Consumer medicine information

Kombiglyze XR

Saxagliptin; Metformin hydrochloride

BRAND INFORMATION

Brand name

Kombiglyze XR

Active ingredient

Saxagliptin; Metformin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kombiglyze XR.

SUMMARY CMI

KOMBIGLYZE XR®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I taking KOMBIGLYZE XR?

KOMBIGLYZE XR contains two active ingredients, saxagliptin and metformin hydrochloride KOMBIGLYZE XR is used to lower blood sugar levels in patients with type 2 diabetes mellitus along with diet and exercise.

For more information, see Section 1. Why am I taking KOMBIGLYZE XR? in the full CMI.

2. What should I know before I take KOMBIGLYZE XR?

Do not use if you have ever had an allergic reaction to saxagliptin or metformin hydrochloride, or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or drink alcohol.

For more information, see Section 2. What should I know before I take KOMBIGLYZE XR? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with KOMBIGLYZE XR and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take KOMBIGLYZE XR?

  • Your doctor will tell you how many KOMBIGLYZE XR tablets to take and how often you should take them.
  • KOMBIGLYZE XR should be taken with or immediately after food in the evening. Swallow tablet whole with a full glass of water.

More instructions can be found in Section 4. How do I take KOMBIGLYZE XR? in the full CMI.

5. What should I know while taking KOMBIGLYZE XR?

Things you should do
  • Make sure that you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia (low blood sugar) and hyperglycaemia (high blood sugar) and know how to treat them.
  • Talk to your doctor if you need to have any medical tests while taking KOMBIGLYZE XR.
  • Remind any doctor, dentist or pharmacist you visit for any new medicine that you are taking KOMBIGLYZE XR.
  • If you become pregnant while taking KOMBIGLYZE XR, tell your doctor immediately.
Things you should not do
  • Do not stop taking your medicine or change the dosage without checking with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how KOMBIGLYZE XR affects you
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep your KOMBIGLYZE XR tablets in the blister until it is time to take them.
  • Keep your tablets in a cool dry place where the temperature stays below 30°C.

For more information, see Section 5. What should I know while taking KOMBIGLYZE XR? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, some can be minor and temporary. However, some side effects may be serious and could require urgent medical attention or hospitalisation. See Section 6. Are there any side effects? in the full CMI and, if you need to, ask your doctor if you have any further questions about side effects. Tell your doctor if you experience any side effects, including those not listed in this leaflet.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

KOMBIGLYZE XR®

Active ingredient(s): saxagliptin/metformin hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about taking KOMBIGLYZE XR. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking KOMBIGLYZE XR.

Where to find information in this leaflet:

1. Why am I taking KOMBIGLYZE XR?
2. What should I know before I take KOMBIGLYZE XR?
3. What if I am taking other medicines?
4. How do I take KOMBIGLYZE XR?
5. What should I know while taking KOMBIGLYZE XR?
6. Are there any side effects?
7. Product details

1. Why am I taking KOMBIGLYZE XR?

KOMBIGLYZE XR contains two active ingredients, saxagliptin and metformin hydrochloride (modified release). Saxagliptin is a member of a class of medicines called DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors), and metformin belongs to a class of medicines called biguanides. Saxagliptin and metformin work together to lower blood sugar levels in patients with type 2 diabetes mellitus.

KOMBIGLYZE XR is used to lower blood sugar levels in patients with type 2 diabetes mellitus along with diet and exercise. KOMBIGLYZE XR may also be used in combination with other medicines including insulin, a sulfonylurea (such as gliclazide) or a SGLT2 inhibitor (such as dapagliflozin) along with diet and exercise to treat type 2 diabetes.

Type 2 diabetes mellitus

Type 2 diabetes mellitus is a condition in which your body does not make enough insulin and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood and can lead to serious medical problems.

The main goal of treating diabetes is to lower your blood sugar to a normal level. Lowering and controlling blood sugar may help prevent or delay complications of diabetes, such as heart disease, kidney disease, blindness and amputation.

2. What should I know before I take KOMBIGLYZE XR?

Warnings

Do not take KOMBIGLYZE XR if you:

  • are allergic to saxagliptin or metformin hydrochloride, or any of the ingredients listed at the end of this leaflet.
    any other medicine in the same class as saxagliptin (ie a DPP-4 inhibitor).
    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 or
    - you may feel faint
  • have type 1 diabetes mellitus that is well controlled by insulin alone
  • have type 2 diabetes that is already well controlled by diet alone
  • diabetic ketoacidosis (a symptom of uncontrolled diabetes, in which substances called ketone bodies build up in the blood - you may notice this as an unusual fruity odour on your breath, difficulty breathing, confusion and frequent urination)
  • severe liver disease
  • excessive alcohol intake, binge drinking, alcohol dependence
  • drink excessive alcohol, binge drinking, alcohol dependence
  • kidney failure or severe kidney disease
  • dehydration, severe blood loss, shock
  • have a severe infection
  • have certain heart or blood vessel problems, including a recent heart attack or severe heart failure (when the heart fails to pump blood effectively)
  • have severe breathing difficulties
  • have blood clots in the lungs (symptoms include coughing, shortness of breath, chest pain and a fast heart rate)
  • have gangrene
  • have inflammation of the pancreas (pancreatitis), symptoms include severe upper stomach pain, often with nausea and vomit

Do not take KOMBIGLYZE XR if you need to have major surgery or an examination such as an X-ray or a scan requiring an injection of iodinated contrast (dye).

You must stop taking KOMBIGLYZE XR for a certain period of time before and after the examination or the surgery. Your doctor will decide whether you need any other treatment for this time. It is important that you follow your doctor's instructions precisely.

Check with your doctor if you:

  • have any allergies to any other medicines, foods, dyes or preservatives.
  • Have or have had any other medical conditions:
    - Kidney or liver problems
    - heart failure
    - drink alcohol. Alcohol can affect the control of your diabetes. Drinking excessive amounts of alcohol while you are being treated with KOMBIGLYZE XR may also lead to serious side effects. Your doctor may suggest you stop drinking or reduce the amount of alcohol you drink.

Your doctor will do some tests for kidney function at the start of treatment and regularly while you are on treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take this medicine if you are pregnant or plan to become pregnant.

The safety of KOMBIGLYZE XR in pregnant women has not been established. Insulin is more suitable for controlling blood glucose during pregnancy. Your doctor will replace KOMBIGLYZE XR with insulin while you are pregnant.

Do not take KOMBIGLYZE XR if you are breastfeeding.

KOMBIGLYZE XR is not recommended while you are breastfeeding. Your doctor will discuss the options available to you.

Children

KOMBIGLYZE XR is not recommended for use in children.

There is not enough information on its effects in children.

3. What if I am taking other medicines?

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

KOMBIGLYZE XR may affect how well other medicines work and some medicines can affect how well KOMBIGLYZE XR works. These include:

  • other medicines used to treat diabetes
  • medicines that contain alcohol, such as cough and cold syrups
  • tetracosactrin, a medicine used in people with multiple sclerosis, and in young children to treat some types of seizures (fits)
  • danazol, a medicine used to treat endometriosis
  • some medicines used to treat high blood pressure and some heart conditions, including beta-blockers, calcium channel blockers and ACE inhibitors
  • medicines used to prevent blood clots, such as warfarin
  • diuretics, also called fluid tablets
  • chlorpromazine, a medicine used to treat schizophrenia and other mental illnesses
  • NSAIDs (non-steroidal anti-inflammatory drugs), medicines used to relieve pain, swelling and other symptoms of inflammation, such as aspirin, diclofenac, ibuprofen, meloxicam, naproxen or piroxicam
  • cimetidine, a medicine used to treat reflux and ulcers
  • corticosteroids such as prednisone or cortisone
  • some medicines used to treat asthma such as salbutamol or terbutaline

If you have not told your doctor about any of these things, tell them before you take any KOMBIGLYZE XR.

4. How do I take KOMBIGLYZE XR?

How to take KOMBIGLYZE XR

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 pack, ask your doctor or pharmacist for help.

Swallow your KOMBIGLYZE XR tablet whole with a full glass of water.

KOMBIGLYZE XR tablets must not be chewed or crushed.

How much to take

  • Your Doctor will tell you how many KOMBIGLYZE XR tablets to take and how often you should take them.
  • The dose varies from person to person. Your doctor will decide the right dose for you.

When to take KOMBIGLYZE XR

  • KOMBIGLYZE XR should be taken with or immediately after food in the evening. This will reduce the chance of a stomach upset.
  • KOMBIGLYZE XR should be taken at approximately the same time each day. Taking your tablets at the same time each day will have the best effect. It will also help you remember when to take the tablets.

How long to take

  • Continue taking your medicine for as long as your doctor tells you. Make sure you keep enough KOMBIGLYZE XR to last over weekends and holidays.

KOMBIGLYZE XR helps control your condition, but does not cure it. Therefore, you must take KOMBIGLYZE XR every day.

If you forget to use KOMBIGLYZE XR

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 you missed.

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

If you take too much KOMBIGLYZE XR

Immediately telephone your doctor or the Poisons Information Centre (13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much KOMBIGLYZE XR. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

5. What should I know while taking KOMBIGLYZE XR?

Things you should do

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking KOMBIGLYZE XR.

If you are about to be started on any new medicines, tell your doctor, dentist or pharmacist that you are taking KOMBIGLYZE XR.

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

Attend your doctor or diabetes centre for regular check-ups about your diabetes.

Tell your doctor if you:

  • become ill
  • become dehydrated
  • are injured
  • have a fever
  • have a serious infection
  • are having surgery (including dental surgery).

Your blood glucose may become difficult to control at these times. You may also be more at risk of developing a serious condition called lactic acidosis or diabetic ketoacidosis. At these times, your doctor may temporarily replace KOMBIGLYZE XR with insulin.

If you need to have any medical tests while you are taking KOMBIGLYZE XR, tell your doctor.

KOMBIGLYZE XR may affect the results of some tests.

Visit your doctor regularly for check ups.

Your doctor may want to perform blood tests to check your kidneys, liver, heart and vitamin B12 level while you are taking KOMBIGLYZE XR.

Metformin may reduce Vitamin B12 levels. Periodic monitoring may be necessary in patients at risk for Vitamin B12 deficiency.

Hypoglycaemia

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

Hypoglycaemia can occur suddenly. Initial signs may include:

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

If not treated promptly, these may progress to:

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

If you experience any of the symptoms of hypoglycaemia, you need to raise your blood glucose immediately.

  • You can do this by doing one of the following:
  • eating 5 to 7 jelly beans
  • eating 3 teaspoons of sugar or honey
  • drinking half a can of non-diet soft drink
  • taking 2 to 3 concentrated glucose tablets.

Unless you are within 10 to 15 minutes of your next meal or snack, follow up with extra carbohydrates such as plain biscuits, fruit or milk.

Taking this extra carbohydrate will prevent a second drop in your blood glucose level.

Hyperglycaemia

If you notice the return of any of the signs of hyperglycaemia, contact your doctor immediately.

Your doctor may need to consider additional or other treatments for your diabetes.

The risk of hyperglycaemia is increased in the following situations:

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

Things you should not do

  • Do not take KOMBIGLYZE XR to treat any other complaints unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if their symptoms seem similar or they have the same condition as you.
  • Do not skip meals while taking KOMBIGLYZE XR.
  • Do not stop taking your medicine or change the dosage without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how KOMBIGLYZE XR affects you.

KOMBIGLYZE XR may cause dizziness in some people. Low blood sugar levels may also slow your reaction time and affect your ability to drive or operate machinery. Do not drive a car if you have signs of low blood sugar.

Make sure you know how you react to XIGDUO XR before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or lightheaded.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol can affect the control of your diabetes. Drinking excessive amounts of alcohol while you are being treated with KOMBIGLYZE XR may also lead to serious side effects. Your doctor may suggest you stop drinking or reduce the amount of alcohol you drink.

Looking after your medicine

  • Keep your KOMBIGLYZE XR tablets in the blister until it is time to take them. If you take KOMBIGLYZE XR out of the blister, it will not keep well.
  • Keep your tablets in a cool dry place where the temperature stays below 30°C.
  • Do not store it or any other medicine in the bathroom or near a sink. Do not leave it in the car or on a window sill.
  • Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking KOMBIGLYZE XR or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

6. Are there any side effects?

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gut-related:
  • vomiting or diarrhoea
  • stomach pain or discomfort
Nervous system-related:
  • loss of appetite
  • loss of taste
  • headache
Others:
  • signs of an infection in the breathing passages including runny nose, sore throat and cough
  • soreness in the back of the nose and throat and discomfort when swallowing
  • difficulty breathing or tightness in the chest
  • signs of urinary tract infection such as an urge to urinate frequently and in small amounts, and painful burning when passing urine
  • feeling depressed or anxious
  • signs of anaemia such as tiredness, headaches, being short of breath when exercising, dizziness and looking pale
  • increased blood pressure
  • back pain.
  • joint pain
  • rash
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergic reaction:
  • severe allergic reaction (may include shortness of breath, wheezing or severe difficulty in breathing, shock, swelling of the face, lips, tongue or other parts of the body, skin rash, itching or hives on the skin hayfever, or you may feel faint)
Hypoglycaemia:
  • signs of hypoglycaemia (low blood sugar) that persist despite administering sugar as described under 'While you are taking Kombiglyze XR' in this leaflet. Signs of hypoglycaemia may include weakness, trembling or shaking, sweating, light-headedness, headache, dizziness, lack of concentration, tearfulness or crying, irritability, hunger and numbness around the lips and fingers. Do not drive a car if you have signs of low blood sugar.
Heart problems:
  • signs and symptoms of heart failure. Signs of heart failure may include, increasing shortness of breath, rapid increase in weight and swelling of the feet.
  • severe upper stomach pain, often with nausea and vomiting
  • signs and symptoms of heart failure. Signs of heart failure may include, increasing shortness of breath, rapid increase in weight and swelling of the feet.
  • develop blisters or the breakdown of your skin (erosion). These symptoms could be a sign of a skin reaction called bullous pemphigoid that can require treatment in a hospital. Your doctor may tell you to stop taking KOMBIGLYZE XR.
Lactic Acidosis
IN RARE CASES, METFORMIN, ONE OF THE MEDICINES IN KOMBIGLYZE XR, CAN CAUSE A SERIOUS SIDE EFFECT CALLED LACTIC ACIDOSIS.
LACTIC ACIDOSIS IS A MEDICAL EMERGENCY THAT CAN CAUSE DEATH AND MUST BE TREATED IN THE HOSPITAL. LACTIC ACIDOSIS IS CAUSED BY A BUILD-UP OF LACTIC ACID IN YOUR BLOOD.
STOP TAKING KOMBIGLYZE XR IF YOU GET ANY OF THE FOLLOWING SYMPTOMS OF LACTIC ACIDOSIS AND SEE YOUR DOCTOR IMMEDIATELY:
  • You feel very weak and tired.
  • You have unusual (not normal) muscle pain.
  • You have trouble breathing.
  • You have stomach pain with nausea and vomiting, or diarrhoea.
  • You feel cold, especially in your arms and legs.
  • You feel dizzy or light-headed.
  • You have a slow or irregular heart beat
  • Your medical condition suddenly changes.
The risk of lactic acidosis is higher in the elderly, those whose diabetes is poorly controlled, those with prolonged fasting, those with certain heart conditions, those who drink alcohol and those with kidney or liver problems.		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell. Do not be alarmed by this list of possible side effects. You may not experience any of them.

Other side effects not listed here may occur in some people.

Occasionally, KOMBIGLYZE XR may be associated with changes in your in your blood. These can only be found when your doctor does tests from time to time to check your progress.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What KOMBIGLYZE XR contains

Active ingredient
(main ingredient)
  • saxagliptin 5 mg and metformin hydrochloride 500 mg
  • saxagliptin 5 mg and metformin hydrochloride 1000 mg
  • saxagliptin 2.5 mg and metformin hydrochloride 1000 mg
Other ingredients
(inactive ingredients)
  • carmellose sodium
  • magnesium stearate
  • hypromellose
  • microcrystalline cellulose
  • macrogol 3350
  • titanium dioxide
  • purified talc
  • iron oxide red CI77491 (5 mg/500 mg and 5 mg/1000 mg tablets)
  • iron oxide yellow CI77492 (5 mg/500 mg and 2.5 mg/1000 mg tablets)
  • Opacode Blue (printing ink).
Potential allergensN/A

Do not take this medicine if you are allergic to any of these ingredients.

KOMBIGLYZE XR tablets do not contain lactose, gluten or sucrose.

What KOMBIGLYZE XR looks like

  • KOMBIGLYZE XR 5mg/500mg, light brown to brown, biconvex, capsule shaped, film-coated tablets, with "5/500" printed on one side and "4221" printed on the other side, in blue ink. Available in blister packs of 7 and 28 tablets (AUST R 202209).
  • KOMBIGLYZE XR 5mg/1000mg, pink, biconvex, capsule shaped, film-coated tablets, with "5/1000" printed on one side and "4223" printed on the other side in blue ink. Available in blister packs of 7 and 28 tablets (AUST R 202208).
  • KOMBIGLYZE XR 2.5mg/1000mg, pale yellow to light yellow, biconvex, capsule shaped, film-coated tablets with "2.5/1000" printed on one side and ‘"4222" printed on the other side. Available in blister packs of 14 and 56 tablets. (AUST R 202207).

Who distributes KOMBIGLYZE XR

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113

Telephone:- 1800 805 342

This leaflet was prepared in July 2023.

® KOMBIGLYZE XR is a registered trade mark of the AstraZeneca group of companies.

© AstraZeneca, 2023

Doc ID-005219403 v1.0

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Kombiglyze XR

Active ingredient

Saxagliptin; Metformin hydrochloride

Schedule

S4

 

1 Name of Medicine

Saxagliptin (as hydrochloride)/ metformin hydrochloride.

2 Qualitative and Quantitative Composition

Kombiglyze XR is available as:
Kombiglyze XR 5/500 tablets containing 5 mg saxagliptin (as hydrochloride) immediate release and 500 mg metformin hydrochloride modified release;
Kombiglyze XR 5/1000 tablets containing 5 mg saxagliptin (as hydrochloride) immediate release and 1000 mg metformin hydrochloride modified release;
Kombiglyze XR 2.5/1000 tablets containing 2.5 mg saxagliptin (as hydrochloride) immediate release and 1000 mg metformin hydrochloride modified release.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Modified release tablets.
Kombiglyze XR 5/500 modified release tablets are light brown to brown, biconvex, capsule shaped, film-coated tablets, with "5/500" printed on one side and "4221" printed on the other side, in blue ink.
Kombiglyze XR 5/1000 modified tablets are pink, biconvex, capsule shaped, film-coated tablets, with "5/1000" printed on one side and "4223" printed on the other side, in blue ink.
Kombiglyze XR 2.5/1000 modified tablets are pale yellow to light yellow, biconvex, capsule shaped, film-coated tablets, with "2.5/1000" printed on one side and "4222" printed on the other side, in blue ink.

4 Clinical Particulars

4.1 Therapeutic Indications

Kombiglyze XR is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate (for data on combinations studied, see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration).

4.2 Dose and Method of Administration

Life threatening lactic acidosis can occur due to accumulation of metformin. The main risk factor is renal impairment, other risk factors include old age associated with reduced renal function and high doses of metformin above 2 g per day.
Kombiglyze XR should be taken with or after food.
The dosage of antihyperglycaemic therapy with Kombiglyze XR should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended dose of saxagliptin 5 mg and metformin extended release 2000 mg. Kombiglyze XR should generally be administered once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin.
Patients should be informed that Kombiglyze XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of Kombiglyze XR will be eliminated in the faeces as a soft, hydrated mass that may resemble the original tablet.

As add-on combination therapy.

If therapy with a combination tablet containing saxagliptin and metformin is considered appropriate, the recommended dose of saxagliptin is 5 mg once daily. The recommended starting dose of metformin extended release is 500 mg once daily, which can be titrated to 2000 mg once daily. The maximum dose of Kombiglyze XR is saxagliptin 5 mg/metformin extended release 2000 mg taken as two 2.5 mg/1000 mg tablets once daily.
No studies have been performed specifically examining the safety and efficacy of Kombiglyze XR in patients previously treated with other antihyperglycaemic agents and switched to Kombiglyze XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycaemic control can occur.

As initial combination therapy.

The recommended starting doses of Kombiglyze XR when used as initial combination therapy is one 5 mg/500 mg tablet once daily. Patients with inadequate glycaemic control on this starting dose should further have their metformin dose increased to 5 mg/1000 mg once daily or two 2.5 mg/1000 mg tablets once daily as appropriate.

Special patient populations.

Renal impairment. Assess renal function prior to initiation of Kombiglyze XR and periodically thereafter (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment; Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment). Factors that may increase the risk of lactic acidosis (see Section 4.4 Special Warnings and Precautions for Use) should be reviewed before considering initiation of Kombiglyze XR in patients with eGFR < 60 mL/min/1.73 m2.

Mild renal impairment (eGFR 60-89 mL/min/1.73 m2).

No dosage adjustment is required for patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2 (by Modified Diet in Renal Disease [MDRD] eGFR equation).

Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2).

No dosage adjustment is required for patients with eGFR ≥ 45 mL/min/1.73 m2.
It is not recommended to initiate treatment with Kombiglyze XR in patients with eGFR < 45 mL/min/1.73 m2. If during treatment eGFR falls to levels persistently below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy and limit the maximum dose of Kombiglyze XR to 2.5 mg/1000 mg once daily (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Severe renal impairment (eGFR < 30 mL/min/1.73 m2).

Kombiglyze XR is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2). (See Section 4.3 Contraindications). See Table 1.
Hepatic impairment. Since impaired hepatic function has been associated with some cases of lactic acidosis in patients taking metformin, Kombiglyze XR should be avoided in patients with clinical or laboratory evidence of hepatic impairment. (See Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
Paediatric and adolescent. Safety and effectiveness of Kombiglyze XR in paediatric and adolescent patients have not been established.
Use in elderly. Saxagliptin and metformin are eliminated in part by the kidney, and therefore, because elderly patients are more likely to have decreased renal function, Kombiglyze XR should be used with caution as age increases. (See Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

4.3 Contraindications

Kombiglyze XR is contraindicated in patients with:
Hypersensitivity to the active substances or to any of the excipients, or a history of any serious hypersensitivity reaction, including anaphylactic reaction and angioedema, to any dipeptidyl peptidase 4 (DPP4) inhibitor (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Metabolic acidosis: Acute or chronic metabolic acidosis, including lactic acidosis or diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Diabetic pre-coma.
Severe renal impairment (eGFR < 30 mL/min/1.73 m2) (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, or intravascular administration of iodinated contrast agents (see Section 4.4 Special Warnings and Precautions for Use).
Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, pulmonary embolism, recent myocardial infarction, shock, acute significant blood loss, sepsis, gangrene, pancreatitis.
During or immediately following surgery where insulin is essential, elective major surgery.
Hepatic impairment.
Acute alcohol intoxication, alcoholism.
Lactation.

4.4 Special Warnings and Precautions for Use

General.

Kombiglyze XR should not be used in patients with type 1 diabetes mellitus. Kombiglyze XR has not been studied in combination with GLP-1 agonists (e.g. exenatide, liraglutide).

Lactic acidosis.

Metformin hydrochloride.

Lactic acidosis is a very rare, but serious and potentially fatal in the absence of prompt treatment, metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency, dehydration, any acute conditions associated with hypoxia or impacting renal function.
Medicinal products that can acutely impair renal function, such as antihypertensives, diuretics and NSAIDs, should be initiated with caution in metformin-treated patients (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis is characterized by symptoms such as acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. Lactic acidosis is a medical emergency that must be treated in a hospital setting. If metabolic acidosis is suspected, treatment with Kombiglyze XR should be discontinued and the patient hospitalized immediately.

Hypersensitivity reactions.

Saxagliptin.

During postmarketing experience the following adverse reactions have been reported with use of saxagliptin: serious hypersensitivity reactions, including anaphylaxis and angioedema. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency. If a serious hypersensitivity reaction to saxagliptin is suspected, discontinue Kombiglyze XR, assess for other potential causes for the event, and institute alternative treatment for diabetes. (See Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)).

Pancreatitis.

Saxagliptin.

During postmarketing experience, there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, Kombiglyze XR should be discontinued. (See Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience - saxagliptin).
In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR) Trial, the incidence of adjudicated pancreatitis events was 0.3% in both saxagliptin-treated patients and placebo-treated patients in the intent-to-treat population. (See Section 4.8 Adverse Effects (Undesirable Effects), Adverse reactions associated with saxagliptin in the SAVOR trial).

Use in renal impairment.

Metformin hydrochloride.

As metformin is excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function, assess renal function prior to initiation of Kombiglyze XR and then periodically thereafter:
at least annually;
at least two to four times per year in patients with renal function where eGFR levels are approaching 45 mL/min/1.73 m2 and in elderly patients.
It is not recommended to initiate treatment with Kombiglyze XR in patients with eGFR < 45 mL/min/1.73 m2.
If during treatment eGFR falls to levels persistently below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy and limit the maximum dose of Kombiglyze XR to 2.5 mg/1000 mg once daily (see Section 4.2 Dose and Method of Administration, Special patient populations, Renal impairment).
Kombiglyze XR is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) (see Section 4.3 Contraindications).

Change in clinical status of patients with previously controlled type 2 diabetes.

Metformin hydrochloride.

A patient with type 2 diabetes previously well controlled on Kombiglyze XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Kombiglyze XR must be stopped immediately and other appropriate corrective measures initiated.

Use in hepatic impairment.

Metformin hydrochloride.

Since impaired hepatic function has been associated with some cases of metformin-associated lactic acidosis, Kombiglyze XR should be avoided in patients with clinical or laboratory evidence of hepatic disease.

Radiologic studies with intravascular iodinated contrast materials.

Metformin hydrochloride.

Intravascular administration of iodinated contrast agents in radiological studies can lead to an acute decrease in renal function and has been associated with lactic acidosis in patients receiving metformin. Kombiglyze XR should temporarily be discontinued prior to, or at the time of the procedure and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be stable (see Section 4.3 Contraindications).

Acute conditions associated with hypoxia or impacting renal function.

Metformin hydrochloride.

Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions characterised by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotaemia. Acute conditions such as dehydration, severe infections, and hypoperfusion, have potential to alter renal function. When such events occur in patients on Kombiglyze XR therapy, the drug should be promptly discontinued.

Surgical procedures.

Metformin hydrochloride.

Use of Kombiglyze XR should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as stable.

Vitamin B12 decrease/deficiency.

Metformin hydrochloride.

Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contraindicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines (see Section 4.8 Adverse Effects (Undesirable Effects)).

Excessive alcohol intake.

Metformin hydrochloride.

Alcohol potentiates the effect of metformin on lactate metabolism. Patients, should be warned against excessive alcohol intake, while receiving Kombiglyze XR.

Loss of control of blood glucose.

Metformin hydrochloride.

When a patient stabilised on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycaemic control may occur. At such times, it may be necessary to withhold Kombiglyze XR and temporarily administer insulin. Kombiglyze XR may be reinstituted after the acute episode is resolved.

Use with medicines known to cause hypoglycaemia.

The sulfonylurea class of antihyperglycaemic agents and insulin are known to cause hypoglycaemia. Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycaemia when used in combination with Kombiglyze XR. (See Section 4.8 Adverse Effects (Undesirable Effects)).

Skin disorders.

Saxagliptin. Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical toxicology studies. Although skin lesions were not observed at an increased incidence in clinical trials, there is limited experience in patients with diabetic skin complications. Postmarketing reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse event for saxagliptin (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience - saxagliptin). Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering, ulceration or rash, is recommended.

Bullous pemphigoid.

Post-marketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving Kombiglyze XR. If bullous pemphigoid is suspected, Kombiglyze XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience - saxagliptin).

Cardiac failure.

In the SAVOR trial a small increase in the rate for hospitalisation for heart failure was observed in the saxagliptin treated patients compared to placebo, although a causal relationship has not been established (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Cardiovascular safety). Additional analysis did not indicate a differential effect among NYHA classes (see Section 4.8 Adverse Effects (Undesirable Effects), Adverse reactions associated with saxagliptin in the SAVOR trial). Caution is warranted if Kombiglyze XR is used in patients who have known risk factors for hospitalisation for heart failure, such as a history of heart failure or moderate to severe renal impairment. Patients should be advised of the characteristic symptoms of heart failure, and to immediately report such symptoms.

Arthralgia.

Joint pain, which may be severe, has been reported in postmarketing reports for DPP4 inhibitors. Patients experienced relief of symptoms after discontinuation of the medication and some experienced recurrence of symptoms with reintroduction of the same or another DPP4 inhibitor. Onset of symptoms following initiation of drug therapy may be rapid or may occur after longer periods of treatment. If a patient presents with severe joint pain, continuation of drug therapy should be individually assessed. (See Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience - saxagliptin).

Immunocompromised patients.

Saxagliptin.

Immunocompromised patients, such as patients who have undergone organ transplantation or patients diagnosed with human immunodeficiency syndrome, have not been studied in the saxagliptin clinical program. Therefore, the efficacy and safety profile of saxagliptin in these patients has not been established.

Use in the elderly.

As saxagliptin and metformin are eliminated in part by the kidney, and because elderly patients are more likely to have decreased renal function, Kombiglyze XR should be used with caution as age increases.

Saxagliptin.

Of the 16,492 patients randomised in the SAVOR trial, 8561 (51.9%) patients were 65 years and over and 2330 (14.1%) were 75 years and over. The number of subjects treated with saxagliptin in the SAVOR study that were 65 years and over was 4290 and the number of subjects that were 75 years and over was 1169.
Of the total number of subjects (N=4148) in six double blind, controlled clinical safety and efficacy studies of saxagliptin, 634 (15.3%) patients were 65 years and over, of which 59 (1.4%) patients were 75 years and over.
No overall differences in safety or effectiveness were observed between subjects 65 years and over, 75 years and over and younger subjects.

Metformin hydrochloride.

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney and the risk of serious adverse reactions to the drug is greater in patients with impaired renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function. (See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Safety and effectiveness of Kombiglyze XR in paediatric patients have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Saxagliptin.

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5) which converts it to an active metabolite. Therefore, drugs which inhibit the activity of this enzyme system may increase plasma concentrations of saxagliptin but reduce those of its metabolite, whereas CYP3A inducers will tend to do the opposite. However, the overall biological effect of saxagliptin is unaffected by coadministration with inhibitors or inducers of CYP3A4/5.
In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolised by these enzymes. Saxagliptin is neither a significant inhibitor of P-glycoprotein (P-gp) nor an inducer of P-gp.
The in vitro protein binding of saxagliptin and its major metabolite in human serum is below measurable levels. Thus, protein binding would not have a meaningful influence on the pharmacokinetics of saxagliptin or other drugs.
In studies conducted in healthy subjects, the pharmacokinetics of saxagliptin, and its major metabolite, were altered by some drugs which affect the CYP3A4/5 system. However, total exposure of the total active components of saxagliptin (parent + metabolite), was not meaningfully altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem, ketoconazole, rifampicin, omeprazole, aluminium hydroxide + magnesium hydroxide + simethicone combination, or famotidine. Saxagliptin also did not meaningfully alter the pharmacokinetics of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem, ketoconazole or an oestrogen/ progestogen combined oral contraceptive.

Metformin hydrochloride.

Cationic drugs.

Cationic drugs (e.g. amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single and multiple dose, metformin cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Glibenclamide.

In a single dose interaction study in type 2 diabetes patients, coadministration of metformin and glibenclamide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glibenclamide AUC and maximum concentration (Cmax) were observed, but were highly variable. The single dose nature of this study and the lack of correlation between glibenclamide blood levels and pharmacodynamic effects makes the clinical significance of this interaction uncertain.

Frusemide.

A single dose, metformin frusemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Frusemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of frusemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in frusemide renal clearance. No information is available about the interaction of metformin and frusemide when coadministered chronically.

Nifedipine.

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

Use with other drugs.

Certain drugs tend to produce hyperglycaemia and may lead to loss of glycaemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving metformin, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, the patient should be observed closely for hypoglycaemia.
In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single dose interaction studies.
Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

Other interactions.

The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of Kombiglyze XR have not been specifically studied.
The safety and efficacy of saxagliptin in combination with alpha-glucosidase inhibitors or orlistat has not been established.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies have been conducted with the combined components of Kombiglyze XR to evaluate effects on fertility.

Saxagliptin.

In a rat fertility study, males were treated with oral gavage doses of 100, 200, and 400 mg/kg/day for two weeks prior to mating, during mating, and up to scheduled termination (approximately four weeks total) and females were treated with oral gavage doses of 125, 300, and 750 mg/kg/day for two weeks prior to mating through gestation day 7. No adverse effects on fertility were observed at 200 mg/kg/day (males) or 125 mg/kg/day (females) resulting in respective exposures (AUC) of approximately 670 (males) and 865 (females) times human exposure at the recommended clinical dose. At higher, maternally toxic doses (300 and 750 mg/kg/day), increased fetal resorptions were observed (approximately 2300 and 6810 times the recommended clinical dose). Additional effects on oestrous cycling, fertility, ovulation, and implantation were observed at 750 mg/kg/day (approximately 6810 times the recommended clinical dose).

Metformin.

Fertility of male and female rats was unaffected by metformin when administered at doses as high as 500 mg/kg/day which is approximately three times the maximum recommended human dose based on body surface area comparisons.
(Category C)
There are no adequate and well controlled studies of Kombiglyze XR or its individual components in pregnant women. Because animal reproduction studies are not always predictive of human response, Kombiglyze XR, like other antidiabetic medications, should be used during pregnancy only if clearly needed.
Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the maximum recommended human doses (MRHD; saxagliptin 5 mg and metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the MRHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of wavy ribs; associated maternal toxicity was limited to weight decrements of 5% to 6% over the course of gestation days 13 through 18, and related reductions in maternal food consumption. In rabbits, coadministration was poorly tolerated in a subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to reduced unformed faeces and transient reductions in food consumption and developmental toxicity in these litters was limited to fetal body weight decrements of 7%, cases of incompletely ossified pubis and a low incidence of delayed ossification of the fetal hyoid.

Saxagliptin.

Saxagliptin was not teratogenic at any dose evaluated in rats or rabbits. At high doses in rats, saxagliptin caused a minor developmental delay in ossification of the foetal pelvis at ≥ 240 mg/kg/day (≥ 1670 times the human exposure [AUC] at the recommended clinical dose). Maternal toxicity and reduced foetal body weights were observed at 900 mg/kg/day (> 8860 times the recommended clinical dose). In rabbits, the effects of saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (200 mg/kg/day, exposures 1520 times the recommended clinical dose).
Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in male and female offspring only at maternally toxic doses (≥ 250 mg/kg/day, exposures ≥ 1810 times the recommended clinical dose). No functional or behavioural toxicity was observed in the offspring of rats administered saxagliptin at any dose.
Saxagliptin and/or its metabolites cross the placenta into the fetus following dosing in pregnant rats.

Metformin hydrochloride.

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 3 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
 No studies in lactating animals have been conducted with the combined components of Kombiglyze XR. In studies performed with the individual components, both saxagliptin and metformin are secreted in the milk of lactating rats. It is not known whether saxagliptin or metformin are secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when Kombiglyze XR is administered to a nursing woman.

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 with Kombiglyze XR or saxagliptin.
Saxagliptin or metformin may have a negligible influence on the ability to drive and use machines. It should be taken into account that dizziness has been reported in studies with saxagliptin.

4.8 Adverse Effects (Undesirable Effects)

Significant adverse events are also described, see Section 4.4 Special Warnings and Precautions for Use.

Clinical experience - saxagliptin.

In randomised, controlled, double blind clinical trials, over 17,000 patients with type 2 diabetes have been treated with saxagliptin.
Adverse reactions associated with saxagliptin in the SAVOR trial. The SAVOR trial included 8240 patients treated with saxagliptin 5 mg or 2.5 mg once daily and 8173 patients on placebo.
The overall incidence of adverse events in patients treated with saxagliptin in this trial was similar to placebo (72.5% versus 72.2%, respectively).
Hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominal statistical significance favouring placebo [HR = 1.27; 95% CI 1.07, 1.51; p = 0.007]. (See Section 5.1 Pharmacodynamic Properties, Clinical trials, Cardiovascular safety).
In the SAVOR trial, the incidence of adjudicated pancreatitis events was 0.3% in both saxagliptin treated patients and placebo treated patients in the intent to treat population.
The incidence of hypersensitivity reactions was 1.1% in both saxagliptin treated patients and placebo treated patients.

Hypoglycaemia.

In the SAVOR trial, the overall incidence of reported hypoglycaemia (recorded in daily patient diaries) was 17.1% in saxagliptin treated patients and 14.8% in placebo treated patients.
The percent of subjects with reported on treatment events of major hypoglycaemia (defined as an event that required assistance of another person) was higher in the saxagliptin group than in the placebo group (2.1% and 1.6%, respectively).
The increased risk of overall hypoglycemia and major hypoglycemia observed in the saxagliptin treated group occurred primarily in subjects treated with a sulfonylurea at baseline and not in subjects on insulin or metformin monotherapy at baseline.
The increased risk of overall and major hypoglycaemia was primarily observed in subjects with HbA1c < 7% at baseline.
Saxagliptin in studies of glycaemic control. There were 4148 patients with type 2 diabetes randomised, including 3021 patients treated with saxagliptin, in six, double blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control.
In a pre-specified pooled analysis of the two monotherapy studies, the add-on to metformin study, the add-on to TZD study, and the add-on to glibenclamide study, the overall incidence of adverse events in patients treated with saxagliptin 5 mg was similar to placebo. In the 24 week short-term period, discontinuation of therapy due to adverse events occurred in 3.3% and 1.8% of patients receiving saxagliptin 5 mg and placebo, respectively. In the 24 week short-term combined with the long-term extension period, discontinuation of therapy due to adverse events occurred in 6.7% and 4.6% of patients receiving saxagliptin 5 mg and placebo, respectively.
The adverse reactions in this short-term pooled analysis reported (regardless of investigator assessment of causality) in ≥ 5% of patients treated with saxagliptin 5 mg and more commonly than in patients treated with placebo are shown in Table 2.
In this pooled analysis, less common adverse reactions that were reported in ≥ 2% of patients treated with saxagliptin 5 mg and ≥ 1% more frequently compared to placebo included the following: sinusitis, gastroenteritis, vomiting, URI and UTI.
Adverse events of uncertain causality that were reported in ≥ 2% of patients treated with Onglyza 5 mg and ≥ 1% more frequently compared to placebo include hypertension, abdominal pain, rash, blood creatine phosphokinase increased, hypertriglyceridaemia, anaemia, depression, and anxiety.
A grouping of hypersensitivity related events in the 5 study pooled analysis up to Week 24 showed an incidence of 1.5% and 0.4% in patients who received Onglyza 5 mg (all non-serious) and placebo, respectively.
Adverse reactions associated with saxagliptin and concomitant therapy. In the combined short-term and long-term extension period, adverse reactions in placebo controlled studies reported in ≥ 2% of patients treated with saxagliptin 5 mg and ≥ 1% more frequently compared to saxagliptin 10 mg alone and metformin alone were: nasopharyngitis and headache. Hypertension, an adverse event of uncertain causality, was reported in ≥ 2% of patients treated with saxagliptin 5 mg and ≥ 1% more frequently compared to placebo.
In a 24 week, active controlled study of initial therapy of saxagliptin in combination with metformin, the adverse reactions reported (regardless of investigator assessment of causality) in ≥ 5% of patients are shown in Table 3.
In this study of initial therapy of saxagliptin in combination with metformin, less common adverse events that were reported in ≥ 2% of patients treated with saxagliptin 5 mg and ≥ 1% more frequently compared to saxagliptin monotherapy and metformin included the following: bronchitis, dyspepsia, and back pain.

Peripheral oedema.

In the add-on to TZD study, the incidence of peripheral oedema was higher for saxagliptin 5 mg plus TZD versus placebo plus TZD (8.1% versus 4.3%). In the combined short-term and long-term extension period, the incidence of peripheral oedema was higher for saxagliptin 5 mg plus TZD versus placebo plus TZD (13.4% versus 9.8%). In a pooled analysis of the two monotherapy studies, the add-on to metformin study and the add-on to SU study (short-term 24 week), the overall incidence of adverse reactions of peripheral oedema observed in patients treated with saxagliptin 5 mg alone or in combination was similar to placebo (1.7% versus 2.4%). In the SAVOR study, the overall incidence of adverse reactions of peripheral oedema observed in patients treated with saxagliptin was similar to those treated with placebo (3.9% versus 4% respectively).

Hypoglycaemia.

Adverse reactions of hypoglycaemia were based on all reports of hypoglycaemia; a concurrent glucose measurement was not required. Confirmed hypoglycaemia was defined as symptomatic hypoglycaemia with a fingerstick glucose value of ≤ 2.8 mmol/L.
In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to TZD study (short-term 24 week), the overall incidence of adverse reactions of hypoglycaemia in patients treated with saxagliptin 5 mg was similar to placebo (4.8% versus 4.3%).
In the 24 week study of initial therapy of saxagliptin in combination with metformin study the incidence of hypoglycaemia was 3.4% in patients given saxagliptin 5 mg plus metformin and 4.0% in patients given metformin alone. In the combined short-term and long-term extension period, the incidence of hypoglycaemia was 4.4% in patients given saxagliptin 5 mg plus metformin, and 5.2% in patients given metformin alone.
In the short-term 24 week add-on to glibenclamide study, the overall incidence of hypoglycaemia was higher for saxagliptin 5 mg plus glibenclamide versus placebo plus up-titrated glibenclamide. The difference (14.6% versus 10.1%) was not statistically significant. The incidence of confirmed hypoglycaemia was 0.8% for saxagliptin 5 mg plus glibenclamide and 0.7% for placebo plus up-titrated glibenclamide. In the combined short-term and long-term extension period of the add-on to glibenclamide study, the overall incidence of hypoglycaemia was 18.2% for saxagliptin 5 mg and 12.0% for up-titrated glibenclamide; the incidence of confirmed hypoglycaemia was 1.6% for saxagliptin 5 mg and 1.9% for up-titrated glibenclamide.
The incidence of reported hypoglycaemia for saxagliptin 5 mg versus placebo given as monotherapy was 5.6% versus 4.1%, respectively, and 5.8% versus 5% given as add-on therapy to metformin.
In the add-on to combination with metformin plus SU study, the overall incidence of hypoglycaemia experienced was 10.1% for saxagliptin 5 mg and 6.3% for placebo. Confirmed hypoglycaemia was reported in 1.6% of the saxagliptin treated patients and none of the placebo treated patients.
In the analysis of pooled safety data of 1169 patients from trials evaluating saxagliptin in combination with dapagliflozin, the overall incidence of hypoglycaemia for the pooled safety data of was low (≤ 1.8% in any treatment group); there was no increase in hypoglycaemia in saxagliptin plus dapagliflozin plus metformin treatment group compared to the saxagliptin plus metformin or dapagliflozin plus metformin treatment groups. The combined use of saxagliptin plus dapagliflozin plus metformin was not associated with an increase in the risk of hypoglycaemia when compared to the individual agents as monotherapy. This was consistent with prior clinical trial experience regardless of whether the combination was added to metformin concurrently or sequentially.
In the add-on to insulin study, the overall incidence of reported hypoglycaemia was 18.4% for saxagliptin 5 mg and 19.9% for placebo.

Vital signs.

No clinically meaningful changes in vital signs have been observed in patients treated with saxagliptin 5 mg.
Laboratory findings - saxagliptin. Across clinical studies, the incidence of laboratory adverse events was similar in patients treated with saxagliptin 5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte count was observed. From a baseline mean absolute lymphocyte count of approximately 2.2 x 109 c/L, a mean decrease of approximately 0.1 x 109 c/L relative to placebo was observed in a pooled analysis of five placebo controlled clinical studies. Mean absolute lymphocyte counts remained stable and within normal limits with daily dosing up to 102 weeks in duration. In the short-term period, the proportion of patients who were reported to have a lymphocyte count ≤ 750 cells/microL was 1.5% and 0.4% in the saxagliptin 5 mg and placebo groups, respectively. In the short-term combined with long-term extension period of the pooled studies, the proportion of patients who were reported to have a lymphocyte count ≤ 750 cells/microL was 1.6% and 1.0% in the saxagliptin 5 mg and placebo groups, respectively. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte count relative to placebo is not known.
In the SAVOR trial, decreased lymphocyte counts were reported in 0.5% of saxagliptin treated patients and 0.4% of placebo treated patients.
Postmarketing experience - saxagliptin. During postmarketing experience the following adverse reactions have been reported with use of saxagliptin: acute pancreatitis, arthralgia, bullous pemphigoid and hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency. (See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.)

Metformin hydrochloride.

Metformin adverse reactions by system organ class and by frequency category. Frequency categories are based on information available from the metformin Product Information available in Australia.

Gastrointestinal.

Very common: mild gastrointestinal symptoms (such as diarrhoea, nausea, vomiting, abdominal pain and loss of appetite) are the most frequent reactions to metformin (> 1/10), especially during the initial treatment period. These symptoms are generally transient and resolve spontaneously during continued treatment.
Occurrence of gastrointestinal symptoms, once a patient is stabilised on any dose of metformin, could be due to lactic acidosis or other serious disease.

Systemic/ metabolic.

Very rare: lactic acidosis (see Section 4.4 Special Warnings and Precautions for Use, Lactic acidosis) is a very rare (< 1/10,000) but serious metabolic complication that can occur due to metformin accumulation during treatment with metformin.
The onset of lactic acidosis is often subtle and accompanied only by non-specific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and non-specific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonaemia).
Lactic acidosis is a medical emergency that must be treated in hospital. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted.

Nervous system disorders.

Common: taste disturbance (3%) is common.

Dermatological.

Very rare: skin reactions such as erythema, pruritus and urticaria have been reported, but the incidence is very rare (< 1/10,000).

Haematological.

Common: a decrease of vitamin B12 absorption with a decrease in serum levels has been observed in patients treated long-term with metformin (> 1/100, < 1/10). Consideration of such an aetiology is recommended if a patient presents with megaloblastic anaemia. Therefore, serum B12 levels should be appropriately monitored or periodic parenteral B12 supplementation considered (see Section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary disorders.

Isolated reports: liver function tests abnormalities or hepatitis resolving upon metformin discontinuation, have been reported.
In clinical trials in children and adolescents with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

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

4.9 Overdose

Saxagliptin.

Once daily, orally administered saxagliptin has been shown to be safe and well tolerated, with no clinically meaningful effect on QTc interval or heart rate at doses up to 400 mg daily for two weeks (80 times the recommended human dose of 5 mg/day [RHD]).
In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. Saxagliptin and its major metabolite are removed by haemodialysis (23% of dose over four hours).

Metformin hydrochloride.

High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital. The most effective method to remove lactate and metformin is haemodialysis. Events of hypoglycaemia have been reported with overdoses of metformin, although a causal association has not been established.
For information on management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Kombiglyze XR combines two anti-hyperglycaemic agents with complementary mechanisms of action to improve both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) in patients with type 2 diabetes: saxagliptin, a DPP-4 inhibitor, and metformin hydrochloride, a member of the biguanide class.
Saxagliptin. Saxagliptin is a member of a class of oral anti-hyperglycaemic agents called DPP-4 inhibitors. Saxagliptin is a reversible, competitive, DPP-4 inhibitor with nanomolar potency. Saxagliptin demonstrates selectivity for DPP-4 versus other DPP enzymes, with greater than 75 fold selectivity over DPP-8 and DPP-9. Saxagliptin has extended binding to the DPP-4 active site, prolonging its inhibition of DPP-4. Saxagliptin exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP). Concentrations of these active intact incretin hormones are increased by saxagliptin, thereby increasing and prolonging the actions of these hormones. Saxagliptin also inhibits the cleavage of other substrates in vitro, but the relevance or consequences of DPP-4 inhibition for these substrates in patients is unknown.
This glucose dependent mechanism is unlike the mechanism seen with sulfonylureas, whereby insulin is released even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon levels lead to lower haemoglobin A1c (HbA1c) and lower fasting and postprandial glucose concentrations.
Incretin hormones are released by the intestine throughout the day and concentrations are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are elevated GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production.
Concentrations of GLP-1 are reduced in patients with type 2 diabetes, but saxagliptin increases active GLP-1 and GIP, potentiating these mechanisms. By increasing and prolonging active incretin concentrations, saxagliptin increases insulin release and decreases glucagon concentrations in the circulation in a glucose dependent manner.
Saxagliptin improves glycaemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through improvements in alpha and beta cell function as reflected by the actions described below.

Fasting glucose dependent insulin secretion.

Saxagliptin increases pancreatic beta cell responsiveness to glucose in the fasting state and leads to enhanced insulin secretion and glucose disposal in the presence of elevated glucose concentrations.

Postprandial glucose dependent insulin secretion.

Saxagliptin increases pancreatic beta cell responsiveness to glucose in the postprandial state and leads to enhanced postprandial insulin secretion and glucose disposal.

Postprandial glucagon secretion.

In type 2 diabetes, paradoxical increases in glucagon secretion from alpha cells following meals stimulate hepatic glucose production and contribute to glycaemic dysregulation. Saxagliptin moderates glucagon secretion and lowers postprandial glucagon concentrations.
Metformin hydrochloride. Metformin is an antihyperglycaemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation. Unlike sulfonylureas, metformin does not produce hypoglycaemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see Section 4.4 Special Warnings and Precautions for Use) and does not cause hyperinsulinaemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day long plasma insulin response may actually decrease.
In humans, independently of its action on glycaemia metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium or long term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

Pharmacodynamics.

Improvement in glycaemic control.

Saxagliptin.

In patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP-4 enzyme activity for a 24 hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2 to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose dependent beta cell responsiveness, which resulted in higher insulin and C peptide concentrations. The rise in insulin and the decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
Treatment with saxagliptin 5 mg and metformin extended release administered once daily with the evening meal for 4 weeks produced significant reductions in average glucose concentration over the 24 hour dosing interval (defined as 24 hour glucose area under the curve divided by 24 hours) when compared to placebo plus metformin extended release (mean placebo corrected reduction of 0.9 mmol/L; P=0.0001) with consistent improvements in measured plasma glucose values throughout the 24 hour dosing interval. Significant reductions in 2 hour postprandial glucose and 2 day average fasting plasma glucose were seen (mean placebo corrected reductions of 2.0 mmol/L; P=0.0010 and 0.8 mmol/L; P=0.0002, respectively).
Cardiac electrophysiology.

Saxagliptin.

In a clinical trial designed to study the effect of saxagliptin on QTc interval, dosing with saxagliptin was not associated with clinically meaningful prolongation of QTc interval or heart rate at daily doses up to 40 mg (8 times the Recommended Human Dose (RHD) of 5 mg/day). In a randomised, double blind, placebo controlled, four way crossover, active comparator study, 40 healthy subjects were administered doses of saxagliptin up to 40 mg, placebo once daily for four days, or a single dose of moxifloxacin 400 mg as a positive control. Following the 40 mg dose, the maximum increase in the placebo corrected mean changes in QTc interval and heart rate from baseline were 2.4 msec at 24 hours post-dose and 4.5 beats per minute at 4 hours post-dose, respectively.

Clinical trials.

Improved glycaemic control. The coadministration of saxagliptin and metformin has been studied in patients with type 2 diabetes inadequately controlled on metformin alone, in treatment naive patients inadequately controlled on diet and exercise alone, compared with sulfonylurea in combination with metformin in patients with inadequate glycaemic control on metformin alone, and studied in a subgroup of patients inadequately controlled on insulin plus metformin. Treatment with saxagliptin plus metformin at all doses produced clinically relevant and statistically significant improvements in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and 2 hour postprandial glucose (PPG) following a standard oral glucose tolerance test (OGTT), compared to placebo in combination with metformin (initial or add-on therapy). Reductions in HbA1c were seen across subgroups including gender, age, race, and baseline BMI.
In the initial combination and add-on to metformin studies, decrease in body weight in the treatment groups given saxagliptin in combination with metformin was similar to that in the groups given metformin alone. Saxagliptin plus metformin was not associated with significant changes from baseline in fasting serum lipids compared to metformin alone.
There have been no clinical efficacy studies conducted with Kombiglyze XR; however, bioequivalence of Kombiglyze XR with coadministered saxagliptin and metformin hydrochloride extended release tablets was demonstrated.
Addition of saxagliptin to metformin. A total of 743 patients with type 2 diabetes participated in this randomised, double blind placebo controlled study of 24 week duration, to evaluate the efficacy and safety of saxagliptin in combination with metformin in patients with inadequate glycaemic control (HbA1c ≥ 7% and ≤ 10%) on metformin alone. Patients were required to be on a stable dose of metformin (1500-2550 mg daily) for at least 8 weeks to be enrolled in this study.
Patients who met eligibility criteria were enrolled in a single blind, two week, dietary and exercise placebo lead in period during which patients received metformin at their pre-study dose, up to 2500 mg daily, for the duration of the study. Following the lead in period, eligible patients were randomised to 2.5 mg, 5 mg, or 10 mg of saxagliptin or placebo in addition to their current dose of open label metformin. Patients who failed to meet specific glycaemic goals during the study were treated with pioglitazone rescue therapy, added on to placebo or saxagliptin plus metformin. Dose titrations of saxagliptin and metformin were not allowed in this study.
In combination with metformin, saxagliptin 5 mg provided significant improvements in HbA1c, FPG, and PPG compared with the placebo plus metformin group (Table 4). Reductions in HbA1c at Week 4 (Figure 1) and FPG at Week 2 were seen in the saxagliptin 5 mg plus metformin treatment groups relative to the placebo plus metformin group, the earliest timepoints of assessment. The proportion of patients achieving HbA1c < 7% (regardless of baseline value) was significantly greater in the saxagliptin 5 mg plus metformin treatment groups compared with the placebo plus metformin group. Significant reductions in 2 hour PPG level following standard oral glucose tolerance test were observed in the saxagliptin 5 mg plus metformin treatment group (-3.2 mmol/L) compared with the placebo plus metformin group (-1.0 mmol/L). The proportion of patients who discontinued for lack of glycaemic control or who were rescued for meeting pre-specified glycaemic criteria was higher in the placebo plus metformin group (27%) than in the saxagliptin 5 mg plus metformin group (13%). Higher baseline HbA1c was associated with a greater adjusted mean change from baseline in HbA1c with saxagliptin 5 mg. The effect of saxagliptin on lipid endpoints in this study was similar to placebo. Similar reductions in body weight were observed in patients who received saxagliptin and placebo therapy (-0.9 kg and -0.9 kg, respectively).

Controlled long-term extension.

Patients who were rescued (based on predefined glucose levels) during the initial 24 week study period as well as those who completed all visits during the initial 24 week study period without need for rescue therapy were eligible to enter a controlled long-term study extension. Patients who received saxagliptin in the initial 24 week study period maintained the same dose of saxagliptin in the long-term extension. All efficacy analyses were based on data obtained prior to rescue therapy. Treatment with saxagliptin 5 mg plus metformin was associated with a greater reduction in HbA1c than in the placebo plus metformin group, and the effect relative to placebo was sustained to Week 102. The HbA1c change for saxagliptin 5 mg plus metformin compared with placebo plus metformin was -0.8% at Week 102.
Coadministration of saxagliptin with metformin in treatment naive patients. A total of 1306 treatment naïve patients with type 2 diabetes participated in this randomised, double blind, placebo controlled study of 24 week duration, to evaluate the efficacy and safety of saxagliptin as initial combination therapy with metformin in patients with inadequate glycaemic control (HbA1c ≥ 8% to ≤ 12%) on diet and exercise alone. Patients were required to be treatment naïve to be enrolled in this study.
Patients who met eligibility criteria were enrolled in a single blind, one week, dietary and exercise placebo lead in period. Patients were randomised to one of four treatment arms: saxagliptin 5 mg + metformin 500 mg, saxagliptin 10 mg + metformin 500 mg, saxagliptin 10 mg + placebo, or metformin 500 mg + placebo. Saxagliptin was dosed once daily. During Weeks 1 through 5, in the saxagliptin 5 mg and the saxagliptin 10 mg plus metformin groups, and the metformin alone group, metformin was up-titrated based on FPG levels in 500 mg per day increments as tolerated to a maximum of 2000 mg per day. Patients who failed to meet specific glycaemic goals during the studies were treated with pioglitazone rescue as add-on therapy.
Initial therapy with the combination of saxagliptin 5 mg plus metformin provided significant improvements in HbA1c, FPG, and PPG compared with metformin alone (Table 5). Reductions in HbA1c at Week 4 and FPG at Week 2 were seen in the saxagliptin 5 mg plus metformin treatment group relative to metformin alone, the earliest timepoints of assessment. The proportion of patients achieving HbA1c < 7% (regardless of baseline value) was significantly greater in the saxagliptin 5 mg plus metformin treatment group compared with metformin alone. Significant reductions in 2 hour PPG level following standard oral glucose tolerance test were observed in the saxagliptin 5 mg plus metformin group (-7.7 mmol/L) compared with the metformin alone group (-5.4 mmol/L). Significant improvements in HbA1c, FPG, and PPG were also seen in the saxagliptin 5 mg plus metformin group compared with the saxagliptin alone group. Higher baseline HbA1c was associated with greater adjusted mean change from baseline in HbA1c in all treatment groups. Similar effects on lipid parameters were observed in all treatment groups. Similar reductions in body weight were seen in the saxagliptin 5 mg plus metformin and in the metformin alone groups (-1.8 kg and 1.6 kg, respectively) with a smaller reduction seen in the saxagliptin 10 mg group.

Controlled long-term study extension.

Patients who were rescued (based on predefined glucose levels) during the initial 24 week study period as well as those who completed all visits during the initial 24 week study period without need for rescue therapy were eligible to enter a controlled long-term study extension. Patients who received saxagliptin in the initial 24 week study period maintained the same dose of saxagliptin in the long-term extension. All efficacy analyses were based on data obtained prior to rescue therapy. Treatment with saxagliptin 5 mg plus metformin was associated with a greater reduction in HbA1c than in the metformin monotherapy group, and the effect relative to control was sustained to Week 76. The HbA1c change for saxagliptin 5 mg plus metformin compared with metformin monotherapy was -0.5% at Week 76.
Saxagliptin add-on combination therapy with metformin versus glipizide add-on combination therapy with metformin. A total of 858 patients with type 2 diabetes participated in this randomised, double blind, active controlled study of 52 week duration, to evaluate the efficacy and safety of saxagliptin in combination with metformin compared with sulfonylurea in combination with metformin in patients with inadequate glycaemic control (HbA1c > 6.5% and ≤ 10%) on metformin alone. Patients were required to be on a stable dose of metformin (at least 1500 mg daily) for at least 8 weeks to be enrolled in this study.
Patients who met eligibility criteria were enrolled in a single blind, two week, dietary and exercise placebo lead in period during which patients received metformin (1500-3000 mg based on their pre-study dose) for the duration of the study. Following the lead in period, eligible patients were randomised to 5 mg of saxagliptin or 5 mg of glipizide in addition to their current dose of open label metformin. Patients in the glipizide plus metformin group were titrated to optimal effect (FPG ≤ 6.1 mmol/L) or the highest tolerable dose during the first 18 weeks using a double dummy technique to a maximum of 20 mg per day (mean dose 15 mg).
Saxagliptin 5 mg added to metformin was non-inferior to glipizide added to metformin in lowering HbA1c as per the primary analysis of the per protocol analysis set (Table 6). The intent to treat analysis showed consistent results.
Saxagliptin 5 mg resulted in a significantly lower proportion of patients with hypoglycaemic events, 3% (19 events in 13 patients) versus 36.3% (750 events in 156 patients) for glipizide.
Patients treated with saxagliptin exhibited a significant decrease from baseline in body weight compared to a weight gain in patients administered glipizide (-1.1 kg versus +1.1 kg, p < 0.0001).

Controlled long-term study extension.

Patients who completed the initial 52 week study period were eligible to enter a controlled 52 week long-term study extension. Patients maintained the same dose of saxagliptin 5 mg or glipizide in the long-term extension. Changes in HbA1c values from baseline were -0.4% for saxagliptin 5 mg (N=184) added to metformin and -0.3% for glipizide (N=160) added to metformin at Week 104.
Treatment with saxagliptin 5 mg plus metformin resulted in a lower proportion of patients with hypoglycaemic events, 3.5% (24 events in 15 patients) versus 38.4% (896 events for 165 patients) for treatment with glipizide plus metformin. Treatment with saxagliptin 5 mg plus metformin resulted in a reduction in mean body weight compared with baseline values (-1.5 kg) whereas treatment with glipizide plus metformin resulted in an increase in mean body weight compared with baseline values (+1.3 kg) at Week 104. The overall safety profile of saxagliptin 5 mg versus glipizide in the long-term treatment period was consistent with that previously observed in the initial 52 week treatment period.
Saxagliptin add-on combination therapy with insulin (with or without metformin). A total of 455 adult patients with type 2 diabetes participated in this randomised, double blind, placebo controlled trial of 24 week duration to evaluate the efficacy and safety of saxagliptin as add-on therapy to a basal or pre-mixed insulin in patients with inadequate glycaemic control (HbA1c ≥ 7.5% and ≤ 11%) on basal or pre-mixed insulin alone (N=141) or on a basal or premixed insulin in combination with a stable dose of metformin (N=314). Patients were required to be on a stable dose of insulin (≥ 30 units to ≤ 150 units daily) with ≤ 20% variation in total daily dose for ≥ 8 weeks prior to screening with or without metformin. Patients using short acting insulins were excluded unless the short acting insulin was administered as part of a premixed insulin.
Patients who met eligibility criteria were enrolled in a single blind, four week, dietary and exercise placebo lead in period during which patients received insulin (and metformin, if applicable) at their prestudy dose(s). Following the lead in period, eligible patients were randomised to saxagliptin 5 mg or placebo in addition to continuing their current dose of insulin (and metformin, if applicable). Patients maintained a stable dose of insulin when possible. Patients who failed to meet specific glycaemic goals or who increased their insulin dose by > 20% were rescued and subsequently switched (rescued) to a flexible insulin dose regimen (including increases in the dose of insulin and the addition of rapid acting or short acting insulin, if needed). Dose titrations of saxagliptin and metformin (if applicable) were not allowed in this study.
Saxagliptin 5 mg add-on to insulin with or without metformin provided significant improvements in HbA1c and PPG compared with placebo add-on to insulin with or without metformin (Table 7). Similar HbA1c reductions versus placebo were achieved for patients using saxagliptin 5 mg add-on to insulin alone and saxagliptin 5 mg add-on to insulin in combination with metformin (-0.4% and -0.4%, respectively). The proportion of patients who discontinued for lack of glycaemic control or who were rescued was 23% in the saxagliptin 5 mg add-on to insulin group and 32% in the placebo add-on to insulin group.
In the above study, the overall incidence of reported hypoglycaemia was 18.4% and 19.9% for the saxagliptin and placebo groups, respectively. No therapeutic interaction was seen with metformin in this study.

Controlled long-term study extension.

Patients who completed all visits during the initial 24 week study period were eligible to enter a controlled long-term study extension. Patients who received saxagliptin in the initial 24 week study period maintained the same dose of saxagliptin in the long-term extension, but patients who completed the 24 week study period with a stable insulin dose were switched to a flexible insulin dose regimen for the extension period. All efficacy analyses were based on data regardless of insulin dose. Treatment with saxagliptin 5 mg add-on to insulin with or without metformin was associated with a greater reduction in HbA1c than placebo add-on to insulin with or without metformin, and the effect relative to placebo was sustained to Week 52. The HbA1c change for saxagliptin 5 mg plus insulin (N=244) compared with placebo plus insulin (N=124) was -0.4% at Week 52.
Saxagliptin in combination with metformin plus a sulfonylurea. A total of 257 patients with type 2 diabetes participated in this randomised, double blind, placebo controlled trial of 24 week duration to evaluate the efficacy and safety of saxagliptin in combination with metformin plus a sulfonylurea in patients with inadequate glycaemic control (HbA1c ≥ 7% and ≤ 10%). Patients were to be on a stable combined dose of metformin extended release or immediate release (at maximum tolerated dose with minimum dose for enrolment being 1500 mg) and a sulfonylurea (at maximum tolerated dose, with minimum dose for enrolment being ≥ 50% of the maximum recommended dose) for at least eight weeks prior to enrolment.
Patients who met eligibility criteria were enrolled in a 2 week enrolment period to allow assessment of inclusion/ exclusion criteria. Following the 2 week enrolment period, eligible patients were randomised to either double blind saxagliptin (5 mg once daily) or double blind matching placebo for 24 weeks. During the 24 week double blind treatment period, subjects were to receive metformin and a sulfonylurea at the same constant dose ascertained during enrolment. Sulfonylurea dose could be down titrated once in the case of major hypoglycaemic event or recurring minor hypoglycaemic events. In the absence of hypoglycaemia, titration (up or down) of study medication during the treatment period was prohibited. Sulfonylureas used by patients in the study were glibenclamide, gliclazide, glimepiride or glipizide.
In combination with metformin and a sulfonylurea, saxagliptin provided significant improvements in HbA1c and PPG compared with placebo plus metformin and sulfonylurea (Table 8).
Add-on combination therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

Concomitant initiation of saxagliptin and dapagliflozin in patients inadequately controlled on metformin.

A total of 534 adult patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone (HbA1c ≥ 8% and ≤ 12%) participated in this 24 week randomised, double blind, active comparator controlled superiority trial with the combination of saxagliptin and dapagliflozin added concurrently to metformin, versus saxagliptin (DPP4 inhibitor) or dapagliflozin (SGLT2 inhibitor) added to metformin. Patients were randomised to one of three double blind treatment groups to receive saxagliptin 5 mg and dapagliflozin 10 mg added to metformin XR, saxagliptin 5 mg and placebo added to metformin XR, or dapagliflozin 10 mg and placebo added to metformin XR. The saxagliptin and dapagliflozin combination group achieved significantly greater reductions in HbA1c versus either saxagliptin group or dapagliflozin group at 24 weeks (see Table 9).

Add-on therapy with saxagliptin in patients inadequately controlled on dapagliflozin plus metformin.

In a 24 week randomised, double blind, placebo controlled study comparing the sequential addition of saxagliptin 5 mg to dapagliflozin 10 mg and metformin to placebo added to dapagliflozin 10 mg (SGLT2 inhibitor) and metformin in subjects with T2DM, the group with saxagliptin sequentially added to dapagliflozin and metformin achieved statistically significant (p-value < 0.0001) greater reductions in HbA1c versus the placebo group at 24 weeks (see Table 10).
Cardiovascular safety. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR) Trial, the effect of saxagliptin on the occurrence of major cardiovascular disease (CVD) events was assessed in 16,492 adult patients with type 2 diabetes who had either established CVD or multiple risk factors for vascular disease. Patients were randomly assigned to placebo (n=8212) or saxagliptin (5 mg or 2.5 mg for patients with moderate or severe renal insufficiency) once daily (n=8280). The demographics and baseline characteristics of subjects were balanced between the saxagliptin and placebo groups (see Table 11). Subjects were followed for a mean duration of 2 (median=2.0) years.
Concomitant medication use was similar for the two treatment groups and was managed throughout the trial to local guideline targets for glycaemic control and CV risk reduction in order to minimise differences between the two treatment groups.
The primary safety and efficacy endpoint was a composite endpoint consisting of the time to first occurrence of any of the following major adverse CV events (MACE): CV death, nonfatal myocardial infarction, or nonfatal ischaemic stroke. The primary and secondary end-points are described in Table 12.
Saxagliptin did not increase the CV risk (CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke) in patients with T2DM compared to placebo when added to current background therapy (HR 1.00; 95% CI: 0.89, 1.12; P < 0.001 for non-inferiority). No increased risk for the primary endpoint was observed between saxagliptin and placebo in any of the following subgroups: CVD, multiple risk factors for CVD, mild, moderate, or severe renal impairment, age, gender, race, region, duration of type 2 diabetes, history of heart failure, baseline HbA1c, albumin/ creatinine ratio, baseline antidiabetic medication, or baseline use of statins, aspirin, ACE inhibitors, ARBs, beta-blockers, or antiplatelet medications.
The primary efficacy endpoint did not demonstrate a statistically significant difference in major adverse coronary events for saxagliptin compared to placebo when added to current background therapy in patients with T2DM. See Table 13 and Figure 2.
One component of the secondary composite endpoint, hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominal statistical significance (i.e. without adjustment for testing of multiple endpoints) favouring placebo [HR = 1.27; (95% CI: 1.07, 1.51); P = 0.007]. Clinically relevant factors predictive of increased relative risk with saxagliptin treatment could not be definitively identified. Subjects at higher risk for hospitalisation for heart failure, irrespective of treatment assignment, could be identified by known risk factors for heart failure such as baseline history of heart failure or impaired renal function. However, subjects on saxagliptin with a history of heart failure or impaired renal function at baseline were not at an increased risk relative to placebo for the primary or secondary composite endpoints or all cause mortality.
Additional endpoints in the SAVOR trial included assessment of the parameters used measure glycaemic control and whether treatment with saxagliptin compared with placebo would result in a reduction in the need for increase in dose or addition of new antidiabetic medication. Despite active management of concomitant antidiabetic therapy in both study arms, mean HbA1c levels were lower in the saxagliptin group compared to the placebo group at Year 1 (7.6% versus 7.9%, difference of -0.35% [95% CI: -0.38, -0.31]) and at Year 2 (7.6% versus 7.9%, difference of -0.30% [95% CI: -0.34, -0.26]). The proportions of subjects with HbA1c < 7% in the saxagliptin group compared to the placebo group were 38% versus 27% at Year 1 and 38% versus 29% at Year 2.
Compared to placebo, saxagliptin resulted in less need for the initiation of new or increases in current oral diabetes medications or insulin. The improvements in HbA1c and the proportion of subjects reaching HbA1c targets among saxagliptin treated subjects were observed despite lower rates of upward adjustments in diabetes medications or initiation of new diabetes medications or insulin compared with placebo.

5.2 Pharmacokinetic Properties

The results of bioequivalence studies in healthy subjects demonstrated that Kombiglyze XR combination tablets are bioequivalent to coadministration of corresponding doses of saxagliptin and metformin hydrochloride modified release as individual tablets.
The following statements reflect the pharmacokinetic properties of the individual active substances of Kombiglyze XR.

Saxagliptin.

The pharmacokinetics of saxagliptin have been extensively characterised in healthy subjects and patients with type 2 diabetes. Saxagliptin was rapidly absorbed after oral administration, with maximum saxagliptin plasma concentrations (Cmax) usually attained within two hours after administration in the fasted state. The Cmax and AUC values increased proportionally to the increment in the saxagliptin dose. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC(INF) values for saxagliptin and its major metabolite were 78 nanogram.h/mL and 214 nanogram.h/mL, respectively. The corresponding plasma Cmax values were 24 nanogram/mL and 47 nanogram/mL, respectively. The intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%.
Following a single oral dose of 5 mg saxagliptin to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin was 2.5 hours, and the mean t1/2 value for plasma DPP-4 inhibition was 26.9 hours. The inhibition of plasma DPP-4 activity by saxagliptin for at least 24 hours after oral administration is due to high potency, high affinity, and extended binding to the active site. No appreciable accumulation was observed with repeated once daily dosing at any dose level. No dose and time dependence was observed in the clearance of saxagliptin and its major metabolite over 14 days of once daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg.
Results from population based exposure modelling indicate that the pharmacokinetics of saxagliptin and its major metabolite were similar in healthy subjects and in patients with type 2 diabetes.

Metformin hydrochloride.

Metformin extended release Cmax is achieved with a median value of 7 hours. The extent of metformin absorption from the metformin extended release tablet is increased by approximately 50% when given with food. At steady state, the AUC and Cmax are less than dose proportional for metformin extended release within the range of 500 to 2000 mg. After repeated administration of metformin extended release, metformin did not accumulate in plasma. Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism.

Absorption.

Saxagliptin.

Based on food effects studies, saxagliptin may be administered with or without food. However, in pivotal efficacy and safety studies saxagliptin was generally taken prior to the morning meal. The amount of saxagliptin absorbed following an oral dose is at least 75%. The absolute oral bioavailability of saxagliptin is approximately 50% (90% CI of 48-53%). Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects. Administration with a high fat meal resulted in no change in saxagliptin Cmax and a 27% increase in AUC compared with the fasted state. The time for saxagliptin to reach Cmax (Tmax) was increased by approximately 0.5 hours with food compared with the fasted state. These changes were not considered to be clinically meaningful.

Metformin hydrochloride.

Following a single oral dose of metformin extended release, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and Cmax are less than dose proportional for metformin extended release within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 microgram/mL for 500, 1000, 1500, and 2000 mg once daily doses, respectively. Although the extent of metformin absorption (as measured by AUC) from the metformin extended release tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin extended release.

Distribution.

Saxagliptin.

The in vitro protein binding of saxagliptin and its major metabolite in human serum is below measurable levels. Thus, changes in blood protein levels in various disease states (e.g. renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.

Metformin hydrochloride.

Distribution studies with extended release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism.

Saxagliptin.

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a reversible, competitive DPP-4 inhibitor, half as potent as saxagliptin. It also demonstrates selectivity for DPP-4 versus other DPP enzymes, with greater than 163 fold selectivity over DPP-8 and DPP-9.

Metformin hydrochloride.

Intravenous single dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.

Excretion.

Saxagliptin.

Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. For the major metabolite, renal clearance values were comparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivity was recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract.

Metformin hydrochloride.

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

Pharmacokinetics of the major metabolite.

Saxagliptin.

The Cmax and AUC values for the major metabolite of saxagliptin increased proportionally to the increment in the saxagliptin dose. Following single oral doses of 2.5 mg to 400 mg saxagliptin in the fed or fasted states, the mean AUC values for the major metabolite ranged from 2-7 times higher than the parent saxagliptin exposures on a molar basis. Following a single oral dose of 5 mg saxagliptin in the fasted state, the mean terminal half-life (t1/2) value for the major metabolite was 3.1 hours and no appreciable accumulation was observed upon repeated once daily dosing at any dose.

Special populations.

Renal impairment.

Saxagliptin.

A single dose, open label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function.
The degree of renal impairment did not affect the Cmax of saxagliptin or its major metabolite. In subjects with renal impairment with > CrCL 50 mL/min (approximately corresponding to eGFR ≥ 45 mL/min/1.73 m2), the AUC values of saxagliptin and its major metabolite were 1.2- and 1.7-fold higher, respectively, than AUC values in subjects with normal renal function. Increases of this magnitude are not clinically relevant, therefore dosage adjustment in these patients is not recommended.
In subjects with renal impairment with CrCL ≤ 50 mL/min (approximately corresponding to eGFR < 45 mL/min/1.73 m2), the AUC values of saxagliptin and its major metabolite were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal function. In these patients, the dose is 2.5 mg once daily (see Section 4.2 Dose and Method of Administration, Special patient populations, Renal impairment; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
Saxagliptin is removed by hemodialysis.

Metformin hydrochloride.

In patients with renal impairment, the plasma and blood half-life of metformin is prolonged in proportion to the decrease in renal function.
Hepatic impairment.

Saxagliptin.

There were no clinically meaningful differences in pharmacokinetics for subjects with mild, moderate, or severe hepatic impairment; therefore, no dosage adjustment for saxagliptin is recommended for patients with hepatic impairment. In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin. The corresponding Cmax and AUC of the major metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful.

Metformin hydrochloride.

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Elderly patients.

Saxagliptin.

No dosage adjustment of saxagliptin is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for parent saxagliptin than young subjects (18-40 years). Differences in major metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in parent saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the major metabolite in young and elderly subjects is likely to be due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as a significant covariate on the apparent clearance of saxagliptin and its major metabolite in an exposure modelling analysis.

Metformin hydrochloride.

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Paediatric and adolescent.

Saxagliptin.

Pharmacokinetics in the paediatric population have not been studied.
Gender.

Saxagliptin.

No dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the major metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as a significant covariate on the apparent clearance of saxagliptin and its major metabolite in an exposure modelling analysis.

Metformin hydrochloride.

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

Saxagliptin.

No dosage adjustment is recommended based on race. An exposure modelling analysis compared the pharmacokinetics of saxagliptin and its major metabolite in 309 white subjects with 105 non-white subjects (consisting of 6 racial groups). No significant difference in the pharmacokinetics of saxagliptin and its major metabolite were detected between these two populations.

Metformin hydrochloride.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycaemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
Body mass index.

Saxagliptin.

No dosage adjustment is recommended based on body mass index (BMI). BMI was not identified as a significant covariate on the apparent clearance of saxagliptin or its major metabolite in an exposure modelling analysis.

5.3 Preclinical Safety Data

Genotoxicity.

Saxagliptin.

The mutagenic and clastogenic potential of saxagliptin was tested at high concentrations and exposures in a battery of genetic toxicity studies including an in vitro Ames bacterial assay, an in vitro cytogenetics assay in primary human lymphocytes, an in vivo oral micronucleus assay in rats, an in vivo oral DNA repair study in rats, and an oral in vivo/ in vitro cytogenetics study in rat peripheral blood lymphocytes. Saxagliptin was not mutagenic or clastogenic based on the combined outcomes of these studies. The major metabolite was not mutagenic in an in vitro Ames bacterial assay.

Metformin hydrochloride.

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

Carcinogenicity.

No carcinogenicity studies have been conducted with the combined components of Kombiglyze XR.

Saxagliptin.

Two year carcinogenicity studies were conducted in mice and rats. Saxagliptin did not induce tumours in mice treated at up to 600 mg/kg/day, producing exposure 1123 times that of humans at the recommended clinical dose. In rats, no increase in tumours was observed in males treated with saxagliptin at up to 150 mg/kg/day and females at up to 300 mg/kg/day (relative exposure at the highest doses, approximately 400 and 2465, respectively).

Metformin hydrochloride.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Each film-coated tablet of Kombiglyze XR contains the following inactive ingredients: carmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, macrogol 3350, titanium dioxide, purified talc, iron oxide red CI77491 (5 mg/500 mg and 5 mg/1000 mg tablets), iron oxide yellow CI77492 (5 mg/500 mg and 2.5 mg/1000 mg tablets) and Opacode monogramming ink S-1-10619 Blue.

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

The tablets should be stored below 30°C.

6.5 Nature and Contents of Container

Kombiglyze XR 5/500 are available in aluminium/ aluminium blister packs of 7 and 28 tablets.
Kombiglyze XR 5/1000 are available in aluminium/ aluminium blister packs of 7 and 28 tablets.
Kombiglyze XR 2.5/1000 are available in aluminium/ aluminium blister packs of 14 and 56 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.

Saxagliptin.


Chemical name: (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo [3.3.1.13,7] dec-1-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3- carbonitrile, monohydrate.
Molecular formula: C18H25N3O2.H2O.
Molecular weight: 333.43 (monohydrate).
Physicochemical characteristics: Saxagliptin is a white to light yellow or light brown powder, non hygroscopic, crystalline. It is soluble in polyethylene glycol 400, acetone, acetonitrile, ethanol, isopropyl alcohol, methanol; sparingly soluble in water and slightly soluble in ethyl acetate.

Metformin hydrochloride.


Chemical name: N,N-dimethylimidodicarbonimidic diamide hydrochloride.
Molecular formula: C4H11N5.HCl.
Molecular weight: 165.63.
Physicochemical characteristics: Metformin hydrochloride is a white to off-white crystalline compound.
Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

CAS number.

Saxagliptin.

945667-22-1.

Metformin hydrochloride.

1115-70-4.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes