Consumer medicine information

Glyxambi

Empagliflozin; Linagliptin

BRAND INFORMATION

Brand name

Glyxambi

Active ingredient

Empagliflozin; Linagliptin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Glyxambi.

What is in this leaflet

This leaflet answers some common questions about Glyxambi. 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 Glyxambi 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 Glyxambi is used for

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

Glyxambi may be used when diet plus exercise do not provide adequate blood sugar level control either: alone or with certain other medicines for diabetes such as metformin.

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

Type 2 diabetes mellitus 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, brain, eyes, circulation, nerves or kidneys.

How Glyxambi works

Glyxambi contains two different active ingredients:

  • empagliflozin, which belongs to a group of medicines called SGLT2 (sodium glucose co-transporter 2) inhibitors, and
  • linagliptin, which belongs to a group of medicines called DPP-4 (dipeptidyl peptidase 4) inhibitors.

Both medicines work together to control blood sugar levels in patients with type 2 diabetes mellitus by increasing the amount of glucose expelled in urine, and producing more insulin to lower blood sugar levels.

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

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

Continue to follow the diet and/or exercises recommended for you while you are on treatment with Glyxambi.

Glyxambi can also be used as an alternative to taking both empagliflozin (or other SGLT2 inhibitors) and linagliptin (or other DPP-4 inhibitors) as single tablets.

In this case, do not continue taking any one of those tablets separately, if you are taking this medicine.

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

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

Before you take Glyxambi

When you must not take it

Do not take Glyxambi if you have an allergy to:

  • any medicine containing empagliflozin or linagliptin (the active ingredients in Glyxambi)
  • 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 Glyxambi 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 whether the active ingredients in Glyxambi pass 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 have 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 included: 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
  • if you have or have had a disease of the pancreas
  • illnesses that will make you dehydrated (e.g. diarrhoea or a severe infection)
  • frequent genital or urinary tract infections (infections of the bladder, kidney, or tubes that carry urine)
  • increased urine loss which may affect the fluid balance in your body.

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

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

Tell your doctor if you are 75 years of age or older. You should not start taking Glyxambi if you are over 75 years of age.

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

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 Glyxambi may interfere with each other. These include:

  • medicines used to treat high blood pressure known as water pills (diuretics)
  • rifampicin (an antibiotic medicine used to treat certain infections such as tuberculosis)
  • carbamazepine, phenobarbital (phenobarbitone) or phenytoin (medicines used to control fits (seizures) or chronic pain)
  • a medicine used to treat and prevent mood disorders (lithium).

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

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

How to take Glyxambi

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 starting dose is one Glyxambi 10 mg/5 mg tablet once a day.

Your doctor may increase your dose to one Glyxambi 25 mg/5 mg tablet once a day.

Your doctor will prescribe Glyxambi 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 does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

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

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

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

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

While you are taking Glyxambi

Things you must do

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

Tell any other doctors, dentists, 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 Glyxambi.

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 Glyxambi and when to start taking it again if you are about to have surgery.

Things you must not do

Do not take Glyxambi 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 change the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Glyxambi 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, or weakness 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 Glyxambi.

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:

  • swelling of the nose or throat (nasopharyngitis)
  • mouth ulceration
  • cough
  • painful, swollen joints
  • signs of dehydration including unusual thirst, light-headedness or dizziness upon standing, fainting or loss of consciousness
  • genital burning, redness, pain and discharge which may be signs of a genital yeast infection.
  • itching
  • passing more urine than normal
  • constipation.

Tell your doctor as soon as possible if you notice 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 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 Glyxambi.

Tell your doctor immediately if you develop blisters or the breakdown of the outer layer of your skin (erosion). These may be signs of a skin reaction called bullous pemphigoid. Your doctor may tell you to stop taking Glyxambi.

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 Glyxambi.

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:

  • allergic reaction (shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other part of the body, rash, itching or hives on the skin)
  • severe upper stomach pain, radiating to the back, nausea, vomiting and fever (which may be symptoms of an inflamed pancreas – pancreatitis)
  • rapid weight loss, feeling sick or being sick, stomach pain, 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 (diabetic ketoacidosis).

In rare cases, empagliflozin, one of the active substances in Glyxambi 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 taking Glyxambi

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 Glyxambi 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

  • Glyxambi 10 mg/5 mg tablets are pale yellow, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol, the other side is debossed with "10/5".
  • Glyxambi 25 mg/5 mg tablets are pale pink, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol, the other side is debossed with "25/5".

Glyxambi is available in blister packs containing 10 (sample) and 30 tablets.

Ingredients

Active ingredients:

Each Glyxambi 10 mg/5 mg tablet contains 10 mg empagliflozin and 5 mg linagliptin.

Each Glyxambi 25 mg/5 mg tablet contains 25 mg empagliflozin and 5 mg linagliptin.

Inactive ingredients:

  • mannitol
  • pregelatinised maize starch
  • maize starch
  • copovidone
  • crospovidone
  • purified talc
  • magnesium stearate
  • hypromellose
  • titanium dioxide
  • macrogol 6000
  • iron oxide yellow (Glyxambi 10 mg/5 mg)
  • iron oxide red (Glyxambi 25 mg/5 mg).

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

Supplier

Glyxambi is supplied in Australia by:

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

This Consumer Medicine Information was updated in September 2022.

® Glyxambi is a registered trademark of Boehringer Ingelheim.

© Boehringer Ingelheim Pty Limited 2022.

Australian Registration Numbers

Glyxambi 10 mg/5 mg
(AUST R 263556)

Glyxambi 25 mg/5 mg
(AUST R 263557)

Published by MIMS November 2022

BRAND INFORMATION

Brand name

Glyxambi

Active ingredient

Empagliflozin; Linagliptin

Schedule

S4

 

1 Name of Medicine

Empagliflozin and linagliptin.

2 Qualitative and Quantitative Composition

Glyxambi are film-coated tablets for oral administration.
Glyxambi 25 mg/5 mg contains 25 mg empagliflozin and 5 mg linagliptin.
Glyxambi 10 mg/5 mg contains 10 mg empagliflozin and 5 mg linagliptin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Glyxambi 10 mg/5 mg film-coated tablets are pale yellow, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol, the other side is debossed with "10/5".
Glyxambi 25 mg/5 mg film-coated tablets are pale pink, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol, the other side is debossed with "25/5".

4 Clinical Particulars

4.1 Therapeutic Indications

Glyxambi tablets are indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

The recommended starting dose is Glyxambi 10 mg/5 mg (empagliflozin 10 mg/linagliptin 5 mg) once daily. In patients tolerating Glyxambi 10 mg/5 mg once daily and requiring additional glycaemic control, the dose can be increased to Glyxambi 25 mg/5 mg (empagliflozin 25 mg/linagliptin 5 mg) once daily. In patients already on empagliflozin, the dose of Glyxambi should provide the dose of empagliflozin similar to the dose already been taken by the patient. Glyxambi can be taken with or without food and at any time of day.

Combination therapy.

When Glyxambi 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.
Glycaemic control is reduced in patients with eGFR < 30 mL/min/1.73 m2.
Glyxambi is contraindicated in patients with eGFR < 30 mL/min/1.73 m2.
Therapeutic experience with Glyxambi is limited in patients with eGFR < 60 mL/min.
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 75 years and older is limited. Initiation of Glyxambi 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.

The safety and effectiveness of Glyxambi in children below 18 years of age have not been established. Glyxambi is not recommended for use in patients under 18 years of age.

4.3 Contraindications

Hypersensitivity to empagliflozin or linagliptin or any of the excipients.
Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2), end-stage renal disease and patients on dialysis. The efficacy of empagliflozin is dependent on renal function (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

General.

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

Diabetic ketoacidosis.

Glyxambi 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 Glyxambi 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 Glyxambi 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, Glyxambi 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 Glyxambi, 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. Glyxambi 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 Glyxambi in clinical situations known to predispose ketoacidosis. In these situations, consider monitoring of ketones, even if Glyxambi treatment has been interrupted.

Surgery.

Treatment with Glyxambi 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 Glyxambi may be restarted once the patient's condition has stabilised and oral intake is normal.

Hypoglycaemia.

In clinical trials of linagliptin or of empagliflozin as part of combination therapy with agents not known to cause hypoglycaemia (e.g. metformin, thiazolidinediones) rates of hypoglycaemia reported with linagliptin or empagliflozin were similar to rates in patients taking placebo (see Section 4.8 Adverse Effects (Undesirable Effects)).
Sulfonylureas and insulin are known to cause hypoglycaemia. Therefore, caution is advised when Glyxambi is used in combination with a sulfonylurea and/or insulin. A dose reduction of the sulfonylurea or insulin may be considered.

Pancreatitis.

Acute pancreatitis has been observed in patients taking linagliptin (see Section 4.8 Adverse Effects (Undesirable Effects)). If pancreatitis is suspected, Glyxambi should be discontinued.

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 anti-hypertensive therapy with a history of hypotension or patients aged 75 years and older.
In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, BP measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving empagliflozin. Temporary interruption of treatment with Glyxambi should be considered until the fluid loss is corrected.

Urosepsis and pyelonephritis.

There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (see Section 4.8 Adverse Effects (Undesirable Effects)).
Discontinuation of 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 Glyxambi who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, Glyxambi should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).

Lower limb amputations.

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

Bullous pemphigoid.

Bullous pemphigoid has been observed in patients taking linagliptin. If bullous pemphigoid is suspected, Glyxambi should be discontinued.

Arthralgia.

There have been postmarketing reports of joint pain, which may be severe, in patients taking DPP-4 inhibitors. Onset of symptoms following initiation of treatment may be rapid or may occur after longer periods. Discontinuation of therapy should be considered in patients who present with or experience an exacerbation of joint symptoms during treatment with linagliptin.

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

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

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.
Glyxambi 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).
Therapeutic experience with Glyxambi is limited in patients with eGFR < 60 mL/min.

Monitoring of renal function.

Due to its mechanism of action, the efficacy of empagliflozin 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.
Glyxambi 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, Glyxambi should be prescribed with caution in these patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Therapeutic experience in patients aged 75 years and older is limited. Initiation of therapy with Glyxambi in this population is not recommended.

Paediatric use.

The safety and effectiveness of Glyxambi in children below 18 years of age have not been established. Glyxambi is not recommended for use in patients under 18 years of age.

Effect on laboratory tests.

Urine will test positive for glucose while patients are taking Glyxambi 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

No interactions between the two components of this fixed-dose combination have been observed in clinical studies.
No drug interaction studies have been performed with Glyxambi and other medicinal products, however, such studies have been conducted with the individual active substances.
No clinically meaningful pharmacokinetic interactions were observed when empagliflozin or linagliptin were co-administered with other commonly used medicinal products. Based on results of pharmacokinetic studies, no dose adjustment of Glyxambi is recommended when co-administered with commonly prescribed medicinal products (see Section 5.1 Pharmacodynamic Properties), except those mentioned below.

Insulin and sulfonylureas.

Insulin and sulfonylureas may increase the risk of hypoglycaemia. Therefore, a lower dose of insulin or sulfonylureas may be required to reduce the risk of hypoglycaemia when used in combination with Glyxambi (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Diuretics.

Empagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see Section 4.4 Special Warnings and Precautions for Use).

Lithium.

Empagliflozin may increase renal lithium excretion and the blood lithium levels may be decreased. Serum concentration of lithium should be monitored more frequently after empagliflozin initiation and dose changes. Please refer the patient to the lithium prescribing doctor in order to monitor serum concentration of lithium.

UGT inhibitors and inducers.

Empagliflozin is primarily metabolised via UGT (see Section 5.2 Pharmacokinetic Properties); however, a clinically relevant effect of UGT inhibitors on empagliflozin is not expected.

Rifampicin.

A study was conducted to assess the effect of rifampicin, a potent inductor of P-glycoprotein and CYP3A4, on the pharmacokinetics of 5 mg linagliptin. Multiple co-administration of linagliptin with rifampicin, resulted in a 39.6% and 43.8% decreased linagliptin steady-state AUC and Cmax and about 30% decreased DPP-4 inhibition at trough. Thus linagliptin in combination with strong P-glycoprotein inducers is expected to be clinically efficacious, although full efficacy might not be achieved.

Ritonavir.

A study was conducted to assess the effect of ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4, on the pharmacokinetics of linagliptin. Co-administration of a single 5 mg oral dose of linagliptin and multiple 200 mg oral doses of ritonavir increased the AUC and Cmax of linagliptin approximately two-fold and three-fold, respectively. Simulations of steady-state plasma concentrations of linagliptin with and without ritonavir indicated that the increase in exposure will not be associated with an increased accumulation. These changes in linagliptin pharmacokinetics were not considered to be clinically relevant. Therefore, clinically relevant interactions would not be expected with other P-glycoprotein or CYP3A4 inhibitors and dose adjustment is not required.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies on the effect on human fertility have been conducted for Glyxambi or with the individual components.
Animal studies conducted with empagliflozin alone and linagliptin alone do not indicate adverse effects on fertility in patients.

Empagliflozin.

Studies in rats at doses of empagliflozin 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.

Linagliptin.

No adverse effects on fertility were observed in male and female rats given linagliptin orally up to the highest dose of 240 mg/kg/day (yielding approximately 1,000 times the plasma AUC obtained in patients at the maximum recommended human dose [MRHD] of 5 mg/day) prior to and throughout mating.
(Category D)
There is a limited amount of data from the use of empagliflozin and linagliptin in pregnant women. It is recommended to avoid the use of Glyxambi during pregnancy unless clearly needed.
In a study in pregnant rats, oral co-administration of 700 mg/kg empagliflozin and 140 mg/kg linagliptin during the period of organogenesis was associated with decreased fetal weight and an increased incidence of minor fetal skeletal abnormalities, occurring in conjunction with maternotoxicity. No adverse effects on embryofetal development were observed with administration of 300 mg/kg empagliflozin and 60 mg/kg linagliptin in combination, yielding approximately 100 and 230 times the exposure to empagliflozin and linagliptin in patients at the maximum recommended human dose.

Empagliflozin.

Empagliflozin administered during the period of organogenesis was not teratogenic at doses up to 300 mg/kg in the rat or rabbit, which corresponds to approximately 48- and 122-times or 128- and 325-times the clinical dose of empagliflozin based on AUC exposure associated with the 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.

Linagliptin.

Linagliptin was shown to cross the placenta in rats and rabbits.
In animal embryofetal development studies, linagliptin was shown to be not teratogenic in rats at oral doses up to 240 mg/kg/day (approximately 1,000 times the exposure in patients at the MRHD, based on plasma AUC) and up to 150 mg/kg/day in the rabbit (approximately 2,000 times human exposure). However, postimplantation loss was increased in both species at these upper dose levels (together with maternotoxicity), and there was an increase in runts and a slight increase in the incidence of fetal visceral variations in the rabbit. No adverse effects on embryofetal development were observed at up to 30 mg/kg/day in the rat (50 times human exposure) and up to 25 mg/kg/day in the rabbit (78 times human exposure).
No data in humans are available on excretion of empagliflozin and linagliptin into milk. Available nonclinical data in animals have shown excretion of empagliflozin and linagliptin and its metabolites in milk. It is recommended to discontinue breast feeding during treatment with Glyxambi.

Empagliflozin.

Reduced body weight was observed in rats exposed to empagliflozin in utero and through the consumption of maternal milk (see Use in pregnancy). Adverse effects on renal development have been observed in juvenile rats treated with other members of this pharmacological class. Similar effects were seen with empagliflozin but the findings were absent after a 13 week drug-free recovery. A risk to human newborns/infants cannot be excluded.

Linagliptin.

Linagliptin and its metabolites were shown to be readily excreted in the milk of lactating rats.

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. If patients experience dizziness, they should avoid potentially hazardous tasks such as driving or operating machinery.

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 https://www.tga.gov.au/reporting-problems.

Adverse events in clinical trials.

A total of 2173 patients with type 2 diabetes were treated in clinical studies to evaluate the safety of Glyxambi, of which 1005 patients were treated with Glyxambi. In clinical trials, patients were treated for up to 24 or 52 weeks.
The most frequent adverse reaction was urinary tract infection (see Description of selected adverse reactions).
Overall, the safety profile of Glyxambi was comparable to the safety profiles of the individual components (empagliflozin and linagliptin).
The adverse reactions shown in Table 1 listed by system organ class, are based on the safety profiles of empagliflozin and linagliptin monotherapy, and were also reported in clinical trials and postmarketing surveillance with Glyxambi. No additional adverse reactions were identified with Glyxambi as compared to the individual components.

Tabulated list of adverse reactions.

The adverse reactions are listed by absolute frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), or very rare (< 1/10,000), and not known (cannot be estimated from the available data).

Description of selected adverse reactions.

The frequencies below are calculated for adverse reactions regardless of causality.
Hypoglycaemia. In pooled clinical trials of Glyxambi in patients with type 2 diabetes and inadequate glycaemic control on background metformin, the incidence of confirmed hypoglycaemic events was low (< 1.5%; for confirmed clinical events per trial see Table 2).
One patient administered Glyxambi experienced a confirmed (investigator-defined), major hypoglycaemic event in the active- or placebo-controlled trials and none required assistance.

Hypoglycaemia for empagliflozin.

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

Major hypoglycaemia with empagliflozin (events requiring assistance).

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

Hypoglycaemia with linagliptin.

The most frequently reported adverse event in clinical trials with linagliptin was hypoglycaemia observed under the triple combination, linagliptin plus metformin plus sulfonylurea (22.9% vs 14.8% in placebo).
Hypoglycaemias in the placebo-controlled studies (10.9%; n=471) were mild (80%; n=384) or moderate (16.6%; n=78) or severe (1.9%; n=9) in intensity.
Urinary tract infection. In clinical trials with Glyxambi, the frequency of urinary tract infection adverse events (Glyxambi 25 mg/5 mg: 9.2%; Glyxambi 10 mg/5 mg: 8.8%) has been comparable to those reported from the empagliflozin clinical trials.
In empagliflozin trials, the overall frequency of urinary tract infection was similar in patients treated with empagliflozin 25 mg (7.0%) and placebo (7.2%), and higher in patients treated with empagliflozin 10 mg (8.8%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin 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. In clinical trials with Glyxambi, the frequency of genital infection adverse events (Glyxambi 25 mg/5 mg: 3.1%; Glyxambi 10 mg/5 mg: 3.5%) has been comparable to those reported from the empagliflozin clinical trials.
In empagliflozin trials, vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently for empagliflozin 10 mg (4.0%) and empagliflozin 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. In clinical trials with Glyxambi, the frequency of increased urination adverse events (Glyxambi 25 mg/5 mg: 1.7%; Glyxambi 10 mg/5 mg: 0.8%) has been comparable to those reported from the empagliflozin clinical trials.
As expected via its mechanism of action, in clinical trials with empagliflozin, increased urination (as assessed by preferred term search including pollakiuria, polyuria, nocturia) was observed at higher frequencies in patients treated with empagliflozin 10 mg (3.5%) and empagliflozin 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 empagliflozin (< 1%).
Volume depletion. In clinical trials with Glyxambi, the frequency of patients with volume depletion adverse events (Glyxambi 25 mg/5 mg: 0.6%; Glyxambi 10 mg/5 mg: 0.5%) has been comparable to those reported from the empagliflozin clinical trials.
In clinical trials with empagliflozin, the overall frequency of patients with 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 empagliflozin 10 mg, 0.4% for empagliflozin 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 age 75 years and older. In patients ≥ 75 years of age the frequency of patients with volume depletion events was similar for empagliflozin 10 mg (2.3%) compared to placebo (2.1%), but it increased with empagliflozin 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.
In clinical trials with Glyxambi, the frequency of patients with increased blood creatinine (Glyxambi 25 mg/5 mg: 0.4%; Glyxambi 10 mg/5 mg: 0%) and decreased glomerular filtration rate (Glyxambi 25 mg/5 mg: 0.4%; Glyxambi 10 mg/5 mg: 0.6%) has been comparable to those reported from the empagliflozin clinical trials.

Laboratory parameters.

Haematocrit increased.

In clinical trials with Glyxambi, mean changes from baseline in haematocrit were 2.9% and 3.2% for Glyxambi 10 mg/5 mg and 25 mg/5 mg.
In the EMPA-REG OUTCOME trial, haematocrit values returned towards baseline values after a follow-up period of 30 days after treatment stop.

Serum lipids increased.

In clinical trials with Glyxambi, mean percent increases from baseline for Glyxambi 10 mg/5 mg and 25 mg/5 mg respectively, were total cholesterol 3.0% and 3.4%; HDL cholesterol 6.8% and 5.8%; LDL cholesterol 5.4% and 5.4%; triglycerides 2.7% and 4.2%.

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 daily recommended dose, were well tolerated.
During controlled clinical trials in healthy subjects, single doses of up to 600 mg linagliptin (equivalent to 120 times the recommended dose) were well tolerated. There is no experience with doses above 600 mg in humans.

Treatment.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g. remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring and institute clinical measures as required. The removal of empagliflozin by haemodialysis has not been studied.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Combinations of oral blood glucose lowering drugs, ATC code: A10BD19.

Mechanism of action.

Combination empagliflozin/linagliptin.

Empagliflozin and linagliptin act by separate and complementary mechanisms to treat type 2 diabetes mellitus (T2DM). The combination of empagliflozin and linagliptin, after single oral dosing, showed a superior effect on glycaemic control (oral glucose tolerance test) as compared to the respective monotherapies tested in diabetic ZDF rats.

Empagliflozin.

Empagliflozin is a reversible competitive inhibitor of SGLT2 with an IC50 of 1.3 nanoM. It has a 5000-fold selectivity over human SGLT1 (IC50 of 6278 nanoM), responsible for glucose absorption in the gut.
SGLT2 is highly expressed in the kidney, whereas expression in other tissues is absent or very low. It is responsible as the predominant transporter for re-absorption of glucose from the glomerular filtrate back into the circulation. In patients with T2DM and hyperglycaemia a higher amount of glucose is filtered and reabsorbed.
Empagliflozin improves glycaemic control in patients with T2DM by reducing renal glucose re-absorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent upon the blood glucose concentration and glomerular filtration rate (GFR). Through inhibition of SGLT2 in patients with T2DM and hyperglycaemia, excess glucose is excreted in the urine.
In patients with T2DM, urinary glucose excretion increased immediately following the first dose of empagliflozin and is continuous over the 24 hour dosing interval. Increased urinary glucose excretion was maintained at the end of 4-week treatment period, averaging approximately 78 g/day with 25 mg empagliflozin once daily. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with T2DM.
Empagliflozin improves both fasting and post-prandial plasma glucose levels.
The insulin independent mechanism of action of empagliflozin contributes to a low risk of hypoglycaemia.
The effect of empagliflozin in lowering blood glucose is independent of beta cell function and insulin pathway. Improvement of surrogate markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) and proinsulin to insulin ratio were noted. In addition urinary glucose excretion triggers calorie loss, associated with body fat loss and body weight reduction.
The glucosuria observed with empagliflozin is accompanied by mild diuresis which may contribute to sustained and moderate reduction of blood pressure (BP).

Linagliptin.

Linagliptin is an inhibitor of the enzyme DPP-4 an enzyme which is involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide). These hormones are rapidly degraded by the enzyme DPP-4. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretins are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Linagliptin binding to DPP-4 is reversible but long lasting and thus leads to a sustained increase and a prolongation of active incretin levels. In vitro, linagliptin inhibits DPP-4 with nanomolar potency and exhibits a > 10,000-fold selectivity versus DPP-8 or DPP-9 activity.

Clinical trials.

A total of 2173 patients with T2DM and inadequate glycaemic control were treated in clinical studies to evaluate the safety and efficacy of Glyxambi; 1005 patients were treated with empagliflozin 10 or 25 mg, and linagliptin 5 mg. In clinical trials, patients were treated for up to 24 or 52 weeks.

Glyxambi added to metformin.

In a factorial design study, patients inadequately controlled on metformin (mean daily dose 1889.0 (± 470.9) mg at baseline), 24-weeks treatment with Glyxambi 10 mg/5 mg and Glyxambi 25 mg/5 mg provided statistically significant improvements in HbA1c and fasting plasma glucose (FPG) compared to linagliptin 5 mg alone and also compared to empagliflozin 10 or 25 mg alone. Compared to linagliptin 5 mg Glyxambi provided statistically significant improvements in body weight. A greater proportion of patients with a baseline HbA1c ≥ 7.0% and treated with Glyxambi achieved a target HbA1c of < 7% compared to the individual components (Table 3).
After 24 weeks' treatment with Glyxambi, both systolic (SBP) and diastolic blood pressures (DBP) were reduced, -5.6/-3.6 mmHg (p < 0.001 versus linagliptin 5 mg for SBP and DBP) for Glyxambi 25 mg/5 mg and -4.1/-2.6 mmHg (p < 0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for Glyxambi 10 mg/5 mg.
Clinically meaningful reductions in HbA1c (Table 3) and both systolic and diastolic blood pressures were observed at week 52, -3.8/-1.6 mmHg (p < 0.05 versus linagliptin 5 mg for SBP and DBP) for Glyxambi 25 mg/5 mg and -3.1/-1.6 mmHg (p < 0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for Glyxambi 10 mg/5 mg.
After 24 weeks, rescue therapy was used in 1 (0.7%) patient treated with Glyxambi 25 mg/5 mg and in 3 (2.2%) patients treated with Glyxambi 10 mg/5 mg, compared to 4 (3.1%) patients treated with linagliptin 5 mg and 6 (4.3%) patients treated with empagliflozin 25 mg and 1 (0.7%) patient treated with empagliflozin 10 mg.
In a pre-specified subgroup of patients with baseline HbA1c greater or equal than 8.5% the reduction from baseline in HbA1c with Glyxambi 25 mg/5 mg was -1.8% at 24 weeks (p < 0.0001 versus linagliptin 5 mg, p < 0.001 versus empagliflozin 25 mg) and -1.8% at 52 weeks (p < 0.0001 versus linagliptin 5 mg, p < 0.05 versus empagliflozin 25 mg) and with Glyxambi 10 mg/5 mg -1.6% at 24 weeks (p < 0.01 versus linagliptin 5 mg, n.s. versus empagliflozin 10 mg) and -1.5% at 52 weeks (p < 0.01 versus linagliptin 5 mg, n.s. versus empagliflozin 10 mg).

Glyxambi in treatment-naïve patients.

In a factorial design study, after 24-weeks treatment, Glyxambi 25 mg/5 mg in treatment-naïve patients provided statistically significant improvement in HbA1c compared to linagliptin 5 mg, but there was no statistically significant difference between Glyxambi 25 mg/5 mg and empagliflozin 25 mg (Table 4). Glyxambi 10 mg/5 mg had a 0.4% decrease in HbA1c as compared to empagliflozin 10 mg. Compared to linagliptin 5 mg both doses of Glyxambi provided statistically relevant improvements in body weight. After 24 weeks' treatment with Glyxambi, both systolic and diastolic blood pressures were reduced, -2.9/-1.1 mmHg (n.s. versus linagliptin 5 mg for SBP and DBP) for Glyxambi 25 mg/5 mg and -3.6/-0.7 mmHg (p < 0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for Glyxambi 10 mg/5 mg. Rescue therapy was used in 2 (1.5%) patients treated with Glyxambi 25 mg/5 mg and in 1 (0.7%) patient treated with Glyxambi 10 mg/5 mg compared to 11 (8.3%) patients treated with linagliptin 5 mg, 1 (0.8%) patient treated with empagliflozin 25 mg and 4 (3.0%) patients treated with empagliflozin 10 mg.
In a pre-specified subgroup of patients with baseline HbA1c greater or equal than 8.5%, the reduction from baseline in HbA1c with Glyxambi 25 mg/5 mg was -1.9% at 24 weeks (p < 0.0001 versus linagliptin 5 mg, n.s. versus empagliflozin 25 mg) and -2.0% at 52 weeks (p < 0.0001 versus linagliptin 5 mg, p < 0.05 versus empagliflozin 25 mg) and with Glyxambi 10 mg/5 mg -1.9% at 24 weeks (p < 0.0001 versus linagliptin 5 mg, p < 0.05 versus empagliflozin 10 mg) and -2.0% at 52 weeks (p < 0.0001 versus linagliptin 5 mg, p < 0.05 versus empagliflozin 10 mg).

Empagliflozin in patients inadequately controlled on metformin and linagliptin.

In patients inadequately controlled on metformin (mean daily dose 1975.7 (± 457.7) mg at baseline), and linagliptin 5 mg, 24-weeks treatment with both empagliflozin 10 mg/linagliptin 5 mg and empagliflozin 25 mg/linagliptin 5 mg provided statistically significant improvements in HbA1c, FPG and body weight compared to placebo/linagliptin 5 mg. A statistically significant difference in the number of patients with a baseline HbA1c ≥ 7.0% and treated with both doses of empagliflozin/linagliptin achieved a target HbA1c of < 7% compared to placebo/linagliptin 5 mg (Table 5). After 24 weeks' treatment with empagliflozin/linagliptin, both systolic and diastolic blood pressures were reduced, -2.6/-1.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 25 mg/linagliptin 5 mg and -1.3/-0.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 10 mg/linagliptin 5 mg.
After 24 weeks, rescue therapy was used in 4 (3.6%) patients treated with empagliflozin 25 mg/linagliptin 5 mg and in 2 (1.8%) patients treated with empagliflozin 10 mg/linagliptin 5 mg, compared to 13 (12.0%) patients treated with placebo/linagliptin 5 mg.
In a pre-specified subgroup of patients with baseline HbA1c greater or equal than 8.5% the reduction from baseline in HbA1c with empagliflozin 25 mg/linagliptin 5 mg was -1.3% at 24 weeks (p < 0.0001 versus placebo + linagliptin 5 mg) and with empagliflozin 10 mg/linagliptin 5 mg -1.3% at 24 weeks (p < 0.0001 versus placebo + linagliptin 5 mg).

Linagliptin 5 mg in patients inadequately controlled on empagliflozin 10 mg and metformin.

In patients inadequately controlled on empagliflozin 10 mg and metformin (mean daily dose 2101.8 (± 478.6) mg at baseline), 24-weeks treatment with empagliflozin 10 mg/linagliptin 5 mg provided statistically significant improvements in HbA1c and FPG compared to placebo/empagliflozin 10 mg. Compared to placebo/empagliflozin 10 mg, empagliflozin 10 mg/linagliptin 5 mg provided similar results on body weight. A statistically significantly greater proportion of patients with a baseline HbA1c ≥ 7.0% and treated with the empagliflozin 10 mg/linagliptin 5 mg achieved a target HbA1c of < 7% compared to placebo/empagliflozin 10 mg (Table 6). After 24 weeks' treatment with empagliflozin 10 mg/linagliptin 5 mg, both systolic and diastolic blood pressures were similar to placebo/empagliflozin 10 mg (n.s. for SBP and DBP).
After 24 weeks, rescue therapy was used in 2 (1.6%) patients treated with empagliflozin 10 mg/linagliptin 5 mg and in 5 (4.0%) patients treated with placebo/empagliflozin 10 mg.
In a pre-specified subgroup of patients (n=66) with baseline HbA1c greater or equal than 8.5%, the reduction from baseline in HbA1c empagliflozin 10 mg/linagliptin 5 mg (n=31) was -0.97% at 24 weeks (p=0.0875 versus placebo/empagliflozin 10 mg).

Linagliptin 5 mg in patients inadequately controlled on empagliflozin 25 mg and metformin.

In patients inadequately controlled on empagliflozin 25 mg and metformin (mean daily dose 2003.9 (± 438.8) mg at baseline), 24-weeks treatment with empagliflozin 25 mg/linagliptin 5 mg provided statistically significant improvements in HbA1c and FPG compared to placebo/empagliflozin 25 mg. Compared to placebo/empagliflozin 25 mg, empagliflozin 25 mg/linagliptin 5 mg provided similar results on body weight. A statistically significantly greater proportion of patients with a baseline HbA1c ≥ 7.0% and treated with the empagliflozin 25 mg/linagliptin 5 mg achieved a target HbA1c of < 7% compared to placebo/empagliflozin 25 mg (Table 6). After 24 weeks' treatment with empagliflozin 25 mg/linagliptin 5 mg, both systolic and diastolic blood pressures were similar to placebo/empagliflozin 25 mg (n.s. for SBP and DBP).
After 24 weeks, rescue therapy was used in 0 (0.0%) patients treated with empagliflozin 25 mg/linagliptin 5 mg and in 3 (2.7%) patients treated with placebo/empagliflozin 25 mg.
In a pre-specified subgroup of patients (n=42) with baseline HbA1c greater or equal than 8.5%, the reduction from baseline in HbA1c with empagliflozin 25 mg/linagliptin 5 mg (n=20) was -1.16% at 24 weeks (p=0.0046 versus placebo + empagliflozin 25 mg).

Cardiovascular safety.

In the EMPA-REG OUTCOME trial, empagliflozin significantly reduced the risk of the combined endpoint of cardiovascular (CV) death, non-fatal myocardial infarction or non-fatal stroke (MACE-3) by 14% compared to placebo when added to standard of care in adults with T2DM and established CV disease, see Jardiance PI for details. This result was driven by a significant reduction in CV death, with no significant change in non-fatal myocardial infarction, or non-fatal stroke.
In the CARMELINA study, linagliptin did not increase the risk of the combined endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke (MACE-3) [Hazard Ratio (HR)=1.02; (95% CI 0.89, 1.17); p=0.0002 for non-inferiority], or the risk of combined endpoint of renal death, ESRD, 40% or more sustained decrease in eGFR [HR=1.04; (95% CI 0.89, 1.22)], when added to standard of care in adult patients with T2DM with increased CV risk evidenced by a history of established macrovascular or renal disease. In addition, linagliptin did not increase the risk of hospitalisation for heart failure [HR=0.90; (95% CI 0.74, 1.08)]. No increased risk of CV death or all-cause mortality was observed. Safety data from this study was in line with previous known safety profile of linagliptin.

Linagliptin cardiovascular safety study (CAROLINA).

CAROLINA was a randomised study in 6033 patients with early type 2 diabetes and increased CV risk or established complications who were treated with linagliptin 5 mg (3023) or glimepiride 1-4 mg (3010) added to standard of care (including background therapy with metformin in 83% of patients) targeting regional standards for HbA1c and CV risk factors. The mean age for study population was 64 years and included 2030 (34%) patients ≥ 70 years of age. The study population included 2089 (35%) patients with cardiovascular disease and 1130 (19%) patients with renal impairment with an eGFR < 60 mL/min/1.73 m2 at baseline. The mean HbA1c at baseline was 7.15%.
The study was designed to demonstrate non-inferiority for the primary cardiovascular endpoint which was a composite of the first occurrence of cardiovascular death or a non-fatal myocardial infarction (MI) or a non-fatal stroke (3P-MACE).
After a median follow up of 6.25 years, linagliptin did not increase the risk of major adverse cardiovascular events (Table 7) as compared to glimepiride. Results were consistent for patients treated with or without metformin.
For the entire treatment period (median time on treatment 5.9 years) the rate of patients with moderate or severe hypoglycaemia was 6.5% on linagliptin versus 30.9% on glimepiride, severe hypoglycaemia occurred in 0.3% of patients on linagliptin versus 2.2% on glimepiride.
There have been no clinical studies establishing conclusive evidence of Glyxambi's effect on cardiovascular morbidity and mortality.

5.2 Pharmacokinetic Properties

The rate and extent of absorption of empagliflozin and linagliptin in Glyxambi (empagliflozin/linagliptin) are equivalent to the bioavailability of empagliflozin and linagliptin when administered as individual tablets.
The pharmacokinetics of empagliflozin and linagliptin have been extensively characterised in healthy volunteers and patients with T2DM. No clinically relevant differences in pharmacokinetics were seen between healthy volunteers and T2DM patients.
The following statements reflect the pharmacokinetic properties of the individual active substances of Glyxambi.

Absorption.

Empagliflozin.

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 Cmax, (tmax) of 1.5 h post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase.
The steady-state mean plasma area under the curve (AUC) was 4740 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.

Linagliptin.

The pharmacokinetics of linagliptin has been extensively characterised in healthy subjects and patients with type 2 diabetes. After oral administration of a 5 mg dose to healthy volunteer patients, linagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1.5 hours post-dose.
Plasma concentrations of linagliptin decline in a triphasic manner with a long terminal half-life (terminal half-life for linagliptin more than 100 hours), that is mostly related to the saturable, tight binding of linagliptin to DPP-4 and does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of 5 mg linagliptin, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of 5 mg linagliptin are reached by the third dose. Plasma area under the curve (AUC) of linagliptin increased approximately 33% following 5 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in a less than dose-proportional manner. The pharmacokinetics of linagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.
The absolute bioavailability of linagliptin is approximately 30%. Because co-administration of a high-fat meal with linagliptin had no clinically relevant effect on the pharmacokinetics, linagliptin may be administered with or without food.
In vitro studies indicated that linagliptin is a substrate of P-glycoprotein and of CYP3A4. Ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4, led to a two-fold increase in exposure (AUC) and multiple co-administration of linagliptin with rifampicin, a potent inducer of P-glycoprotein and CYP3A, resulted in an approximate 40% decreased linagliptin steady-state AUC, presumably by increasing/decreasing the bioavailability of linagliptin by inhibition/induction of P-glycoprotein.

Distribution.

Empagliflozin.

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%.

Linagliptin.

As a result of tissue binding, the mean apparent volume of distribution at steady-state following a single 5 mg intravenous dose of linagliptin to healthy subjects is approximately 1110 litres, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nanomol/L to 75-89% at ≥ 30 nanomol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At the peak plasma concentration in humans at 5 mg/day, approximately 10% of linagliptin is unbound.

Metabolism.

Empagliflozin.

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.

Linagliptin.

Following a [14C]-linagliptin oral 10 mg dose, only 5% of the radioactivity was excreted in urine. Metabolism plays a subordinate role in the elimination of linagliptin. One main metabolite with a relative exposure of 13.3% of linagliptin at steady-state was detected and was found to be pharmacologically inactive and thus does not contribute to the plasma DPP-4 inhibitory activity of linagliptin.

Excretion.

Empagliflozin.

The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. The inter-subject and residual variabilities for empagliflozin oral clearance were 39.1% and 35.8%, respectively. With once-daily dosing, steady-state plasma concentrations of empagliflozin were reached by the fifth dose. Consistent with half-life, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state. Following administration of an oral [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.

Linagliptin.

Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated in faeces (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady-state was approximately 70 mL/min.

Pharmacokinetics in special patient groups.

Pharmacokinetics in children. Studies characterising the pharmacokinetics of empagliflozin or linagliptin in paediatric patients have not been performed.
Pharmacokinetics in the elderly. Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin or linagliptin based on population pharmacokinetic analysis. Elderly subjects (65 to 78 years) had comparable plasma concentrations of linagliptin compared to younger subjects.
Renal impairment. Based on pharmacokinetics, no dosage adjustment is recommended for Glyxambi in patients with renal impairment.

Empagliflozin.

In patients with mild (eGFR: 60 - < 90 mL/min/1.73 m2), moderate (eGFR: 30 - < 60 mL/min/1.73 m2), severe (eGFR: < 30 mL/min/1.73 m2) renal impairment and patients with kidney failure/end stage renal disease (ESRD), AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairment and kidney failure/ESRD compared to patients with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in subjects with mild and severe renal impairment as compared to subjects with normal renal function. In line with the Phase I study, the population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased with a decrease in eGFR leading to an increase in drug exposure. Based on pharmacokinetics, no dosage adjustment is recommended in patients with renal impairment.

Linagliptin.

A multiple-dose, open-label study was conducted to evaluate the pharmacokinetics of linagliptin (5 mg dose) in patients with varying degrees of chronic renal impairment compared to normal healthy control subjects. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (50 to < 80 mL/min), moderate (30 to < 50 mL/min), and severe (< 30 mL/min), as well as patients with end stage renal disease (ESRD) on haemodialysis. In addition, patients with type 2 diabetes mellitus and severe renal impairment (< 30 mL/min) were compared to patients with type 2 diabetes mellitus and normal renal function.
Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula: CrCl = [140 - age (years)] x weight (kg) {x 0.85 for female patients} / [72 x serum creatinine (mg/dL)]. Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects. In moderate renal impairment, a moderate increase in exposure of about 1.7-fold was observed compared with control. Exposure in patients with type 2 diabetes mellitus and severe renal impairment was increased by about 1.4-fold compared to patients with type 2 diabetes mellitus and normal renal function. Steady-state predictions for AUC of linagliptin in patients with ESRD indicated comparable exposure to that of patients with moderate or severe renal impairment. In addition, linagliptin is not expected to be eliminated to a therapeutically significant degree by haemodialysis or peritoneal dialysis. Therefore, no dosage adjustment of linagliptin is necessary in patients with any degree of renal impairment. In addition, mild renal impairment had no effect on linagliptin pharmacokinetics in patients with type 2 diabetes mellitus as assessed by population pharmacokinetic analyses.
Pharmacokinetics in patients with hepatic impairment. Based on pharmacokinetics of the two individual components, no dosage adjustment of Glyxambi is recommended in patients with hepatic impairment.

Empagliflozin.

In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased approximately by 23%, 47%, and 75% and Cmax by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.

Linagliptin.

In patients with mild, moderate and severe hepatic insufficiency (according to the Child-Pugh classification), mean AUC and Cmax of linagliptin were similar to healthy matched controls following administration of multiple 5 mg doses of linagliptin.
Body mass index (BMI). No dosage adjustment is necessary for Glyxambi based on BMI. Body mass index had no clinically relevant effect on the pharmacokinetics of empagliflozin or linagliptin based on population pharmacokinetic analysis.
Gender. No dosage adjustment is necessary based on gender. Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin or linagliptin based on population pharmacokinetic analysis.
Race. No dosage adjustment is necessary based on race.

Empagliflozin.

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.

Linagliptin.

Race had no obvious effect on the plasma concentrations of linagliptin based on a composite analysis of available pharmacokinetic data, including patients of Caucasian, Hispanic, African-American, and Asian origin. In addition the pharmacokinetic characteristics of linagliptin were found to be similar in dedicated phase I studies in Japanese, Chinese and Caucasian healthy volunteers and African American type 2 diabetes patients.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies with the combination of empagliflozin and linagliptin have been performed.

Empagliflozin.

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

Linagliptin.

Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay in the rat.

Carcinogenicity.

No carcinogenicity studies with the combination of empagliflozin and linagliptin have been performed.

Empagliflozin.

Two-year oral carcinogenicity studies were conducted in mice and rats. There was an increase in renal adenomas and carcinomas in male mice given empagliflozin at 1000 mg/kg/day. No renal tumours were seen at 300 mg/kg/day (11- and 28-times the exposure at the clinical dose of 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.

Linagliptin.

No evidence of carcinogenicity was observed with linagliptin in 2-year studies in mice and rats given oral doses up to 80 mg/kg/day and 60 mg/kg/day, respectively.
These doses correspond to approximately 300- and 400-times the human exposure (plasma AUC) at the MRHD of 5 mg/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each film-coated tablet of Glyxambi 25 mg/5 mg contains the following inactive ingredients: mannitol, pregelatinised maize starch, maize starch, copovidone, crospovidone, purified talc, magnesium stearate, hypromellose, titanium dioxide, macrogol 6000, iron oxide red.
Each film-coated tablet of Glyxambi 10 mg/5 mg contains the following inactive ingredients: mannitol, pregelatinised maize starch, maize starch, copovidone, crospovidone, purified talc, magnesium stearate, hypromellose, titanium dioxide, macrogol 6000, 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

Glyxambi 10 mg/5 mg is available in blister packs containing 10 (sample) and 30 tablets.
Glyxambi 25 mg/5 mg is available in 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

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.
Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water. Linagliptin is soluble in methanol, sparingly soluble in ethanol, very slightly soluble in isopropanol and very slightly soluble in acetone. Dissociation Constants: pKa1 = 8.6; pKa2 = 1.9. Partition Co-efficient: Log P = 1.7 (free base); Log D (pH 7.4) = 0.4.

Chemical structure.

Glyxambi contains two oral antihyperglycaemic drugs used in the management of type 2 diabetes mellitus: empagliflozin (a SGLT2 inhibitor) and linagliptin (a dipeptidyl peptidase-4 (DPP-4) inhibitor).

Empagliflozin.

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

Linagliptin.

Chemical name: 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl].
Molecular formula: C25H28N8O2.
Molecular weight: 472.54.
Structural formula:

CAS number.

Empagliflozin: 864070-44-0.
Linagliptin: 668270-12-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes