Consumer medicine information

Segluromet

Ertugliflozin; Metformin hydrochloride

BRAND INFORMATION

Brand name

Segluromet

Active ingredient

Ertugliflozin; Metformin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Segluromet.

SUMMARY CMI

SEGLUROMET®

Consumer Medicine Information (CMI) summary

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

▼ This medicine is new or being taken differently. Please report side effects. See the full CMI for further details.

1. Why am I taking SEGLUROMET?

SEGLUROMET contains the active ingredients ertugliflozin and metformin. SEGLUROMET can be used to lower your blood sugar alone or in combination with certain other medicines that lower blood sugar, along with a recommended diet and exercise program.

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

2. What should I know before I take SEGLUROMET?

Do not use if you have ever had an allergic reaction to ertugliflozin or metformin 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 are pregnant or plan to become pregnant or are breastfeeding.

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

3. What if I am taking other medicines?

Some medicines may interfere with SEGLUROMET 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 SEGLUROMET?

  • Take one tablet two times a day.

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

5. What should I know while taking SEGLUROMET?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking SEGLUROMET.
Things you should not do
  • Do not stop taking this medicine suddenly unless your doctor tells you.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how SEGLUROMET affects you.
Looking after your medicine
  • Keep SEGLUROMET in its original packaging in a cool dry place where the temperature stays below 30°C.

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

6. Are there any side effects?

Less serious side effects include yeast infections of the vagina or penis, changes in urination, low blood sugar if you take SEGLUROMET with insulin or certain other diabetes medicines

Serious side effects include dehydration (losing too much water from your body), ketoacidosis (increased ketones in your blood or urine), genital infection or urinary tract infection. In rare cases, metformin, one of the medicines in SEGLUROMET, can cause lactic acidosis. Stop taking SEGLUROMET and call your doctor right away if you get the following symptoms: feeling very weak and tired, dizzy or lightheaded, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, or diarrhoea, cold in your hands or feet, a slow or irregular heartbeat.

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.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

SEGLUROMET®

Active ingredients: Ertugliflozin pyroglutamic acid/Metformin hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about taking SEGLUROMET. 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 SEGLUROMET.

Where to find information in this leaflet:

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

1. Why am I taking SEGLUROMET?

SEGLUROMET contains the active ingredients ertugliflozin and metformin. Ertugliflozin is a medicine called a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin is called a biguanide. Both medicines work together to lower blood sugar levels in patients with type 2 diabetes mellitus. SEGLUROMET helps remove sugar from the body through urination and by blocking sugar (glucose) production by the liver. SEGLUROMET by itself is unlikely to cause low blood sugar because it does not work when your blood sugar is low.

SEGLUROMET can be used to lower your blood sugar (glucose) alone or in combination with certain other medicines, along with a recommended diet and exercise program.

2. What should I know before I take SEGLUROMET?

Warnings

Do not take SEGLUROMET if:

  • you are allergic to ertugliflozin or metformin, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can take this medicine.
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.
  • you have poorly functioning kidneys since ertugliflozin requires good functioning kidneys to work well
  • have or have had increased ketones in the blood and urine (a condition called metabolic acidosis or diabetic ketoacidosis).
  • have liver problems
  • drink alcohol to excess, either every day or only from time to time or in the short term (" binge" drinking).
  • have dehydration, severe blood loss, shock
  • have a severe infection
  • have gangrene
  • have heart or blood vessel problems, including a recent heart attack or congestive heart failure
  • have severe breathing difficulties
  • have blood clots in the lungs (symptoms include coughing, shortness of breath, chest pain and a fast heart rate)
  • have pancreatitis (symptoms include severe and persistent stomach pain, with or without vomiting)

Tell your doctor if you:

  • have type 1 diabetes
  • are going to have surgery
  • are eating less due to illness, surgery, or a change in your diet
  • have a condition that may cause dehydration (losing too much water from your body)
  • have other kidney problems
  • have or have had yeast infections of the vagina or penis
  • take other diabetes medicines; you are more likely to get low blood sugar with certain medicines
  • have allergies to any other medicines or other substances such as foods, preservatives or dyes.
  • are going to get an injection of dye or contrast agents for an x-ray procedure. SEGLUROMET may need to be stopped for a short time. Talk to your doctor about when you should stop SEGLUROMET and when you should start SEGLUROMET again.

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?

SEGLUROMET contains ertugliflozin and metformin. If you have more than one metformin-containing medicine in your possession, you may accidentally take too much (overdose). Accidentally taking too much metformin can cause a very serious side effect called lactic acidosis. ACCIDENTAL METFORMIN OVERDOSING IS A SIGNIFICANT SAFETY RISK.

  • Discard any other medicines containing ertugliflozin or metformin that your doctor might have prescribed to you in the past and that you may still have in your possession by taking it to any pharmacy for safe disposal.
  • Ask your doctor or pharmacist if you are unsure if you have any other medicines containing metformin. Metformin is sold under many different brand names in Australia. He or she will know which other medicines also contain metformin.

Pregnancy and breastfeeding

Talk to your doctor if you are pregnant or intend to become pregnant. It is not known if SEGLUROMET may harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant. Do not use SEGLUROMET if you are pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known if SEGLUROMET passes into breast milk. Talk with your doctor about the best way to feed your baby if you take SEGLUROMET. Do not use SEGLUROMET if you are breast-feeding or plan to breast-feed.

Children

It is not known if SEGLUROMET is safe and effective in children under 18 years of age.

Elderly

In studies, ertugliflozin worked well in and was generally well-tolerated by older patients. People 65 years or older were more likely to get dehydrated while taking SEGLUROMET compared to younger patients. Elderly people are more likely to have kidney problems. No dose adjustment is necessary based on age.

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 herbal supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

SEGLUROMET may be taken with most medicines.

Some medicines may interfere with SEGLUROMET and affect how it works.

Be sure to tell your doctor if you are taking water pills (diuretics), as you may be more likely to get dehydrated. See Section 6. Are there any side effects?

When you take SEGLUROMET with certain other diabetes medicines, you are more likely to get low blood sugar. See Section 6. Are there any side effects?

Tell your doctor or pharmacist if you are taking lithium because SEGLUROMET can lower the amount of lithium in your blood.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SEGLUROMET.

4. How do I take SEGLUROMET?

How much to take

  • Take one tablet two times a day. Your doctor will decide the dose of SEGLUROMET suitable for you.
  • Take SEGLUROMET until your doctor tells you to stop.

When to take SEGLUROMET

  • Take SEGLUROMET at about the same time each day.
  • Take SEGLUROMET with food to lower your chance of an upset stomach.

If you forget to take SEGLUROMET

SEGLUROMET should be taken regularly at the same times each day. If you miss your dose at the usual time, take it as soon as you remember.

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

Do not take 2 doses at the same time to make up for the dose you missed.

If you take too much SEGLUROMET

If you think that you have taken too much SEGLUROMET, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking SEGLUROMET?

Things you should do

  • If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking SEGLUROMET.
  • If you become pregnant while taking SEGLUROMET, tell your doctor immediately.
  • Continue to take SEGLUROMET for as long as your doctor prescribes it so that you can continue to help control your blood sugar. This medicine helps to control your condition but will not cure it. It is important to keep taking your medicine even if you feel well.

Call your doctor straight away if:

  • your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery. The amount of diabetes medicine you need may change.

Remind any doctor, dentist or pharmacist you visit that you are taking SEGLUROMET.

Things you should not do

  • Do not stop taking this medicine suddenly or lower your dosage without checking with your doctor.
  • Do not take SEGLUROMET to treat any other complaints unless your doctor tells you to.
  • Do not give SEGLUROMET to anyone else, even if they have the same condition as you. Remember that your doctor has prescribed this medicine only for you.

Foot care

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

Blood tests

Your doctor may do blood tests before you start SEGLUROMET and while you take it. These tests look to see if your blood sugar level is normal at that moment and how well you have managed your blood sugar over time (called haemoglobin A1c). Blood tests may show changes related to kidney function or reduced vitamin B12 level or high levels of bad cholesterol. Your doctor may change your dose of SEGLUROMET based on the results.

Driving or using machines

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

SEGLUROMET has no or negligible influence on the ability to drive and use machines.

  • Do not drive or use any tools or machines if you feel dizzy while taking SEGLUROMET.

Taking this medicine in combination with insulin or medicines called insulin secretagogues can cause blood sugar levels to drop too low, which may cause symptoms such as shaking, sweating and change in vision, and may affect your ability to drive and use machines.

Drinking alcohol

Tell your doctor if you drink alcohol very often or drink a lot of alcohol in the short term ("binge" drinking).

Looking after your medicine

  • Keep SEGLUROMET in its original packaging in a cool dry place where the temperature stays below 30°C.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Do not take SEGLUROMET if the packaging is torn or shows signs of tampering.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to take this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not take this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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
Yeast infections of the vagina or penis
  • in women, symptoms include bad smell from your vagina, white or yellow discharge coming out of your vagina that may be lumpy or look like cottage cheese and itchiness.
  • in men, symptoms include swelling of the penis, red skin, itchiness or rash, bad smell and discharge coming out of your penis, pain in the skin around your penis. If you haven't been circumcised, it may be hard to pull back the skin around the tip of your penis.
Changes in urination
  • urgent need to urinate more often, in larger amounts, or at night, or thirst
Low blood sugar (hypoglycaemia)

If you take SEGLUROMET with insulin or certain other diabetes medicines, your blood sugar might get too low. Your doctor might need to lower the dose of your insulin or other diabetes medicine.

  • headache
  • drowsiness, dizziness or confusion, irritability or feeling jittery, sweating, weakness, fast heartbeat
  • hunger
Other side effects
  • Stomach discomfort, diarrhoea, nausea, vomiting
  • Itching or blisters of the skin or redness or an itchy rash (urticaria)
  • loss of appetite or changes in taste
Speak to your doctor if you have any of these side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Risk of Lactic acidosis
SEGLUROMET may cause a very rare, but very serious side effect called lactic acidosis, particularly if your kidneys are not working properly. Lactic acidosis is a medical emergency that can cause death and must be treated in hospital.
The risk of developing lactic acidosis is also increased with uncontrolled diabetes, serious infections, prolonged fasting or alcohol intake, dehydration, liver problems and any medical conditions in which a part of the body has a reduced supply of oxygen (such as acute severe heart disease).
If any of the above apply to you, talk to your doctor for further instructions.
Stop taking SEGLUROMET for a short time if you have a condition that may be associated with dehydration (significant loss of body fluids) such as severe vomiting, diarrhoea, fever, exposure to heat or if you drink less fluid than normal. Talk to your doctor for further instructions.
Stop taking SEGLUROMET and call your doctor right away if you get the following symptoms of lactic acidosis:
  • feeling very weak and tired, dizzy or lightheaded
  • unusual (not normal) muscle pain
  • trouble breathing
  • stomach pain with nausea and vomiting, or diarrhoea
  • feeling cold in your hands or feet
  • a slow or irregular heartbeat

You have a higher chance of getting lactic acidosis if you:

  • have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye
  • drink a lot of alcohol (very often or short-term 'binge' drinking)
  • have surgery
  • have a heart attack, severe infection, or stroke
  • get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting or diarrhoea, exposure to heat, when you sweat a lot with activity or exercise, or if you drink less fluid than normal.

Stop taking SEGLUROMET for a short time if you have a condition that may be associated with dehydration and talk to your doctor for further instructions.
Dehydration (losing too much water from your body):

  • dry mouth, feeling dizzy, light-headed, or weak, especially when you stand up, fainting

You may be more likely to get dehydrated if you:

  • have kidney problems or take water tablets (diuretics) or
  • are 65 years or older
Ketoacidosis (increased ketones in your blood or urine)
  • nausea or vomiting
  • tiredness or trouble breathing
  • stomach-area (abdominal) pain
  • excessive thirst
If possible, check for ketones in your urine, even if your blood sugar is less than 14.0 mmol/L. You may need to be treated in a hospital.
Genital infection

These symptoms could be a sign of a rare but serious life-threatening infection called necrotising fasciitis of the perineum or Fournier's gangrene. This must be treated immediately.

  • pain or tenderness, redness, swelling of the genitals or the area between the genitals and the anus
  • fever and feeling generally unwell.
Urinary tract infection
  • burning or pain when you pass urine, more frequent or urgent need to urinate, fever, chills, or blood in the urine
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.

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

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 SEGLUROMET contains

Active ingredient
(main ingredient)		ertugliflozin pyroglutamic acid, and metformin hydrochloride
Other ingredients
(inactive ingredients)		Povidone
Microcrystalline cellulose
Crospovidone
Sodium lauryl sulfate
Magnesium stearate
Hypromellose
Hyprolose
Titanium dioxide
Iron oxide red
Carnauba wax

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

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

What SEGLUROMET looks like

SEGLUROMET 2.5 /500 is a pink, oval, film-coated tablet debossed with '2.5/500' on one side and plain on the other side (AUST R 287636).

SEGLUROMET 2.5/1000 is a pink, oval, film-coated tablet debossed with '2.5/1000' on one side and plain on the other side (AUST R 287635).

SEGLUROMET 7.5 /500 is a red, oval, film-coated tablet debossed with '7.5/500' on one side and plain on the other side (AUST R 287633).

SEGLUROMET 7.5 /1000 is a red, oval, film-coated tablet debossed with '7.5/1000' on one side and plain on the other side (AUST R 287627).

Who distributes SEGLUROMET

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road, Macquarie Park NSW 2113

This leaflet was prepared in April 2023.

RCN000025646-AU, RCN000024834-AU

Copyright © 2023 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved.

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Segluromet

Active ingredient

Ertugliflozin; Metformin hydrochloride

Schedule

S4

 

1 Name of Medicine

Ertugliflozin/metformin hydrochloride.

2 Qualitative and Quantitative Composition

Segluromet contains ertugliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Segluromet is available for oral use as film-coated tablets containing:
3.24 mg ertugliflozin pyroglutamic acid equivalent to 2.5 mg of ertugliflozin and 500 mg metformin hydrochloride (Segluromet 2.5/500);
3.24 mg ertugliflozin pyroglutamic acid equivalent to 2.5 mg of ertugliflozin and 1000 mg metformin hydrochloride (Segluromet 2.5/1000);
9.71 mg ertugliflozin pyroglutamic acid equivalent to 7.5 mg of ertugliflozin and 500 mg metformin hydrochloride (Segluromet 7.5/500);
9.71 mg ertugliflozin pyroglutamic acid equivalent to 7.5 mg of ertugliflozin and 1000 mg metformin hydrochloride (Segluromet 7.5/1000).
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Segluromet 2.5/500 pink, oval, film-coated tablets debossed with "2.5/500" on one side and plain on the other side.
Segluromet 2.5/1000 pink, oval, film-coated tablets debossed with "2.5/1000" on one side and plain on the other side.
Segluromet 7.5/500 red, oval, film-coated tablets debossed with "7.5/500" on one side and plain on the other side.
Segluromet 7.5/1000 red, oval, film-coated tablets debossed with "7.5/1000" on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

General.

Take Segluromet twice daily with meals, with gradual dose escalation for those initiating metformin to reduce the gastrointestinal side effects due to metformin.
Individualise the starting dose of Segluromet (ertugliflozin and metformin hydrochloride) based on the patient's current regimen:
in patients on metformin, switch to Segluromet tablets containing 2.5 mg ertugliflozin, with a similar total daily dose of metformin;
in patients already treated with ertugliflozin and metformin, switch to Segluromet tablets containing the same total daily dose of ertugliflozin and a similar daily dose of metformin.
Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 15 mg ertugliflozin and 2,000 mg metformin HCl.

Renal impairment.

An eGFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.
Initiation of Segluromet is not recommended in patients with an eGFR less than 45 mL/min/1.73 m2 (see Section 4.4 Special Warnings and Precautions for Use).
In patients with an eGFR of 45 to less than 60 mL/min/1.73 m2, tolerating Segluromet containing 2.5 mg ertugliflozin titrate to Segluromet containing 7.5 mg ertugliflozin as needed for glycaemic control.
Discontinue Segluromet if the patient's eGFR falls below 30 mL/min/1.73 m2.
The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. 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 metformin in patients with eGFR < 60 mL/min/1.73 m2.
If no adequate strength of Segluromet is available, individual mono-components should be used instead of the fixed-dose combination. See Table 1.

Discontinuation for iodinated contrast imaging procedures.

Discontinue Segluromet at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Segluromet if renal function is acceptable (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Segluromet is not recommended in patients with hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric population.

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

Elderly.

No dosage adjustment of Segluromet is recommended based on age. Elderly patients are more likely to have decreased renal function. Because renal function abnormalities can occur after initiating ertugliflozin, and metformin is known to be substantially excreted by the kidneys, care should be taken in dose selection in the elderly. It may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

History of a serious hypersensitivity reaction to Segluromet, ertugliflozin, metformin hydrochloride, or to any of the excipients.
Patients with chronic kidney disease (CKD) receiving dialysis; eGFR < 30 mL/min/1.73 m2 (CKD stage 4 and 5). The efficacy of Segluromet is dependent on renal function (see Section 4.4 Special Warnings and Precautions for Use).
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
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.
Due to its metformin component, Segluromet is contraindicated in patients with conditions that can lead to severe hepatic insufficiency such as: acute alcohol intoxication, alcoholism.

4.4 Special Warnings and Precautions for Use

General.

Segluromet should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Lactic acidosis.

Life-threatening lactic acidosis can occur due to accumulation of metformin.
Risk factors include renal impairment, old age and the use of high doses of metformin above 2000 mg per day.
There have been post-marketing cases of lactic acidosis in patients receiving metformin, a component of Segluromet, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonaemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally > 5 microgram/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Segluromet. In Segluromet-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt haemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good haemodynamic conditions). Haemodialysis has often resulted in reversal of symptoms and recovery.
Information on the known and possible risk factors for metformin-associated lactic acidosis is provided below.

Renal impairment.

The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney (see Section 4.4 Special Warnings and Precautions for Use, Use in patients with renal impairment).

Drug interactions.

The concomitant use of Segluromet with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant haemodynamic change, interfere with acid base balance, or increase metformin accumulation (e.g. cationic drugs) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Therefore, consider more frequent monitoring of patients.

Age 65 or greater.

The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients (see Section 4.4 Special Warnings and Precautions for Use).

Radiological studies with contrast.

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop Segluromet at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart Segluromet if renal function is stable.

Surgery.

See Section 4.4 Special Warnings and Precautions for Use, Surgery.

Hypoxic states.

Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotaemia. When such events occur, discontinue Segluromet.

Excessive alcohol intake.

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving Segluromet (see Section 4.3 Contraindications).

Hepatic impairment.

Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Segluromet is not recommended in patients with hepatic impairment.

Hypotension/volume depletion.

Ertugliflozin, a component of Segluromet, can cause intravascular volume contraction that may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients (≥ 65 years), or patients on diuretics may be at increased risk for volume depletion or hypotension. Before initiating Segluromet in patients with one or more of these characteristics, intravascular volume status should be assessed and patients advised on the importance of adequate hydration. Monitor intravascular volume status in addition to blood pressure and renal function after initiating therapy.
In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness, heat stress or severe infections), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving Segluromet. Temporary interruption of Segluromet should be considered until the fluid loss is corrected.

Ketoacidosis.

Segluromet should not be used for the treatment of diabetic ketoacidosis.
Reports of ketoacidosis, including diabetic ketoacidosis, a serious life-threatening condition requiring urgent hospitalisation, have been identified in clinical trials and postmarketing surveillance in patients receiving sodium glucose co-transporter-2 (SGLT2) inhibitors. Fatal cases of ketoacidosis have been reported in patients taking SGLT2 inhibitors. Segluromet is not indicated for the treatment of patients with type 1 diabetes mellitus.
Patients treated with Segluromet who present with signs and symptoms consistent with severe metabolic acidosis should be promptly assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with SGLT2 inhibitors may be present even if blood glucose levels are less than 14 mmol/L. If ketoacidosis is suspected, Segluromet should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis generally requires insulin, fluid, potassium and carbohydrate replacement. Signs and symptoms of ketoacidosis may include excessive thirst, nausea, vomiting, abdominal pain, generalised malaise, and shortness of breath.
Restarting SGLT2 inhibitor treatment in patients with previous diabetic ketoacidosis while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
Before initiating Segluromet, consider factors in the patient history that may predispose to ketoacidosis.
Factors that predispose patients to ketoacidosis include a low carbohydrate diet, dehydration, acute illness, surgery [see Surgery below], a previous ketoacidosis, insulin dose reduction, malnourishment/ reduced caloric intake or increased insulin requirements due to infections, insulin deficiency from any cause (including insulin pump failure, or history of pancreatitis or pancreatic surgery), and alcohol abuse. Segluromet should be used with caution in these patients. Consider monitoring for ketoacidosis and temporarily discontinuing Segluromet in clinical situations known to predispose to ketoacidosis.

Surgery.

Treatment with Segluromet must be discontinued at least 48 hours prior to major surgery (see Section 4.4 Special Warnings and Precautions for Use, Ketoacidosis, Lactic acidosis). An increase in other glucose lowering agents may be required during this time.
Patients scheduled for non-urgent surgery who have not ceased Segluromet should be assessed and consideration should be given to postponing the procedure.
Therapy may be restarted not earlier than 48 hours following surgery, once the patient's condition has stabilised, oral intake is normal, and only if normal renal function has been established, as withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment.

Hypoglycaemia with concomitant use with insulin and insulin secretagogues.

Ertugliflozin.

Insulin and insulin secretagogues are known to cause hypoglycaemia. Ertugliflozin, a component of Segluromet, may increase the risk of hypoglycaemia when used in combination with insulin and/or an insulin secretagogue (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycaemia when used in combination with Segluromet.

Metformin.

Hypoglycaemia does not occur in patients receiving metformin, a component of Segluromet, alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycaemic effects. Hypoglycaemia may be difficult to recognize in the elderly and in people who are taking β-adrenergic blocking drugs.

Genital mycotic infections.

Ertugliflozin, a component of Segluromet, increases the risk of genital mycotic infections. In trials with SGLT2 inhibitors, patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitor and treat appropriately.

Necrotising fasciitis of the perineum.

Postmarketing cases of necrotising fasciitis of the perineum (also known as Fournier's gangrene), a rare, but serious and life-threatening necrotising infection, have been reported in female and male patients with diabetes mellitus treated with SGLT2 inhibitors. Serious outcomes have included hospitalisation, multiple surgeries, and death.
Patients treated with Segluromet who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, and malaise should be evaluated for necrotising fasciitis. If suspected, Segluromet should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).
Caution is advised in patients at increased risk of genital infections including patients with recurrent or pre-existing urogenital infections, obesity, immunosuppressed states, smoking, alcohol abuse, end-stage renal or liver failure, and HbA1c > 10%.

Vitamin B12 levels.

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

Use in patients with renal impairment.

Segluromet.

Segluromet should not be used in patients with CKD stage 4 or 5 (severely impaired renal function including patients receiving dialysis; eGFR < 30 mL/min/1.73 m2) (see Section 4.3 Contraindications).
Monitoring of renal function is recommended:
prior to initiating Segluromet and periodically thereafter, i.e. at least yearly;
prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter;
more frequently (2 to 4 times per year) in patients approaching moderate renal impairment (eGFR of 60 mL/min/1.73 m2) or those at increased risk for the development of renal impairment (e.g. the elderly).
Segluromet should be discontinued when eGFR falls below 30 mL/min/1.73 m2 (see Section 4.3 Contraindications).

Ertugliflozin.

The efficacy of ertugliflozin is dependent on renal function.
Ertugliflozin, a component of Segluromet, increases serum creatinine and decreases eGFR; patients with moderate renal impairment at baseline have larger mean changes (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.4 Special Warnings and Precautions for Use). In VERTIS CV, initiation of treatment with ertugliflozin was associated with decreases in eGFR followed by a return toward baseline. Continued treatment with ertugliflozin was associated with a slower decline in eGFR compared to placebo over time (see Section 4.8 Adverse Effects (Undesirable Effects)).
The efficacy and safety of ertugliflozin have not been established in patients with severe renal impairment, with ESRD, or receiving dialysis. Ertugliflozin is not expected to be effective in these patient populations.

Metformin hydrochloride.

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example in case of dehydration, or when initiating antihypertensive therapy or diuretic therapy and when starting therapy with an NSAID.
Segluromet is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2.

Urosepsis and pyelonephritis.

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

Use with other antidiabetic agents.

The use of ertugliflozin in combination with GLP-1 analogues, alpha-glucosidase inhibitors and thiazolidinediones has not been evaluated.

Use in the elderly.

Segluromet.

Elderly patients are more likely to have decreased renal function. Because renal function abnormalities can occur after initiating ertugliflozin, and metformin is known to be substantially excreted by the kidneys, care should be taken in dose selection in the elderly. Assess renal function in these patients prior to initiating dosing and periodically thereafter (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Ertugliflozin.

No dose adjustment of ertugliflozin is recommended based on age. Across seven Phase 3 clinical trials in the ertugliflozin development program, a total of 876 (25.7%) patients treated with ertugliflozin were 65 years and older, and 152 (4.5%) patients treated with ertugliflozin were 75 years and older. Patients 65 years and older treated with ertugliflozin had a higher incidence of adverse reactions related to volume depletion compared to younger patients events were reported in 2.2%, 2.6%, and 1.1% of patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and comparator, respectively (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). Ertugliflozin is expected to have diminished efficacy in elderly patients with renal impairment.

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. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis.
The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Segluromet is expected to have diminished efficacy in elderly patients with renal impairment (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)). Assess renal function more frequently in elderly patients.

Paediatric use.

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

Lower limb amputations.

In a long-term cardiovascular outcomes study VERTIS CV, a study in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease, non-traumatic lower limb amputations (primarily of the toe) were reported with an incidence of 2.0% (0.57 subjects with event per 100 patient years), 2.1% (0.60 subjects with event per 100 patient years) and 1.6% (0.47 subjects with event per 100 patient years) for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo groups respectively.
A numerical imbalance in non-traumatic lower limb amputations (primarily of the toe) was observed in patients treated with ertugliflozin across 7 Phase 3 clinical trials in the ertugliflozin development program. In these trials, 11 patients in the ertugliflozin group (0.3%) and 1 patient in the comparator group (0.1%) reported lower limb amputations. A causal association between ertugliflozin and lower limb amputation has not been definitively established.
An increase in cases of lower limb amputation (primarily of the toe) has also been observed in clinical trials with another SGLT2 inhibitor. It is important to counsel patients on routine preventative foot-care.

Effects on laboratory tests.

Ertugliflozin.

Positive urine glucose test.

Monitoring glycaemic control with urine glucose tests is not recommended in patients taking medicines containing an SGLT2 inhibitor as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycaemic control.

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

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

Segluromet.

No clinically significant pharmacokinetic interaction was seen when ertugliflozin was coadministered with metformin.
Pharmacokinetic drug interaction studies with Segluromet have not been performed; however, such studies have been conducted with ertugliflozin and metformin, the individual components of Segluromet.

Drug interactions with ertugliflozin.

Pharmacokinetic interactions.

Lithium.

SGLT2 inhibitors, including ertugliflozin, may increase renal lithium excretion and the blood lithium levels may be decreased. Serum concentration of lithium should be monitored more frequently after ertugliflozin initiation and dose changes. Please refer the patient to the lithium prescribing doctor in order to monitor serum concentration of lithium.
In vitro assessment of drug interactions with ertugliflozin. In in vitro studies, ertugliflozin and its two major glucuronide metabolites did not inhibit CYP450 isoenzymes (CYPs) 1A2, 2C9, 2C19, 2C8, 2B6, 2D6, or 3A4 at clinically relevant concentrations, and did not induce CYPs 1A2, 2B6, or 3A4. Ertugliflozin was not a time-dependent inhibitor of CYP3A in vitro. As well ertugliflozin and its two major glucuronide metabolites did not inhibit UGT1A1, 1A4, 1A6, 1A9, or 2B7 in vitro at clinically relevant concentrations. Only weak inhibitory activity was observed, with the IC50 at the most sensitive target (39 microM for ertugliflozin against UGT1A4) almost 1000 times higher than the peak plasma concentration of unbound drug in patients at the MRHD of 15 mg/day. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of drugs eliminated by these enzymes. Ertugliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters and is not a substrate of organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1, OCT2), or organic anion transporting polypeptides (OATP1B1, OATP1B3, OATP2B1). Ertugliflozin or its two major glucuronide metabolites do not meaningfully inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3 transporters, or transporting polypeptides OATP1B1 or OATP1B3 in vitro at clinically relevant concentrations. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are substrates of these transporters.
In vivo assessment of drug interactions with ertugliflozin. No dose adjustment of Segluromet is recommended when coadministered with commonly prescribed medicinal products. Ertugliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, sitagliptin, and simvastatin in healthy subjects (see Figure 1). Coadministration of ertugliflozin with multiple doses of 600 mg once daily rifampicin (an inducer of UGT and CYP enzymes) resulted in approximately 39% and 15% mean reductions in ertugliflozin AUC and Cmax, respectively, relative to ertugliflozin administered alone. These changes in exposure are not considered clinically relevant. Ertugliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, sitagliptin, and simvastatin when coadministered in healthy subjects (see Figure 2). Physiologically-based PK (PBPK) modelling suggests that coadministration of mefenamic acid (UGT inhibitor) may increase the AUC and Cmax of ertugliflozin by 1.51- and 1.19-fold, respectively. These predicted changes in exposure are not considered clinically relevant.

Clinical studies of the effects of other drugs on the pharmacokinetics of ertugliflozin (see Figure 1).

The effects of coadministered drugs on the pharmacokinetics of ertugliflozin have been assessed in drug-drug interaction studies. There were no clinically significant drug interactions identified.

Sitagliptin.

Single-dose administration of sitagliptin 100 mg had no clinically meaningful effect on the exposure of ertugliflozin 15 mg. The geometric mean ratios (GMR) and 90% CI (expressed as percentages) for ertugliflozin AUCinf and Cmax for coadministration with sitagliptin vs. ertugliflozin alone were 102.27% (99.72%, 104.89%) and 98.18% (91.20%, 105.70%), respectively.

Metformin.

Single-dose administration of metformin 1,000 mg had no clinically meaningful effect on the exposure of ertugliflozin 15 mg. The GMR and 90% CI (expressed as percentages) for ertugliflozin AUCinf and Cmax for coadministration with metformin vs. ertugliflozin alone were 100.34% (97.43%, 103.34%) and 97.14% (88.77%, 106.30%), respectively.

Glimepiride.

Single-dose administration of glimepiride 1 mg had no clinically meaningful effect on the exposure of ertugliflozin 15 mg. The GMR and 90% CI (expressed as percentages) for ertugliflozin AUCinf and Cmax for coadministration with glimepiride vs. ertugliflozin alone were 102.11% (97.19%, 107.27%) and 98.20% (92.17%, 104.63%), respectively.

Simvastatin.

Single-dose administration of simvastatin 40 mg had no clinically meaningful effect on the exposure of ertugliflozin 15 mg. The GMR and 90% CI (expressed as percentages) for ertugliflozin AUCinf and Cmax for coadministration with simvastatin vs. ertugliflozin alone were 102.40% (99.57%, 105.31%) and 105.16% (98.26%, 112.54%), respectively.

Rifampicin.

Multiple-dose administration of rifampicin 600 mg q.d. x 10 days was associated with a decrease in exposure of ertugliflozin 15 mg. The GMR and 90% CI (expressed as percentages) for ertugliflozin AUCinf and Cmax for coadministration with rifampicin vs. ertugliflozin alone were 61.16% (57.22%, 65.37%) and 84.62% (74.17%, 96.53%), respectively.

Clinical studies of the effects of ertugliflozin on the pharmacokinetics of other drugs (see Figure 2).

The effects of ertugliflozin on the pharmacokinetics of coadministered drugs have been assessed in drug-drug interaction studies. There were no clinically significant drug interactions identified.

Sitagliptin.

No clinically meaningful change in sitagliptin exposure was observed following concomitant administration of a single 100 mg sitagliptin dose with 15 mg ertugliflozin compared to sitagliptin alone. The GMR and 90% CI (expressed as percentages) for sitagliptin AUCinf and Cmax for coadministration with ertugliflozin vs. sitagliptin alone were 101.67% (98.40%, 105.04%) and 101.68% (91.65%, 112.80%), respectively.

Metformin.

No clinically meaningful change in metformin exposure was observed following concomitant administration of a single 1,000 mg metformin dose with 15 mg ertugliflozin compared to metformin alone. The GMR and 90% CI (expressed as percentages) for metformin AUCinf and Cmax for coadministration with ertugliflozin vs. metformin alone were 100.94% (90.62%, 112.44%) and 94.00% (82.94%, 106.55%), respectively.

Glimepiride.

No clinically meaningful change in glimepiride exposure was observed following concomitant administration of a single 1 mg glimepiride dose with 15 mg ertugliflozin compared to glimepiride alone. The GMR and 90% CI (expressed as percentages) for glimepiride AUCinf and Cmax for coadministration with ertugliflozin vs. glimepiride alone were 109.80% (98.14%, 122.86%) and 97.39% (71.07%, 133.46%), respectively.

Simvastatin.

Coadministration of a single 40 mg simvastatin dose with a single dose of ertugliflozin 15 mg resulted in a small, non-clinically meaningful increase in AUCinf and Cmax of simvastatin and simvastatin acid. The GMR and 90% CI (expressed as percentages) for simvastatin AUCinf and Cmax for coadministration with ertugliflozin vs. simvastatin alone were 123.83% (90.92%, 168.66%) and 119.05% (97.22%, 145.77%), respectively. The GMR and 90% CI for simvastatin acid AUCinf and Cmax for coadministration with ertugliflozin vs. simvastatin alone were 130.46% (108.32%, 157.13%) and 115.66% (95.74%, 139.71%), respectively.

Drug interactions with metformin hydrochloride.

Drugs that increase the risk of lactic acidosis.

Carbonic anhydrase inhibitors.

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

Loop diuretics.

May increase the risk of lactic acidosis due to their potential to decrease renal function.
Drugs that reduce metformin clearance. Drugs that are eliminated by renal tubular secretion have the potential for interaction with metformin by competing for common renal tubular transport systems, and may increase the accumulation of metformin and the risk for lactic acidosis. Consider more frequent monitoring of these patients.
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 Segluromet, and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Alcohol. The risk of lactic acidosis increases with acute intoxication, particularly in cases of fasting or malnutrition and hepatic insufficiency. Alcohol may make the signs of hypoglycaemia less clear, and delayed hypoglycaemia can occur. The CNS depressant effects of alcohol plus hypoglycaemia can make driving and operation of dangerous machinery much more hazardous.

Drugs that affect glycaemic control.

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 Segluromet, the patient should be closely observed to maintain adequate glycaemic control.

Glyburide.

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

Furosemide.

A single-dose, metformin furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide 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 furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide 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.

Beta-blockers.

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

Other.

In healthy volunteers, the pharmacokinetics of 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of Segluromet or its individual components on fertility in humans has not been studied. No animal fertility studies have been performed with ertugliflozin and metformin in combination.

Ertugliflozin.

In rats, no effects on male or female fertility were observed with oral administration of ertugliflozin up to the highest dose of 250 mg/kg/day (yielding approximately 280 and 380 times the clinical plasma AUC for unbound ertugliflozin at the maximum recommended human dose (MRHD) of 15 mg/day in the respective sexes).

Metformin hydrochloride.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.
(Category D)

Segluromet.

There are no adequate and well-controlled studies of Segluromet or its individual components in pregnant women. Based on results from animal studies, ertugliflozin may affect renal development and maturation. No animal embryofetal development studies have been performed with ertugliflozin and metformin in combination. Use of Segluromet during pregnancy is not recommended.

Ertugliflozin.

In animal studies, ertugliflozin did not adversely affect developmental outcomes in rats and rabbits at oral doses up to 100 mg/kg/day and 250 mg/kg/day in the respective species (yielding approximately 240 and > 1000 times the clinical AUC for unbound ertugliflozin at the MRHD of 15 mg/day). At a maternally toxic dose in rats (250 mg/kg/day), lower fetal viability and a higher incidence of cardiac malformation were observed (510 times the clinical exposure at the MRHD, based on AUC). Ertugliflozin and/or its metabolites were shown to cross the placenta in rats.
The developing kidney is seen to be more sensitive to ertugliflozin than the mature organ. When ertugliflozin was administered to juvenile rats from postnatal day (PND) 21 to PND 90, increased kidney weights, dilatation of the renal pelvis and tubules, and renal mineralization were seen at all dose levels tested (≥ 5 mg/kg/day, yielding 13 times the clinical exposure at the MRHD) with effects more prominent than observed in adult animals.

Metformin hydrochloride.

Metformin did not adversely affect developmental outcomes when administered to 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 dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
 There is no information regarding the presence of ertugliflozin in human milk, the effects on the breast-fed infant, or the effects on milk production. Metformin is present in human breast milk. Ertugliflozin was shown to be excreted in the milk of lactating rats. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney, based on data with ertugliflozin (see Use in pregnancy).
Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants Segluromet is not recommended during breast-feeding.

4.7 Effects on Ability to Drive and Use Machines

Segluromet has no or negligible influence on the ability to drive or use machines. Patients should be alerted to the risk of hypoglycaemia when Segluromet is used in combination with insulin or an insulin secretagogue and to the elevated risk of adverse reactions related to volume depletion, such as postural dizziness (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Ertugliflozin and metformin.

The safety of concomitantly administered ertugliflozin and metformin has been evaluated in 1,083 patients with type 2 diabetes mellitus for 26 weeks in a pool of two placebo-controlled trials: as ertugliflozin add-on therapy to metformin and as ertugliflozin add-on therapy to sitagliptin and metformin (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The incidence and type of adverse reactions in these two trials were similar to the adverse reactions seen with ertugliflozin. There were no additional adverse reactions identified in the pooling of the two placebo-controlled trials that included metformin relative to the three placebo-controlled studies with ertugliflozin (see below).

Ertugliflozin.

Pool of placebo-controlled trials evaluating ertugliflozin 5 and 15 mg. The primary assessment of safety and tolerability was conducted in a pooled analysis of three 26-week placebo-controlled trials with similar study design, duration of treatment, and baseline characteristics. Ertugliflozin was used as monotherapy in one trial and as add-on therapy in two trials (see Section 5.1 Pharmacodynamic Properties, Clinical trials). These data reflect exposure of 1,029 patients to ertugliflozin with a mean exposure duration of approximately 25 weeks. Patients received ertugliflozin 5 mg (N=519), ertugliflozin 15 mg (N=510), or placebo (N=515) once daily. The data in Table 1 are derived from this pooled analysis.
The overall incidence of subjects with 1 or more adverse events was not notably different across the ertugliflozin 5 mg (45.5%), ertugliflozin 15 mg (50.4%), and placebo (51.1%) groups. The incidence of non-fatal serious adverse events was low and similar in the ertugliflozin 5 mg and 15 mg groups relative to the placebo group (3.3%, 2.4%, and 2.9% for the ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo groups, respectively). The incidence of adverse events resulting in discontinuation from study medication was low overall and not notably different in the ertugliflozin 5 mg and 15 mg groups (2.3% and 1.4%, respectively) relative to the placebo groups (1.7%).
The adverse drug reactions (ADRs) listed in Table 2 are presented by System Organ Class (SOC).
Description of selected adverse reactions.

Volume depletion.

Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion, particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2). In the pool of three placebo-controlled clinical trials, adverse reactions related to volume depletion (e.g. dehydration, dizziness postural, presyncope, syncope, hypotension, and orthostatic hypotension) were not more frequent in patients treated with ertugliflozin compared to those treated with placebo; events were reported by 0.8%, 1.0%, and 1.7% of patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. A higher incidence was seen in a study of patients with moderate renal impairment; events were reported by 4.4%, 1.9%, and 0% of patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. Ertugliflozin may also increase the risk of hypotension in other patients at risk for volume contraction (see Section 4.4 Special Warnings and Precautions for Use).

Ketoacidosis.

In VERTIS CV, ketoacidosis was identified in 19 (0.3%) ertugliflozin-treated patients and in 2 (0.1%) placebo-treated patients. Across seven other Phase 3 clinical trials in the ertugliflozin development program, ketoacidosis was identified in 3 (0.1%) ertugliflozin-treated patients and 0.0% of comparator-treated patients (see Section 4.4 Special Warnings and Precautions for Use).

Impairment in renal function.

Use of ertugliflozin was associated with increases in serum creatinine and decreases in eGFR (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests). Patients with moderate renal impairment at baseline had larger mean changes; these changes were observed to reverse after treatment discontinuation, suggesting acute haemodynamic changes may play a role in the renal function abnormalities observed with ertugliflozin (see Section 4.4 Special Warnings and Precautions for Use, Use in patients with renal impairment).
In VERTIS CV initiation of treatment with ertugliflozin was associated with decreases in eGFR observed at Week 6 (-2.7, -3.8 and -0.4 mL/min/1.73 m2 for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo respectively) followed by a return toward baseline at Week 52 (-0.4, -1.1 and -0.2 mL/min/1.73 m2 for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo respectively). Continued treatment with ertugliflozin was associated with a slower decline in eGFR compared to placebo up to Week 260. In patients with moderate renal impairment, the mean change from baseline in eGFR was -0.4, -2.0 and 2.2 mL/min/1.73 m2 for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo respectively at Week 6 and 2.0, 1.1 and 3.2 mL/min/1.73 m2 for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo respectively at Week 52.
In VERTIS CV, the incidences for renal-related adverse reactions (e.g. acute kidney injury, renal impairment, acute prerenal failure) were 4.2%, 4.3% and 4.7% in patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo respectively in the general study population. In patients with moderate renal impairment the incidences of renal-related adverse reactions were 9.7%, 10.0% and 10.2% in patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively.

Hypoglycaemia.

In all clinical trials, hypoglycaemia was defined as any event regardless of symptoms, where biochemical hypoglycaemia was documented (any glucose value below or equal to 3.9 mmol/L). Severe hypoglycaemia was defined as an event consistent with hypoglycaemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained).
The incidence of hypoglycaemia by study is shown in Table 3. The incidence of hypoglycaemia may be higher when ertugliflozin is administered with insulin and/or an insulin secretagogue (see Section 4.4 Special Warnings and Precautions for Use).

Genital mycotic infections.

In the pool of three placebo-controlled clinical trials, female genital mycotic infections (e.g. genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis) occurred in 9.1%, 12.2%, and 3.0% of females treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. In females, discontinuation due to genital mycotic infections occurred in 0.6% and 0% of patients treated with ertugliflozin and placebo, respectively. (See Section 4.4 Special Warnings and Precautions for Use.)
In the same pool, male genital mycotic infections (e.g. balanitis candida, balanoposthitis, genital infection, genital infection fungal) occurred in 3.7%, 4.2%, and 0.4% of males treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males. In males, discontinuations due to genital mycotic infections occurred in 0.2% and 0% of patients treated with ertugliflozin and placebo, respectively. In rare instances, phimosis was reported and sometimes circumcision was performed. (See Section 4.4 Special Warnings and Precautions for Use).

Urinary tract infections.

In VERTIS CV urinary tract infections (e.g. urinary tract infection, cystitis, dysuria) occurred in 12.2%, 12.0% and 10.2% of patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. The incidences of serious urinary tract infections were 0.9%, 0.4%, and 0.8% with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively.

Metformin.

Metformin adverse reactions are shown below by system organ class and by frequency category. Frequency categories are based on information available from the Product Information for metformin available in Australia. Frequencies are defined as follows: very common > 1/10; common > 1/100, < 1/10; uncommon > 1/1,000, < 1/100; rare > 1/10,000, < 1/1,000; very rare < 1/10,000; not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders.

Common: Taste disturbance.

Gastrointestinal disorders.

Very common: Gastrointestinal disorders such as diarrhoea, nausea, vomiting, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Skin and subcutaneous tissue disorders.

Very rare: Skin reactions such as erythema, pruritus and urticaria.

Metabolism and nutrition disorders.

Very rare: Lactic acidosis (see Section 4.4 Special Warnings and Precautions for Use).
Decrease of vitamin B12 absorption with a decrease in serum levels has been observed in patients treated long-term with metformin. 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 should be considered (see Section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary disorders.

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

Laboratory tests.

Ertugliflozin.

Increases in serum creatinine and decreases in eGFR.

Initial increases in mean creatinine and decreases in mean eGFR in patients treated with ertugliflozin were generally transient during continuous treatment. In the pool of three placebo-controlled clinical trials, mean changes from baseline in creatinine at 6 weeks were 2.41 and 2.76 micromol/L for ertugliflozin 5 mg and 15 mg, respectively, compared to 0.24 micromol/L for placebo. Mean changes from baseline in eGFR were -2.7 and -3.1 mL/min/1.73 m2 for ertugliflozin 5 mg and 15 mg, respectively, compared to -0.3 mL/min/1.73 m2 for placebo. At 26 weeks, mean changes from baseline in creatinine were -0.08 and 0.80 micromol/L for ertugliflozin 5 mg and 15 mg, respectively, compared to -0.57 micromol/L for placebo. Mean changes from baseline in eGFR at 26 weeks were 0.5 and -0.6 mL/min/1.73 m2 for ertugliflozin 5 mg and 15 mg, respectively, compared to 0.7 mL/min/1.73 m2 for placebo. Patients with moderate renal impairment at baseline had larger mean changes at 6 weeks (approximately 1 mL/min/1.73 m2) with some attenuation but not a complete return to baseline by 26 weeks. These changes were observed to reverse after treatment discontinuation.

Increases in low-density lipoprotein cholesterol (LDL-C).

In the pool of three placebo-controlled trials, dose-related increases in LDL-C were observed in patients treated with ertugliflozin. Mean percent changes from baseline in LDL-C relative to placebo were 2.6% and 5.4% with ertugliflozin 5 mg and ertugliflozin 15 mg, respectively. The range of mean baseline LDL-C was 2.50 to 2.53 mmol/L across treatment groups.

Increases in haemoglobin.

In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in haemoglobin were 4.6 g/L (3.5%) with ertugliflozin 5 mg, 4.8 g/L (3.5%) with ertugliflozin 15 mg, and -2.1 g/L (-1.4%) with placebo. The range of mean baseline haemoglobin was 139.0 to 140.0 g/L across treatment groups. At the end of treatment, 0.2%, 0.4%, and 0.0% of patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively, had a haemoglobin increase greater than 20 g/L and above the upper limit of normal. This change in laboratory parameter is of unknown clinical significance.

Increases in serum phosphate.

In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in serum phosphate were 0.07 mmol/L (6.8%) with ertugliflozin 5 mg, 0.08 mmol/L (8.5%) with ertugliflozin 15 mg, and 0.01 mmol/L (1.9%) with placebo. The mean baseline serum phosphate was 1.14 mmol/L across treatment groups. In a clinical trial of patients with moderate renal impairment, mean changes (percent changes) from baseline at Week 26 in serum phosphate were 0.09 mmol/L (9.7%) with ertugliflozin 5 mg, 0.08 mmol/L (7.8%) with ertugliflozin 15 mg, and -0.00 mmol/L (0.8%) with placebo. This change in laboratory parameter is of unknown clinical significance.

Adverse reactions in specific populations.

Elderly patients.

Ertugliflozin.

Across the clinical program, a total of 876 (25.7%) patients treated with ertugliflozin were 65 years and older, and 152 (4.5%) patients treated with ertugliflozin were 75 years and older. Patients 65 years and older had a higher incidence of adverse reactions related to volume depletion compared to younger patients; events were reported in 2.2%, 2.6%, and 1.1% of patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and comparator, respectively (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

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 (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Renal impairment.

Ertugliflozin.

The efficacy and safety of ertugliflozin were evaluated in a study of patients with moderate renal impairment. In this study, 202 patients exposed to ertugliflozin had an eGFR between 45 and 60 mL/min/1.73 m2 and 111 patients exposed to ertugliflozin had an eGFR between 30 and 45 mL/min/1.73 m2. The glucose-lowering efficacy of ertugliflozin decreased in patients with worsening renal function. Compared to placebo-treated patients, patients with moderate renal impairment treated with ertugliflozin had increases in serum creatinine and decreases in eGFR, and increased risks for renal-related and volume depletion adverse reactions (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Metformin.

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment (see Section 4.3 Contraindications).

Reporting suspected adverse reactions.

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

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
In the event of an overdose with Segluromet, employ the usual supportive measures (e.g. remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient's clinical status.

Ertugliflozin.

Ertugliflozin did not show any toxicity in healthy subjects at single oral doses up to 300 mg and multiple doses up to 100 mg daily for 2 weeks. No potential acute symptoms and signs of overdose were identified.
Removal of ertugliflozin by haemodialysis has not been studied.

Metformin hydrochloride.

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 g. Hypoglycaemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see Section 4.4 Special Warnings and Precautions for Use). Metformin is dialyzable with a clearance of up to 170 mL/min under good haemodynamic conditions. Therefore, haemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Segluromet. Segluromet combines two antihyperglycaemic agents with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: ertugliflozin, a SGLT2 inhibitor, and metformin hydrochloride, a member of the biguanide class.
Ertugliflozin. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Patients with diabetes have been shown to have elevated reabsorption of glucose which may result in persistence of hyperglycaemia. Ertugliflozin is an inhibitor of SGLT2 with an IC50 of 0.88 nanoM. It displays > 2,200-fold selectivity for SGLT2 over SGLT1 (responsible for glucose absorption in the gut). By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion (UGE), which lowers fasting plasma glucose (FPG) and haemoglobin A1C levels in an insulin-independent manner. Additionally, UGE results in caloric loss and with ensuing weight loss. Ertugliflozin also causes an osmotic diuresis, which may result in reduction of blood pressure. UGE is observed after the first dose. UGE with ertugliflozin depends on plasma glucose levels and glomerular filtration rate. Consequently, UGE is reduced as plasma glucose levels fall, which reduces the risk of hypoglycaemia.

Urinary glucose excretion and urinary volume.

Dose-dependent increases in the amount of glucose excreted in urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following single- and multiple-dose administration of ertugliflozin. Dose-response modelling indicates that ertugliflozin 5 mg and 15 mg result in near maximal urinary glucose excretion (UGE), with the 15 mg dose providing incrementally greater UGE relative to the 5 mg dose. Enhanced UGE is maintained after multiple-dose administration. UGE with ertugliflozin also results in increases in urinary volume. Ertugliflozin acts independently of insulin secretion and insulin action. Over time, significant improvement in beta cell function (HOMA-beta) has been observed in clinical studies with ertugliflozin.

Cardiac electrophysiology.

In a randomised, placebo-controlled, active-comparator, crossover study, 42 healthy subjects were administered a single oral supratherapeutic dose of ertugliflozin 100 mg (6.7 times the maximum recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with 100 mg ertugliflozin.
Metformin hydrochloride. Metformin is an antihyperglycaemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycaemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycaemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) 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.

Clinical trials.

There have been no clinical efficacy studies conducted with Segluromet. However, bioequivalence of Segluromet with coadministered ertugliflozin and metformin tablets was demonstrated.

Glycaemic control trials in patients with type 2 diabetes.

The efficacy and safety of ertugliflozin in combination with metformin have been studied in 4 multicentre, randomised, double blind, placebo- and active comparator-controlled, Phase 3 clinical studies involving 3,643 patients with type 2 diabetes. These studies included White, Hispanic, Black, Asian, and other racial and ethnic groups, and patients with an age range of 21 to 86 years.
In VERTIS CV, there were two sub-studies where ertugliflozin has been studied as add on to insulin (with or without metformin) and as add on to metformin plus a sulfonylurea.
In patients with type 2 diabetes, treatment with ertugliflozin in combination with metformin produced clinically and statistically significant improvements in HbA1c and FPG compared to placebo or active comparator.
In patients with type 2 diabetes treated with ertugliflozin in combination with metformin, the improvement in HbA1c was generally similar across subgroups defined by age, sex, race, geographic region, baseline BMI, and duration of type 2 diabetes mellitus.

Ertugliflozin as add-on combination therapy with metformin.

A total of 621 patients with type 2 diabetes inadequately controlled on metformin monotherapy (≥ 1,500 mg/day) participated in a randomised, double-blind, multi-centre, 26-week, placebo-controlled study to evaluate the efficacy and safety of ertugliflozin in combination with metformin. Patients were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo administered once daily in addition to continuation of background metformin therapy.
At Week 26, treatment with ertugliflozin at 5 mg or 15 mg daily provided statistically significant improvements in HbA1c, FPG, and body weight compared to placebo. Treatment with ertugliflozin at 5 mg or 15 mg daily provided a statistically significant improvement in systolic and diastolic blood pressure compared to placebo. Ertugliflozin also resulted in a greater proportion of patients achieving an HbA1c < 7% compared to placebo (see Table 4 and Figure 3).

Factorial study with ertugliflozin and sitagliptin (Januvia) as add-on combination therapy with metformin.

A total of 1,233 patients with type 2 diabetes participated in a randomised, double-blind, multi-centre, 26-week, active-controlled study to evaluate the efficacy and safety of ertugliflozin 5 mg or 15 mg in combination with Januvia 100 mg compared to the individual components. Patients with type 2 diabetes inadequately controlled on metformin monotherapy (≥ 1,500 mg/day) were randomised to one of five active-treatment arms: ertugliflozin 5 mg or 15 mg, Januvia 100 mg, or Januvia 100 mg in combination with 5 mg or 15 mg ertugliflozin administered once daily in addition to continuation of background metformin therapy.
At Week 26, ertugliflozin 5 mg or 15 mg used in combination with Januvia 100 mg provided statistically significant improvement in HbA1c and FPG compared to the individual components (see Table 5). More patients receiving ertugliflozin 5 mg or 15 mg in combination with Januvia 100 mg achieved an HbA1c < 7% compared to the individual components. Treatment with ertugliflozin 5 mg or 15 mg in combination with Januvia 100 mg also resulted in a statistically significant reduction in body weight and systolic blood pressure compared to Januvia 100 mg.

Ertugliflozin as add-on combination therapy with metformin and sitagliptin (Januvia).

A total of 463 patients with type 2 diabetes inadequately controlled on metformin (≥ 1,500 mg/day) and Januvia 100 mg once daily participated in a randomised, double-blind, multi-centre, 26-week, placebo-controlled study to evaluate the efficacy and safety of ertugliflozin. Patients were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo administered once daily in addition to continuation of background metformin and Januvia therapy.
At Week 26, treatment with ertugliflozin at 5 mg or 15 mg daily provided statistically significant improvements in HbA1c, FPG, body weight, and systolic blood pressure compared to placebo. Ertugliflozin also resulted in a greater proportion of patients achieving an HbA1c < 7% compared to placebo (see Table 6).

Active-controlled study of ertugliflozin versus glimepiride as add-on combination therapy with metformin.

A total of 1,326 patients with type 2 diabetes inadequately controlled on metformin monotherapy participated in a randomised, double-blind, multi-centre, 52-week, active comparator-controlled study to evaluate the efficacy and safety of ertugliflozin in combination with metformin. These patients, who were receiving metformin monotherapy (≥ 1,500 mg/day), were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or glimepiride administered once daily in addition to continuation of background metformin therapy.
Glimepiride was initiated at 1 mg/day and titrated up to a maximum dose of 6 or 8 mg/day (depending on maximum approved dose in each country) or a maximum tolerated dose or down-titrated to avoid or manage hypoglycaemia. The mean daily dose of glimepiride was 3.0 mg.
At Week 52, ertugliflozin 5 mg and 15 mg provided similar reductions in HbA1c from baseline compared to glimepiride when added to metformin therapy. Ertugliflozin 15 mg was non-inferior to glimepiride after 52 weeks of treatment. At Week 52, ertugliflozin 15 mg resulted in a statistically significant difference in change from baseline for body weight compared to glimepiride (-3.4 kg for ertugliflozin 15 mg vs. +0.9 kg for glimepiride; treatment difference -4.3 kg; p < 0.001). (See Table 7 and Figure 4).

Ertugliflozin as add-on combination therapy with insulin (with or without metformin).

In an 18-week randomised, double-blind, multi-centre, placebo-controlled, glycaemic sub-study of VERTIS CV (see Section 5.1 Pharmacodynamic Properties, Clinical trials), a total of 1065 subjects patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease with inadequate glycaemic control (HbA1c between 7% and 10.5%) on background therapy of insulin ≥ 20 units/day (59% patients were also on metformin ≥ 1,500 mg/day) were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg or placebo once daily treatment.
Compared to placebo, treatment with ertugliflozin at 5 mg or 15 mg daily provided statistically significant reductions in HbA1c at Week 18. Ertugliflozin also resulted in a higher proportion of patients achieving an HbA1c < 7% compared to placebo (see Table 8).

Ertugliflozin as add-on combination therapy with metformin and sulfonylurea.

In an 18-week randomised, double-blind, multi-centre, placebo-controlled, glycaemic sub-study of VERTIS CV [see Section 5.1 Pharmacodynamic Properties, Clinical trials], a total of 330 subjects patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease with inadequate glycaemic control (HbA1c between 7% and 10.5%) with background therapy of metformin ≥ 1,500 mg/day and a sulfonylurea (SU) were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg or placebo once daily treatment.
Compared to placebo, treatment with ertugliflozin at 5 mg or 15 mg daily provided statistically significant reductions in HbA1c at Week 18. Ertugliflozin also resulted in a higher proportion of patients achieving an HbA1c < 7% compared to placebo (see Table 9).

Cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease.

The effect of ertugliflozin on cardiovascular risk in adult patients with type 2 diabetes and established, stable, atherosclerotic cardiovascular disease was evaluated in the VERTIS CV study, a multicentre, multi-national, randomised, double-blind, placebo-controlled, event-driven trial. The study compared the risk of experiencing a major adverse cardiovascular event (MACE) between ertugliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease.
A total of 8246 patients were randomized (ertugliflozin 5 mg N = 2752, ertugliflozin 15 mg N = 2747, or placebo N = 2747) and followed for a median of 3 years. Approximately 88% of the study population was Caucasian, 6% was Asian, and 3% was Black. The mean age was 64 years and approximately 70% were male.
All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean duration of type 2 diabetes mellitus was 13 years, the mean HbA1c at baseline was 8.2% and the mean eGFR was 76 mL/min/1.73 m2. At baseline, patients were treated with one (32%) or more (67%) antidiabetic medications including metformin (76%), insulin (47%), sulfonylureas (41%), DPP-4 inhibitors (11%) and GLP-1 receptor agonists (3%).
Almost all patients (99%) had established atherosclerotic cardiovascular disease at baseline including: a documented history of coronary artery disease (76%), cerebrovascular disease (23%) or peripheral artery disease (19%). Approximately 24% patients had a history of heart failure (HF). At baseline, the mean systolic blood pressure was 133 mmHg, the mean diastolic blood pressure was 77 mmHg, the mean LDL was 2.3 mmol/L, and the mean HDL was 1.1 mmol/L. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 69% with beta-blockers, 43% with diuretics, 82% with statins, 4% with ezetimibe, and 89% with antiplatelet agents.
The primary endpoint in VERTIS CV was the time to first occurrence of a Major Adverse Cardiac Event (MACE). A major adverse cardiac event was defined as occurrence of either a cardiovascular death or a nonfatal myocardial infarction (MI) or a nonfatal stroke. The statistical analysis plan pre-specified that the 5 and 15 mg doses would be combined for the analysis. A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE. Type-1 error was controlled across multiples tests using a hierarchical testing strategy.
The incidence rate of MACE was similar between the ertugliflozin-treated and placebo-treated patients. The estimated hazard ratio of MACE associated with ertugliflozin relative to placebo was 0.97 with 95.6% confidence interval (0.85, 1.11). The upper bound of this confidence interval, 1.11, excluded a risk larger than 1.3 (Table 10). Results for the individual 5 mg and 15 mg doses were consistent with results for the combined dose group.

5.2 Pharmacokinetic Properties

Segluromet.

Segluromet has been shown to be bioequivalent to coadministration of corresponding doses of ertugliflozin and metformin tablets.

Ertugliflozin.

The pharmacokinetics of ertugliflozin are similar in healthy subjects and patients with type 2 diabetes. The steady-state mean area under the curve (AUC) and peak concentration (Cmax) were 398 nanogram.hr/mL and 81.3 nanogram/mL, respectively, with 5 mg ertugliflozin once daily treatment, and 1,193 nanogram.hr/mL and 268 nanogram/mL, respectively, with 15 mg ertugliflozin once daily treatment. Steady-state is reached after 4 to 6 days of once-daily dosing with ertugliflozin. Ertugliflozin does not exhibit time dependent pharmacokinetics and accumulates in plasma up to 10-40% following multiple dosing.

Absorption.

Segluromet.

The effects of a high-fat meal on the pharmacokinetics of ertugliflozin and metformin when administered as Segluromet tablets are comparable to those reported for the individual tablets. Food had no meaningful effect on AUCinf of ertugliflozin or metformin, but reduced mean ertugliflozin Cmax by approximately 41% and metformin Cmax by approximately 29% compared to the fasted condition.

Ertugliflozin.

Following single dose oral administration of 5 mg and 15 mg of ertugliflozin, peak plasma concentrations (median Tmax) of ertugliflozin occur at 1 hour postdose under fasted conditions. Plasma Cmax and AUC of ertugliflozin increase in a dose proportional manner following single doses from 0.5 mg to 300 mg and following multiple doses from 1 mg to 100 mg. The absolute oral bioavailability of ertugliflozin following administration of a 15 mg dose is approximately 100%.
Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin Cmax by 29% and prolongs Tmax by 1 hour, but does not alter AUC as compared with the fasted state. The observed effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and ertugliflozin may be administered with or without food. In Phase 3 clinical trials, ertugliflozin was administered without regard to meals.

Metformin hydrochloride.

The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution.

Ertugliflozin.

The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 85.5 L. Plasma protein binding of ertugliflozin is 93.6% and is independent of ertugliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The blood-to-plasma concentration ratio of ertugliflozin is 0.66.

Metformin hydrochloride.

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 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. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady-state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 microgram/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 microgram/mL, even at maximum doses.

Metabolism.

Ertugliflozin.

Metabolism is the primary clearance mechanism for ertugliflozin. The major metabolic pathway for ertugliflozin is UGT1A9 and UGT2B7-mediated O glucuronidation to two glucuronides. These are present in plasma at levels 2- and 4-times lower than ertugliflozin and are pharmacologically inactive at clinically relevant concentrations. CYP mediated (oxidative) metabolism of ertugliflozin is minimal (12%).

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) nor biliary excretion.

Excretion.

Ertugliflozin.

The mean systemic plasma clearance following an intravenous 100 microgram dose was 11.2 L/hr. The mean elimination half life in type 2 diabetic patients with normal renal function was estimated to be 16.6 hours based on the population pharmacokinetic analysis. Following administration of an oral [14C]-ertugliflozin solution to healthy subjects, approximately 40.9% and 50.2% of the drug-related radioactivity was eliminated in faeces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged ertugliflozin in urine and 33.8% as unchanged ertugliflozin in faeces, which is likely due to biliary excretion of glucuronide metabolites and subsequent hydrolysis to parent.

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.

Special populations.

Renal impairment.

Segluromet.

Studies characterising the pharmacokinetics of ertugliflozin and metformin after administration of Segluromet in renally impaired patients have not been performed (see Section 4.2 Dose and Method of Administration).

Ertugliflozin.

In a Phase 1 clinical pharmacology study in patients with type 2 diabetes and mild, moderate, or severe renal impairment (as determined by estimated glomerular filtration rate (eGFR)), following a single-dose administration of 15 mg Segluromet, the mean increases in AUC of ertugliflozin were ≤ 1.7-fold, compared to subjects with normal renal function. These increases in ertugliflozin AUC are not considered clinically relevant. There were no clinically meaningful differences in the ertugliflozin Cmax values among the different renal function groups. The 24-hour urinary glucose excretion declined with increasing severity of renal impairment. The plasma protein binding of ertugliflozin was unaffected in patients with renal impairment.

Metformin hydrochloride.

In patients with decreased renal function (based on measured eGFR), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in eGFR (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Hepatic impairment.

Ertugliflozin.

Moderate hepatic impairment (based on the Child-Pugh classification) did not result in an increase in exposure of ertugliflozin. The AUC of ertugliflozin decreased by approximately 13%, and Cmax decreased by approximately 21% compared to subjects with normal hepatic function. This decrease in ertugliflozin exposure is not considered clinically meaningful. There is no clinical experience in patients with Child-Pugh class C (severe) hepatic impairment. The plasma protein binding of ertugliflozin was unaffected in patients with moderate hepatic impairment.

Metformin hydrochloride.

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.
Paediatric. No studies with Segluromet have been performed in paediatric patients.
Effects of age, body weight, gender, and race.

Ertugliflozin.

Based on a population pharmacokinetic analysis, age, body weight, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of ertugliflozin.

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.
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.
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).

5.3 Preclinical Safety Data

Genotoxicity.

Ertugliflozin.

Ertugliflozin was not mutagenic in the bacterial reverse mutation assay, in vitro (cytogenetic assay in human lymphocytes), or in vivo (rat bone marrow micronucleus test).

Metformin hydrochloride.

There was no evidence of a genotoxic 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 ertugliflozin and metformin in combination.

Ertugliflozin.

The carcinogenic potential of ertugliflozin was examined in 2-year studies in mice and rats. Administration was by oral gavage. There were no ertugliflozin-related neoplastic findings in mice at doses up to 40 mg/kg/day (approximately 41 times human exposure at the MRHD of 15 mg/day based on plasma AUC for unbound ertugliflozin) or in female rats at doses up to 15 mg/kg/day (approximately 50 times human exposure), the highest dose levels tested. In male rats, treatment with ertugliflozin at 15 mg/kg/day increased the incidence of benign adrenal medullary phaeochromocytoma. This finding was attributed to carbohydrate malabsorption leading to altered calcium homeostasis and is not considered relevant to human risk. The no-observed-effect level (NOEL) for neoplasia in male rats was 5 mg/kg/day (approximately 13 times human exposure at the MRHD of 15 mg/day) and no neoplasia was observed in female rats.

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 1,500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2,000 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 Segluromet contains the following inactive ingredients: povidone, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, magnesium stearate, and carnauba wax.
The film coating contains: hypromellose, hyprolose, titanium dioxide, and iron oxide red.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C. Store in original packaging.

6.5 Nature and Contents of Container

Available in aluminium/ aluminium blister packs of 14 tablets (starter packs) and 56 tablets.
Not all packs may be supplied.

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.

Ertugliflozin.

Segluromet tablets contain ertugliflozin pyroglutamic acid, the isolated form of the active ingredient ertugliflozin. The chemical name of ertugliflozin pyroglutamic acid is (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl) phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, compound with (2S)-5-oxopyrrolidine-2-carboxylic acid. The molecular formula is C27H32ClNO10 and the molecular weight is 566.00.
The chemical structure is:
Ertugliflozin pyroglutamic acid is a white to off-white powder that is soluble in ethyl alcohol and acetone, slightly soluble in ethyl acetate and acetonitrile and very slightly soluble in water.

Metformin hydrochloride.

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycaemic agents. The structural formula is as shown:
Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5.HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

CAS number.

Ertugliflozin.

The CAS Registry Number is 1210344-83-4.

Metformin hydrochloride.

The CAS Registry Number is 1115-70-4.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes