Consumer medicine information

Steglatro

Ertugliflozin

BRAND INFORMATION

Brand name

Steglatro

Active ingredient

Ertugliflozin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Steglatro.

What is in this leaflet

This leaflet answers some common questions about STEGLATRO.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

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

Keep this leaflet with the medicine. You may need to read it again.

What STEGLATRO is used for

STEGLATRO is used to lower your blood sugar (glucose), which is too high because of your type 2 diabetes. STEGLATRO can be used alone or in combination with certain other medicines that lower blood sugar, along with a recommended diet and exercise program.

Type 2 diabetes mellitus
Type 2 diabetes is also called non-insulin-dependent diabetes mellitus, or NIDDM. Type 2 diabetes mellitus is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should.

Your body can also make too much sugar. When this happens, sugar builds up in the blood. This can lead to serious medical problems.

High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary.

Your doctor will do blood tests regularly to check your diabetes. These tests look to see if your blood sugar is normal at that moment (blood sugar levels) and how well you have managed your blood sugar over time (called haemoglobin A1c).

How STEGLATRO works

STEGLATRO is a member of a class of medicines you take by mouth called sodium-glucose co-transporter 2 (SGLT2) inhibitors that lowers blood sugar levels in patients with type 2 diabetes mellitus.

STEGLATRO helps remove sugar from the body through urination.

STEGLATRO by itself is unlikely to cause low blood sugar (hypoglycaemia) because it does not work when your blood sugar is low.

Talk to your doctor about the symptoms of low blood sugar and high blood sugar.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Before you take STEGLATRO

When you must not take it

Do not take STEGLATRO if:

  • you have poorly functioning kidneys since STEGLATRO requires good functioning kidneys to work well
  • you are allergic to any of the ingredients in STEGLATRO listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin or you may feel faint.
  • the packaging is torn or shows signs of tampering.
  • the expiry date on the pack has passed.
    If you take this medicine after the expiry date has passed, it may not work.

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

Before you start to take it

Tell your doctor if you:

  • have type 1 diabetes
  • have or have had diabetic ketoacidosis (increased ketones in the blood or urine)
  • are going to have surgery
  • are eating less due to illness, surgery, or a change in your diet
  • drink alcohol very often, or drink a lot of alcohol in the short term ("binge" drinking)
  • have kidney problems
  • have liver problems, because STEGLATRO is not recommended for patients with severe liver disease
  • take other diabetes medicines, you are more likely to get low blood sugar with certain medicines
  • have or have had yeast infections of the vagina or penis

You may obtain further information from your doctor or pharmacist, who has more detailed information.

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

Elderly:
In studies, STEGLATRO worked well in and was generally well-tolerated by older adult patients. Patients 65 years or older were more likely to get dehydrated while taking STEGLATRO compared to younger patients. No dose adjustment is necessary based on age.

Tell your doctor if you are pregnant or planning to become pregnant. It is not known if STEGLATRO may harm your unborn baby.

Do not use if you are pregnant. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant.

Tell your doctor if you are breast-feeding or plan to breast-feed. It is not known if STEGLATRO passes into breast milk.

Do not use STEGLATRO if you are breast-feeding or plan to breast-feed.

Talk with your doctor about the best way to feed your baby if you take STEGLATRO.

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

If you have not told your doctor about any of the above, tell him/her before you take any STEGLATRO.

Taking other medicines

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

STEGLATRO may be taken with most medicines.

Be sure to tell you doctor if you are taking water pills (diuretics), as you may be more likely to get dehydrated. See 'Side Effects'.

When you take STEGLATRO with certain other diabetes medicines, you are more likely to get low blood sugar. See 'Side Effects'.

How to take STEGLATRO

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

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

It is important to eat right and exercise while you take STEGLATRO.

How much to take

The recommended dose is one 5 mg or one 15 mg tablet once a day. Your doctor will decide the dose of STEGLATRO suitable for you.

Your doctor may do blood tests before you start STEGLATRO and while you take it. Your doctor may change your dose of STEGLATRO based on the results.

When 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.

Tell your doctor right away if you have any of these conditions and follow your doctor's instructions.

When to take it

Take STEGLATRO at the same time every morning. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

STEGLATRO can be taken with or without food.

How long to take it

Continue to take STEGLATRO for as long as your doctor prescribes it so 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.

If you forget to take it

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

Do not take 2 doses of STEGLATRO on the same day.

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

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 131 126), or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much STEGLATRO. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using STEGLATRO

Things you must do

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

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

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

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

Tell your doctor immediately if you experience pain or tenderness, redness, swelling of the genitals or the area between the genitals and the anus, fever and feeling generally unwell. These symptoms could be a sign of a rare but serious life-threatening infection called necrotising fasciitis of the perineum or Fournier's gangrene. Fournier's gangrene must be treated immediately.

Things you must not do

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

Do not give STEGLATRO to anyone else, even if they have the same condition as you. Remember that your doctor has prescribed this medicine only for you.

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

Things to be careful of

Be careful driving or operating machinery until you know how STEGLATRO affects you. STEGLATRO has no or negligible influence on the ability to drive and use machines. Taking this medicine in combination with insulin or medicines called insulin secretagogues can cause blood sugar levels to drop too low (hypoglycaemia), which may cause symptoms such as shaking, sweating and change in vision, and may affect your ability to drive and use machines.

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

Side Effects

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

Like all prescription medicines, STEGLATRO may cause side effects.

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

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

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

  • yeast infections of the vagina or penis
Symptoms of yeast infection in women 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.
Symptoms of yeast infection in men include swelling of the penis, if you haven't been circumcised, it may be hard to pull back the skin around the tip of your penis, red skin, itchiness or rash, bad smell and discharge coming out of your penis, pain in the skin around your penis.
  • changes in urination , including urgent need to urinate more often, in larger amounts, or at night
  • thirst
  • vaginal itching

Tell your doctor if you experience any of the following other side effects, as some may be serious and require urgent medical attention:

Dehydration (losing too much water from your body)

Symptoms of dehydration are:

  • 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
  • take water tablets (diuretics)
  • are 65 years or older

Ketoacidosis (increased ketones in your blood or urine)
Ketoacidosis has happened in people who have type 1 diabetes or type 2 diabetes during treatment with products containing SGLT2 inhibitors. Ketoacidosis can be life-threatening and may need to be treated in a hospital.

Ketoacidosis can happen with STEGLATRO even if your blood sugar is less than 14.0 mmol/L.

Stop taking STEGLATRO and call your doctor right away if you think you have ketoacidosis. Symptoms of ketoacidosis may include:

  • nausea
  • tiredness
  • vomiting
  • trouble breathing
  • stomach-area (abdominal) pain
  • excessive thirst

If you get these symptoms during treatment with STEGLATRO, if possible, check for ketones in your urine, even if your blood sugar is less than 14.0 mmol/L.

Low blood sugar (hypoglycaemia)
If you take STEGLATRO 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 while you use STEGLATRO.

Signs and symptoms of low blood sugar may include:

  • headache
  • drowsiness
  • irritability
  • hunger
  • dizziness
  • confusion
  • sweating
  • feeling jittery
  • weakness
  • fast heart beat

Kidney problems
Blood tests may show changes related to kidney function (for example, creatinine)

Urinary tract infection
If you take STEGLATRO you may be at a greater risk for urinary tract infections.

If you have symptoms, such as burning or pain when you pass urine, more frequent or urgent need to urinate, fever, chills, or blood in the urine, contact your doctor as soon as possible.

Higher levels of bad cholesterol, called LDL (a type of fat in your blood)

These are not all possible side effects of STEGLATRO. For more information, ask your doctor or pharmacist.

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

Tell your doctor if you notice any other effects.

After using STEGLATRO

Storage

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

Keep STEGLATRO in its original packaging in a cool dry place where the temperature stays below 30°C. Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

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

Disposal

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

Product description

What it looks like

STEGLATRO comes as two strengths of tablets:

  • 5 mg tablet - A pink, triangular-shaped, film-coated tablet marked with '701' on one side and plain on the other side.
  • 15 mg tablet - A red, triangular-shaped, film-coated tablet marked with '702' on one side and plain on the other side.

A box of STEGLATRO contains 28 tablets. STEGLATRO tablets may also be supplied in packs of 7 tablets to start treatment.

Not all packs may be supplied in Australia.

Ingredients

Active ingredient:

Ertugliflozin pyroglutamic acid, equivalent to ertugliflozin 5 or 15 mg per tablet

Inactive ingredients:

  • Microcrystalline cellulose
  • Lactose monohydrate
  • Sodium starch glycollate Type A
  • Magnesium stearate

Ingredients of film-coating:

  • Hypromellose
  • Lactose monohydrate
  • Macrogol 3350
  • Triacetin
  • Titanium dioxide
  • Iron oxide red

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

Supplier

STEGLATRO is supplied in Australia by:

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

Date of Preparation

This leaflet was prepared in February 2019.

Australian Register Numbers:

STEGLATRO 5 - AUST R: 287619

STEGLATRO 15 - AUST R: 287622

This CMI leaflet was current at the time of printing. To check if it has been updated, please view our website www.msd-australia.com.au or ask your pharmacist.

(CCPPI-MK8835-T-032018)

Published by MIMS April 2019

BRAND INFORMATION

Brand name

Steglatro

Active ingredient

Ertugliflozin

Schedule

S4

 

1 Name of Medicine

Ertugliflozin.

2 Qualitative and Quantitative Composition

Ertugliflozin tablets contain ertugliflozin pyroglutamic acid, the isolated form of the active ingredient ertugliflozin. Ertugliflozin tablets contain 6.48 or 19.43 mg of ertugliflozin pyroglutamic acid, which is equivalent to 5 and 15 mg of the active ingredient ertugliflozin.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Steglatro 5 mg tablets are pink, triangular-shaped, film-coated tablets debossed with "701" on one side and plain on the other side.
Steglatro 15 mg tablets are red, triangular-shaped, film-coated tablets debossed with "702" on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Steglatro (ertugliflozin) is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus as:
monotherapy when metformin is considered inappropriate due to intolerance; or
in combination with other anti-hyperglycaemic agents.
[See Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use for available data on different add-on combination therapies.]

4.2 Dose and Method of Administration

General.

The recommended starting dose of Steglatro is 5 mg once daily, taken in the morning, with or without food. In patients tolerating Steglatro 5 mg once daily the dose may be increased to 15 mg once daily if additional glycaemic control is needed.

Renal impairment.

Assessment of renal function is recommended prior to initiation of Steglatro and periodically thereafter [see Section 4.4 Special Warnings and Precautions for Use].
Initiation of Steglatro 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, individually assess the risk benefit as HbA1c reduction was only demonstrated in a post hoc analysis for ertugliflozin 15 mg.
Discontinue Steglatro if the patient's eGFR falls persistently below 45 mL/min/1.73 m2.

Hepatic impairment.

No dose adjustment of Steglatro is necessary in patients with mild or moderate hepatic impairment. Steglatro has not been studied in patients with severe hepatic impairment and is not recommended for use in these patients.

Paediatric population.

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

Elderly.

No dose adjustment of Steglatro is recommended based on age.

4.3 Contraindications

History of a serious hypersensitivity reaction to Steglatro or to any of the excipients.
Patients with chronic kidney disease (CKD) receiving dialysis; eGFR < 30 mL/min/1.73 m2 or eGFR persistently < 45 mL/min/1.73 m2 (CKD stage 3B, 4 and 5). The efficacy of Steglatro is dependent on renal function [see Section 4.4 Special Warnings and Precautions for Use].

4.4 Special Warnings and Precautions for Use

General.

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

Hypotension.

Steglatro causes an osmotic diuresis, which may lead to intravascular volume contraction. Therefore, symptomatic hypotension may occur after initiating Steglatro [see Section 4.8 Adverse Effects (Undesirable Effects)] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients (≥ 65 years), or patients on diuretics. Before initiating Steglatro, 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 Steglatro. Temporary interruption of Steglatro should be considered until the fluid loss is corrected.

Ketoacidosis.

Steglatro 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. Steglatro is not indicated for the treatment of patients with type 1 diabetes mellitus.
Patients treated with Steglatro 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, Steglatro 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 Steglatro, consider factors in the patient history that may predispose to ketoacidosis.
Factors that predispose patients to ketoacidosis include a low carbohydrate diet, dehydration, acute illness, surgery, a previous ketoacidosis, insulin 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. Steglatro should be used with caution in these patients. Consider monitoring for ketoacidosis and temporarily discontinuing Steglatro in clinical situations known to predispose to ketoacidosis.

Surgery.

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

Hypoglycaemia with concomitant use with insulin and insulin secretagogues.

Insulin and insulin secretagogues are known to cause hypoglycaemia. Steglatro 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 Steglatro.

Genital mycotic infections.

Steglatro 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 Steglatro 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, Steglatro 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%.

Use in patients with renal impairment.

The efficacy of Steglatro is dependent on renal function. Steglatro 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) or eGFR persistently < 45 mL/min/1.73 m2 (CKD stage 3B, 4 and 5) [see Section 4.3 Contraindications].
Steglatro 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].
Monitoring of renal function is recommended:
prior to initiating Steglatro and periodically thereafter, i.e. at least yearly;
prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter;
more frequently in patients with an eGFR below 60 mL/min/1.73 m2.
Steglatro should be discontinued when eGFR is persistently below 45 mL/min/1.73 m2 [see Section 4.3 Contraindications].
The efficacy and safety of Steglatro have not been established in patients with severe renal impairment, with end-stage renal disease (ESRD), or receiving dialysis. Steglatro is not expected to be effective in these patient populations.

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 Steglatro may be considered in cases of recurrent urinary tract infections.

Use with other antidiabetic agents.

The use of ertugliflozin in combination with insulin and/or sulphonylureas was assessed in one study of patients with moderate renal impairment. Furthermore, efficacy and safety of ertugliflozin in combination with GLP-1 analogues, acarbose and thiazolidinediones has not been evaluated.

Use in the elderly.

Elderly patients may be at an increased risk of volume depletion. Patients 65 years and older treated with ertugliflozin had a higher incidence of adverse reactions related to volume depletion compared to younger patients. Ertugliflozin is expected to have diminished efficacy in elderly patients with renal impairment.

Paediatric use.

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

Lower limb amputations.

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 Steglatro 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 Steglatro 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.

Positive urine glucose test.

Monitoring glycaemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors 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 SGLT2 inhibitors. Use alternative methods to monitor glycaemic control.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinically significant pharmacokinetic interaction was seen when Steglatro was coadministered with metformin, sitagliptin, simvastatin, or glimepiride. Rifampicin had no clinically meaningful effects on the pharmacokinetics of Steglatro.

In vitro assessment of drug interactions.

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 OATPB3 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.

No dose adjustment of Steglatro 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of ertugliflozin on fertility in humans has not been studied. 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).
(Category D)
There are no adequate and well-controlled studies of Steglatro in pregnant women. Based on results from animal studies, ertugliflozin may affect renal development and maturation. Use of Steglatro during pregnancy is not recommended.
Ertugliflozin and/or its metabolites were shown to cross the placenta in rats.
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). The developing kidney is seen to be more sensitive to ertugliflozin than the mature organ. When ertugliflozin was administered to juvenile rats from post-natal 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.
 There is no information regarding the presence of ertugliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. 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 [see Use in pregnancy].
Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants Steglatro is not recommended during breast feeding.

4.7 Effects on Ability to Drive and Use Machines

Ertugliflozin has no or negligible influence on the ability to drive or use machines. Patients should be alerted to the risk of hypoglycaemia when Steglatro 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.

The safety and tolerability of Steglatro were evaluated in seven Phase 3 studies which included 4,859 subjects who were randomised and received at least 1 dose of study medication (3,409 of whom were exposed to Steglatro with a mean exposure duration of approximately 51 weeks). The overall incidence of patients with 1 or more adverse events was not notably different across the Steglatro 5 mg (62.6%), Steglatro 15 mg (62.0%), and placebo (64.8%) groups.

Pool of placebo-controlled trials evaluating Steglatro 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. Steglatro 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 Steglatro with a mean exposure duration of approximately 25 weeks. Patients received Steglatro 5 mg (N=519), Steglatro 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 Steglatro 5 mg (45.5%), Steglatro 15 mg (50.4%), and placebo (51.1%) groups. The incidence of non-fatal serious adverse events was low and similar in the Steglatro 5 mg and 15 mg groups relative to the placebo group (3.3%, 2.4%, and 2.9% for the Steglatro 5 mg, Steglatro 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 Steglatro 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 1 are presented by System Organ Class (SOC).

Description of selected adverse reactions.

Volume depletion.

Steglatro 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 Steglatro compared to those treated with placebo; events were reported by 0.8%, 1.0%, and 1.7% of patients treated with Steglatro 5 mg, Steglatro 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 Steglatro 5 mg, Steglatro 15 mg, and placebo, respectively. Steglatro 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.

Across the clinical program, ketoacidosis was identified in 3 of 3,409 (0.1%) Steglatro-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 play a role in the renal function abnormalities observed with Steglatro [see Section 4.4 Special Warnings and Precautions for Use, Use in patients with renal impairment].
Renal-related adverse reactions (e.g. acute kidney injury, renal impairment, acute prerenal failure) may occur in patients treated with ertugliflozin, particularly in patients with moderate renal impairment where the incidence of renal-related adverse reactions was 2.5%, 1.3%, and 0.6% 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 2. The incidence in clinical trials was low; hypoglycaemia may be higher when Steglatro 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 Steglatro 5 mg, Steglatro 15 mg, and placebo, respectively. In females, discontinuation due to genital mycotic infections occurred in 0.6% and 0% of patients treated with Steglatro 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 Steglatro 5 mg, Steglatro 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 Steglatro and placebo, respectively. In rare instances, phimosis was reported and sometimes circumcision was performed [see Section 4.4 Special Warnings and Precautions for Use].

Laboratory tests.

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 Steglatro. Mean percent changes from baseline in LDL-C relative to placebo were 2.6% and 5.4% with Steglatro 5 mg and Steglatro 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 Steglatro 5 mg, 4.8 g/L (3.5%) with Steglatro 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 Steglatro 5 mg, Steglatro 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 Steglatro 5 mg, 0.08 mmol/L (8.5%) with Steglatro 15 mg, and 0.01 mmol/L (1.9%) with placebo. The range of mean baseline serum phosphate was 1.14 to 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 Steglatro 5 mg, 0.08 mmol/L (7.8%) with Steglatro 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.

Across the clinical program, a total of 876 (25.7%) patients treated with Steglatro were 65 years and older, and 152 (4.5%) patients treated with Steglatro 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 Steglatro 5 mg, Steglatro 15 mg, and comparator, respectively [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)].

Renal impairment.

The efficacy and safety of Steglatro were evaluated in a study of patients with moderate renal impairment. In this study, 202 patients exposed to Steglatro had an eGFR between 45 and 60 mL/min/1.73 m2 and 111 patients exposed to Steglatro had an eGFR between 30 and 45 mL/min/1.73 m2. The glucose-lowering efficacy of Steglatro decreased in patients with worsening renal function. Compared to placebo-treated patients, patients with moderate renal impairment treated with Steglatro had increases in serum creatinine and decreases in eGFR, and increased risks for renal-related 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)].

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).
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.
In the event of an overdose, 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. Removal of ertugliflozin by haemodialysis has not been studied.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Steglatro tablets contain ertugliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor.
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 Steglatro 100 mg (6.7 times the maximum recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with 100 mg ertugliflozin.

Clinical trials.

The efficacy and safety of Steglatro have been studied in 7 multi-centre, randomised, double-blind, placebo- or active comparator-controlled, Phase 3 clinical studies involving 4,863 patients with type 2 diabetes. These studies included White, Hispanic, Black, Asian, and other racial and ethnic groups, and patients with an average age of approximately 57.8 years.
Steglatro has been studied as monotherapy and in combination with metformin and/or a dipeptidyl peptidase 4 (DPP-4) inhibitor. In a study in patients with type 2 diabetes with moderate renal impairment, Steglatro has also been studied in combination with current diabetes treatments, including insulin and a sulfonylurea.
In patients with type 2 diabetes as monotherapy or in combination with metformin and/or a DPP-4 inhibitor, treatment with Steglatro produced clinically and statistically significant improvements in HbA1c and FPG compared to placebo after 26 weeks of treatment. In a 52-week study, glycaemic control (HbA1c) was maintained with ertugliflozin treatment.
In patients with type 2 diabetes treated with Steglatro, 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.

Monotherapy.

A total of 461 patients with type 2 diabetes inadequately controlled on diet and exercise participated in a randomised, double-blind, multi-centre, 26-week, placebo-controlled study to evaluate the efficacy and safety of Steglatro monotherapy. These patients, who were not receiving any background antihyperglycaemic treatment, were randomised to Steglatro 5 mg, Steglatro 15 mg, or placebo administered once daily.
At Week 26, treatment with Steglatro at 5 mg or 15 mg daily provided statistically significant improvements in HbA1c, FPG, body weight, and 2-hour post-prandial glucose (PPG) compared to placebo. Steglatro also resulted in a greater proportion of patients achieving an HbA1c < 7% compared with placebo (see Table 3 and Figure 3).

Steglatro 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 Steglatro in combination with metformin. Patients were randomised to Steglatro 5 mg, Steglatro 15 mg, or placebo administered once daily in addition to continuation of background metformin therapy.
At Week 26, treatment with Steglatro at 5 mg or 15 mg daily provided statistically significant improvements in HbA1c, FPG, and body weight compared to placebo. Treatment with Steglatro at 5 mg or 15 mg daily provided a statistically significant improvement in systolic and diastolic blood pressure compared to placebo. Steglatro also resulted in a greater proportion of patients achieving an HbA1c < 7% compared to placebo (see Table 4 and Figure 4).

Active-controlled study of Steglatro 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 Steglatro in combination with metformin. These patients, who were receiving metformin monotherapy (≥ 1,500 mg/day), were randomised to Steglatro 5 mg, Steglatro 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, Steglatro 5 mg and 15 mg provided similar reductions in HbA1c from baseline compared to glimepiride when added to metformin therapy. Steglatro 15 mg was non-inferior to glimepiride after 52 weeks of treatment. At Week 52, Steglatro 15 mg resulted in a statistically significant difference in change from baseline for body weight compared to glimepiride (-3.4 kg for Steglatro 15 mg vs. +0.9 kg for glimepiride; treatment difference -4.3 kg; p < 0.001) (see Table 5 and Figure 5).

Factorial study with Steglatro and Januvia (sitagliptin) 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 Steglatro 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: Steglatro 5 mg or 15 mg, Januvia 100 mg, or Januvia 100 mg in combination with 5 mg or 15 mg Steglatro administered once daily in addition to continuation of background metformin therapy.
At Week 26, Steglatro 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 6). More patients receiving Steglatro 5 mg or 15 mg in combination with Januvia 100 mg achieved an HbA1c < 7% compared to the individual components. Treatment with Steglatro 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.

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

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 Steglatro. Patients were randomised to Steglatro 5 mg, Steglatro 15 mg, or placebo administered once daily in addition to continuation of background metformin and Januvia therapy.
At Week 26, treatment with Steglatro at 5 mg or 15 mg daily provided statistically significant improvements in HbA1c, FPG, body weight, and systolic blood pressure compared to placebo. Steglatro also resulted in a greater proportion of patients achieving an HbA1c < 7% compared to placebo (see Table 7).

Initial combination therapy of Steglatro and Januvia (sitagliptin).

A total of 291 patients with type 2 diabetes inadequately controlled on diet and exercise participated in a randomised, double-blind, multi-centre, placebo-controlled 26-week study to evaluate the efficacy and safety of Steglatro in combination with Januvia. These patients, who were not receiving any background antihyperglycaemic treatment, were randomised to Steglatro 5 mg or Steglatro 15 mg in combination with Januvia (100 mg) or to placebo once daily.
At Week 26, treatment with Steglatro 5 mg and 15 mg in combination with Januvia at 100 mg daily provided significant improvements in HbA1c, FPG, body weight, 2-hour PPG, and systolic blood pressure compared to placebo. Steglatro 5 mg and 15 mg in combination with Januvia at 100 mg daily also resulted in a significantly higher proportion of patients achieving an HbA1c < 7% compared with placebo (see Table 8).

Moderate renal impairment.

The efficacy of Steglatro was also assessed separately in a dedicated study of diabetic patients with moderate renal impairment (468 patients with eGFR ≥ 30 to < 60 mL/min/1.73 m2). The pre-specified primary efficacy hypothesis was not met. However, the glycaemic efficacy analysis may have been confounded by use of metformin. A post-hoc analysis which excluded data from metformin users showed some evidence of greater reduction in A1C with ertugliflozin, with the higher 15 mg dose. In patients with Stage 3A CKD (eGFR > 45 and < 60 mL/min/1.73 m2), LS mean (95% CI) placebo-corrected reductions in HbA1c of -0.20% (-0.48%, 0.08%) and -0.35% (-0.64%, -0.05%) were observed for ertugliflozin 5 mg and ertugliflozin 15 mg, respectively.

5.2 Pharmacokinetic Properties

The pharmacokinetics of ertugliflozin are similar in healthy subjects and patients with type 2 diabetes. The steady state mean plasma 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.

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, Steglatro was administered without regard to meals.

Distribution.

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.

Metabolism.

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%).

Excretion.

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.

Special populations.

Renal impairment.

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 Steglatro, 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 [see Section 4.4 Special Warnings and Precautions for Use]. The plasma protein binding of ertugliflozin was unaffected in patients with renal impairment.

Hepatic impairment.

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.

Paediatric.

No studies with Steglatro have been performed in paediatric patients.

Effects of age, body weight, gender, and race.

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

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ertugliflozin tablets contain the inactive ingredients: microcrystalline cellulose, lactose monohydrate, sodium starch glycollate Type A, and magnesium stearate. The film coating contains hypromellose, lactose monohydrate, macrogol 3350, triacetin, 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 7 tablets (starter packs) and 28 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

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.
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.

Chemical structure.

The chemical structure is:

CAS number.

The CAS Registry Number is 1210344-83-4.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes