empagliflozin 25 mg and -0.02% for placebo).

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

In patients inadequately controlled on metformin and linagliptin, 24 weeks treatment with both doses (10 mg and 25 mg) of empagliflozin provided statistically significant improvements in HbA1c, FPG and bodyweight compared to placebo (background linagliptin 5 mg). A statistically significantly greater number of patients with a baseline HbA1c ≥ 7.0% and treated with empagliflozin achieved a target HbA1c of < 7% compared to placebo (background linagliptin 5 mg) (Table 12). After 24 weeks' treatment with empagliflozin, both SBPs and DBPs were reduced, -2.6/-1.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 25 mg/linagliptin 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 (background 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 [background linagliptin 5 mg]) and with empagliflozin 10 mg/linagliptin 5 mg -1.3% at 24 weeks (p < 0.0001 versus placebo [background linagliptin 5 mg]).

Patients with renal impairment, 52 weeks placebo controlled data.

The efficacy and safety of empagliflozin as add-on to antidiabetic therapy was evaluated in patients with mild and moderate renal impairment in a double blind, placebo controlled study for 52 weeks.
Treatment with Jardiance led to statistically significant reduction of HbA1c and clinically meaningful improvement in FPG, bodyweight and BP compared to placebo at week 24 (Table 13). The improvement in HbA1c, FPG, bodyweight, and BP was sustained up to 52 weeks.

Patients with high baseline HbA1c > 10%.

In a prespecified pooled analysis of three phase 3 studies, treatment with open label empagliflozin 25 mg in patients with severe hyperglycaemia (n = 184, mean baseline HbA1c 11.15%) resulted in a clinically meaningful reduction in HbA1c from baseline (-3.27%) at week 24.

Bodyweight.

In a prespecified pooled analysis of 4 placebo controlled studies, treatment with empagliflozin resulted in bodyweight reduction compared to placebo at week 24 (-2.04 kg for empagliflozin 10 mg, -2.26 kg for empagliflozin 25 mg and -0.24 kg for placebo) that was maintained up to week 52 (-1.96 kg for empagliflozin 10 mg, -2.25 kg for empagliflozin 25 mg and -0.16 kg for placebo).

Waist circumference.

At 24 weeks, treatment with empagliflozin as monotherapy or as add-on to metformin, pioglitazone, or metformin plus sulfonylurea resulted in sustained reduction of waist circumference over the duration of studies in a range of -1.7 cm to -0.9 cm for empagliflozin and -0.5 cm to +0.2 cm for placebo.

Blood pressure.

The efficacy and safety of empagliflozin (10 mg and 25 mg) was evaluated in a double blind, placebo controlled study of 12 weeks duration in patients with T2DM and high BP on different oral antidiabetic drugs and up to 2 antihypertensive agents (Table 14). Treatment with empagliflozin once daily resulted in statistically significant improvement in HbA1c and reduction in 24 hour mean SBP and DBP as determined by ambulatory BP monitoring. Treatment with empagliflozin also provided reductions in seated SBP (change from baseline of -0.67 mmHg for placebo, -4.60 mmHg for empagliflozin 10 mg and -5.47 mmHg for empagliflozin 25 mg) and seated DBP (change from baseline of -1.13 mmHg for placebo, -3.06 mmHg for empagliflozin 10 mg and -3.02 mmHg for empagliflozin 25 mg).
In a prespecified pooled analysis of 4 placebo controlled studies, treatment with empagliflozin resulted in a reduction in SBP (-3.9 mmHg for empagliflozin 10 mg and -4.3 mmHg for empagliflozin 25 mg) compared with placebo (-0.5 mmHg), and in DBP (-1.8 mmHg for empagliflozin 10 mg and -2.0 mmHg for empagliflozin 25 mg) compared with placebo (-0.5 mmHg), at week 24, that were maintained up to week 52.

Cardiovascular outcome.

The EMPA-REG OUTCOME study is a multicentre, multinational, randomised, double blind, placebo controlled trial investigating the effect of Jardiance as adjunct to standard care therapy in reducing cardiovascular (CV) events in patients with type 2 diabetes and one or more CV risk factors, including coronary artery disease, peripheral artery disease, history of myocardial infarction (MI), or history of stroke. The primary endpoint was the time to first event in the composite of CV death, nonfatal MI, or nonfatal stroke (Major Adverse Cardiovascular Events (MACE-3)). Additional prespecified 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 Jardiance (empagliflozin 10 mg: 2345, empagliflozin 25 mg: 2342, placebo: 2333) and followed for a median of 3.1 years.
The population was 72.4% Caucasian, 21.6% Asian, and 5.1% black. The mean age was 63 years and 71.5% were male. At baseline, approximately 81% of patients were being treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 89% with anticoagulants, and 81% with lipid lowering medication. Approximately 74% of patients were being treated with metformin at baseline, 48% with insulin and 43% with sulfonylurea. The baseline HbA1c was < 7% in 6.0% of the patients, 7 to < 8% in 43.7% of the patients, 8 to < 9% in 33.2% of the patients, and ≥ 9% in 17.0% of the patients. The time since diagnosis of diabetes was ≤ 5 years for 18.0% of the patients, > 5 to 10 years for 24.9% of the patients, and > 10 years for 57.1% of the patients.
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, and high density lipoprotein (HDL) 1.1 mmol/L. The urinary albumin to creatinine ratio (UACR) was normal in 59.4% of the patients, 28.7% had microalbuminuria, and 11% had macroalbuminuria.

Reductions in risk of CV death and all cause mortality.

Jardiance was superior in reducing the primary composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke compared to placebo. The incidence rate was 37.1 for Jardiance (10 and 25 mg, pooled) compared to 43.9 with placebo. The treatment effect reflected a significant reduction in cardiovascular death with no significant change in nonfatal MI, or nonfatal stroke (Table 15 and Figure 1).
Jardiance also improved all cause mortality (Table 15), which was driven by a reduction in cardiovascular death with Jardiance. There was no statistically significant difference between empagliflozin and placebo in noncardiovascular mortality.

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

Jardiance significantly reduced the risk of hospitalisation for heart failure and cardiovascular death or hospitalisation for heart failure compared with placebo (Table 16 and Figure 2).
The cardiovascular benefits (CV death and hospitalisation for heart failure or CV death) of Jardiance observed were consistent across major demographic and disease subgroups.

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 17 and Figure 3).
Jardiance compared with placebo showed a significantly higher occurrence of sustained normo or microalbuminuria in patients with baseline macroalbuminuria (HR 1.82, 95% CI: 1.40, 2.37).
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).

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

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 (Cmax) with a median time to reach Cmax (tmax) of 1.5 h postdose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady-state mean plasma area under the curve (AUC) was 4740 nanomol.h/L and Cmax was 687 nanomol/L with 25 mg empagliflozin once daily. Systemic exposure of empagliflozin increased in a dose proportional manner. The single dose and steady-state pharmacokinetics parameters of empagliflozin were similar suggesting linear pharmacokinetics with respect to time. There were no clinically relevant differences in empagliflozin pharmacokinetics between healthy volunteers and patients with T2DM.
Administration of 25 mg empagliflozin after intake of a high fat and high calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and 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 UGT2B7, UGT1A3, UGT1A8, and UGT1A9.

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 intersubject and residual variabilities for empagliflozin oral clearance were 39.1% and 35.8%, respectively. With once daily dosing, steady-state plasma concentrations of empagliflozin were reached by the fifth dose. Consistent with half-life, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state. Following administration of an oral [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.

Pharmacokinetics in special patient groups.

Pharmacokinetics in children.

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

Pharmacokinetics in the elderly.

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

Pharmacokinetics in patients with renal impairment.

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/endstage renal disease (ESRD) patients, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairment and kidney failure/ESRD compared to patients with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in subjects with mild and severe renal impairment as compared to subjects with normal renal function. In line with the phase I study, 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 insufficiency. However, due to the mechanism of action, the efficacy of Jardiance is dependent on renal function, and therefore Jardiance is contraindicated for use in patients with persistent eGFR < 45 mL/min/1.73 m2 (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Pharmacokinetics in patients with hepatic impairment.

In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased approximately by 23%, 47%, and 75% and 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.

Body mass index (BMI).

No dosage adjustment is necessary based on BMI. Body mass index had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.

Gender.

No dosage adjustment is necessary based on gender. Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.

Race.

No dosage adjustment is necessary based on race. Based on the population pharmacokinetic analysis, AUC was estimated to be 13.5% higher in Asian patients with a BMI of 25 kg/m2 compared to non-Asian patients with a BMI of 25 kg/m2.

5.3 Preclinical Safety Data

Genotoxicity.

Empagliflozin was not mutagenic or clastogenic in a battery of genotoxicity studies, including the Ames bacterial mutagenicity assay (bacterial reverse mutation), in vitro mouse lymphoma tk assays and in vivo rat bone marrow micronucleus assays.

Carcinogenicity.

Two year oral carcinogenicity studies were conducted in mice and rats. There was an increase in renal adenomas and carcinomas in male mice given empagliflozin at 1000 mg/kg/day. No renal tumours were seen at 300 mg/kg/day (11 and 28 times the exposure at the clinical dose of 25 mg and 10 mg, respectively). These tumours are likely associated with a metabolic pathway not present in humans, and are considered to be irrelevant to patients given 10 or 25 mg empagliflozin. No drug related tumours were seen in female mice or female 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 10 or 25 mg empagliflozin. In male rats, treatment related benign vascular proliferative lesions (haemangiomas) of the mesenteric lymph node, were observed at 700 mg/kg/day, but not at 300 mg/kg/day (approximately 26 and 65 times the exposure at the clinical does of 25 mg and 10 mg, respectively). These tumours are common in rats and are unlikely to be relevant to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Lactose monohydrate, microcrystalline cellulose, hyprolose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate.

Tablet coating.

Hypromellose, titanium dioxide, purified talc, macrogol 400, iron oxide yellow.

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

Jardiance 10 mg is available in PVC/Aluminium blister packs containing 10 (sample) and 30 tablets.
Jardiance 25 mg is available in PVC/Aluminium blister packs containing 10 (sample) and 30 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

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.
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:

CAS number.

864070-44-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes