STEGLUJAN 5mg / 100mg tablets medication leaflet

Steglujan 5 mg/100 mg film-coated tablets

Steglujan 15 mg/100 mg film-coated tablets

Steglujan 5 mg/100 mg film-coated tablets

Each tablet contains ertugliflozin L-pyroglutamic acid, equivalent to 5 mg of ertugliflozin, andsitagliptin phosphate monohydrate, equivalent to 100 mg of sitagliptin.

Steglujan 15 mg/100 mg film-coated tablets

Each tablet contains ertugliflozin L-pyroglutamic acid, equivalent to 15 mg of ertugliflozin, andsitagliptin phosphate monohydrate, equivalent to 100 mg of sitagliptin.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Steglujan 5 mg/100 mg film-coated tablets

Beige, 12 x 7.4 mm, almond-shaped, film-coated tablets debossed with “554” on one side and plain onthe other side.

Steglujan 15 mg/100 mg film-coated tablets

Brown, 12 x 7.4 mm, almond-shaped, film-coated tablets debossed with “555” on one side and plainon the other side.

Steglujan is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct todiet and exercise:

* to improve glycaemic control when metformin and/or a sulphonylurea (SU) and one of themonocomponents of Steglujan do not provide adequate glycaemic control.

* in patients already being treated with the combination of ertugliflozin and sitagliptin as separatetablets.

(For study results with respect to combinations and effects on glycaemic control, see sections 4.4, 4.5,and 5.1)

The recommended starting dose is 5 mg ertugliflozin/100 mg sitagliptin once daily. In patientstolerating the starting dose, the dose may be increased to 15 mg ertugliflozin/100 mg sitagliptin, oncedaily, if additional glycaemic control is needed.

For patients treated with ertugliflozin who are being switched to Steglujan, the dose of ertugliflozincan be maintained.

When Steglujan is used in combination with insulin or an insulin secretagogue, a lower dose of insulinor the insulin secretagogue may be required to reduce the risk of hypoglycaemia (see sections 4.4, 4.5,and 4.8).

In patients with volume depletion, correcting this condition prior to initiation of Steglujan isrecommended (see section 4.4).

If a dose is missed, it should be taken as soon as the patient remembers. Patients should not take twodoses of Steglujan on the same day.

Assessment of renal function is recommended prior to initiation of Steglujan and periodicallythereafter (see section 4.4).

Initiation of this medicinal product is not recommended in patients with an estimated glomerularfiltration rate (eGFR) less than 45 mL/min/1.73 m2 or creatinine clearance (CrCl) less than 45 mL/min(see section 4.4).

In patients with an eGFR ≥ 45 to < 60 mL/min/1.73 m2, Steglujan should be initiated at 5 mg/100 mgand up-titrated to 15 mg/100 mg as needed for glycaemic control.

Because the glycaemic lowering efficacy of ertugliflozin is reduced in patients with moderate renalimpairment and likely absent in patients with severe renal impairment, if further glycaemic control isneeded, the addition of other anti-hyperglycaemic agents should be considered (see section 4.4).

Steglujan should be discontinued when eGFR is persistently less than 45 mL/min/1.73 m2 or CrCl ispersistently less than 45 mL/min.

The fixed-dose combination of ertugliflozin and sitagliptin should not be used in patients with severerenal impairment, with end-stage renal disease (ESRD), or receiving dialysis, as there is no clinicaldata to support effectiveness in these patients.

No dose adjustment of Steglujan is necessary in patients with mild or moderate hepatic impairment.

Steglujan has not been studied in patients with severe hepatic impairment and is not recommended foruse in these patients (see section 5.2).

No dose adjustment of Steglujan is recommended based on age. Elderly patients are more likely tohave decreased renal function. Because renal function abnormalities can occur after initiatingertugliflozin, and sitagliptin is known to be substantially excreted by the kidneys, renal functionshould be assessed more frequently in elderly patients. Renal function and risk of volume depletionshould be taken into account (see sections 4.4 and 4.8).

The safety and efficacy of Steglujan in children under 18 years of age have not been established. Nodata are available.

Steglujan should be taken orally once daily in the morning, with or without food. In case ofswallowing difficulties, the tablet could be broken or crushed as it is an immediate-release dosageform.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Steglujan should not be used in patients with type 1 diabetes mellitus. It may increase the risk ofdiabetic ketoacidosis (DKA) in these patients.

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors has been associated with a risk of developing acutepancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis:persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuationof sitagliptin (with or without supportive treatment), but very rare cases of necrotising orhaemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Steglujan andother potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed,

Steglujan should not be restarted. Caution should be exercised in patients with a history ofpancreatitis.

Hypotension/Volume depletion

Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction.

Therefore, symptomatic hypotension may occur after initiating Steglujan (see section 4.8), particularlyin patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2 or CrCl less than60 mL/min), elderly patients (≥ 65 years), patients on diuretics, or patients on anti-hypertensivetherapy with a history of hypotension. Before initiating Steglujan, volume status should be assessedand corrected if indicated. Monitor for signs and symptoms after initiating therapy.

Due to its mechanism of action, ertugliflozin induces an osmotic diuresis and increases serumcreatinine and decreases eGFR. Increases in serum creatinine and decreases in eGFR were greater inpatients with moderate renal impairment (see section 4.8).

In case of conditions that may lead to fluid loss (e.g., gastrointestinal illness), careful monitoring ofvolume status (e.g., physical examination, blood pressure measurements, laboratory tests includinghaematocrit) and electrolytes is recommended for patients receiving Steglujan. Temporary interruptionof treatment with Steglujan should be considered until the fluid loss is corrected.

Rare cases of DKA, including life-threatening and fatal cases, have been reported in clinical trials andpost-marketing in patients treated with sodium glucose co-transporter-2 (SGLT2) inhibitors, includingertugliflozin. In a number of cases, the presentation of the condition was atypical with only moderatelyincreased blood glucose values, below 14 mmol/L (250 mg/dL). It is not known if DKA is more likelyto occur with higher doses of ertugliflozin.

The risk of DKA must be considered in the event of non-specific symptoms such as nausea, vomiting,anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue orsleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur,regardless of blood glucose level.

In patients where DKA is suspected or diagnosed, treatment with Steglujan should be discontinuedimmediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acuteserious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement ofblood ketone levels is preferred to urine. Treatment with Steglujan may be restarted when the ketonevalues are normal and the patient’s condition has stabilised.

Before initiating Steglujan, factors in the patient history that may predispose to ketoacidosis should beconsidered.

Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g.,type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) orpatients with a history of pancreatitis), patients with conditions that lead to restricted food intake orsevere dehydration, patients for whom insulin doses are reduced and patients with increased insulinrequirements due to acute medical illness, surgery, or alcohol abuse. SGLT2 inhibitors should be usedwith caution in these patients.

Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitortreatment is not recommended, unless another clear precipitating factor is identified and resolved.

The safety and efficacy of Steglujan in patients with type 1 diabetes have not been established and

Steglujan should not be used for treatment of patients with type 1 diabetes. Limited data from clinicaltrials suggest that DKA occurs with common frequency when patients with type 1 diabetes are treatedwith SGLT2 inhibitors.

In a long-term cardiovascular outcomes study VERTIS CV (eValuation of ERTugliflozin effIcacy and

Safety, CardioVascular), a study in patients with type 2 diabetes mellitus and establishedatherosclerotic cardiovascular disease, non-traumatic lower limb amputations (primarily of the toe)were reported with an incidence of 2% (0.57 subjects with event per 100 patient-years), 2.1% (0.60subjects 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. The event rates of lower limbamputations were 0.75 and 0.96 versus 0.74 events per 100 patient-years for ertugliflozin 5 mg andertugliflozin 15 mg versus placebo, respectively. An increase in cases of lower limb amputation(primarily of the toe) has been observed in long-term clinical studies in type 2 diabetes mellitus with

SGLT2 inhibitors. It is not known whether this constitutes a class effect. It is important to counselpatients with diabetes on routine preventative foot care.

The efficacy of ertugliflozin for glycaemic control is dependent on renal function, and glycaemicefficacy is reduced in patients who have moderate renal impairment and likely absent in patients withsevere renal impairment (see section 4.2).

Steglujan should not be initiated in patients with an eGFR below 45 mL/min/1.73 m2 or CrCl below45 mL/min. Steglujan should be discontinued when eGFR is persistently below 45 mL/min/1.73 m2 or

CrCl is persistently below 45 mL/min due to a reduction of efficacy.

Monitoring of renal function is recommended as follows:

- Prior to Steglujan initiation and periodically during treatment (see section 4.2).

- More frequently in patients with an eGFR below 60 mL/min/1.73 m2 or a CrCl below60 mL/min.

Hypoglycaemia with concomitant use with insulin and insulin secretagogues

Ertugliflozin may increase the risk of hypoglycaemia when used in combination with insulin and/or aninsulin secretagogue, which are known to cause hypoglycaemia (see section 4.8). Hypoglycaemia hasbeen observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, alower dose of insulin or insulin secretagogue may be required to minimise the risk of hypoglycaemiawhen used in combination with Steglujan (see sections 4.2 and 4.5).

Genital mycotic infections

Ertugliflozin increases the risk of genital mycotic infections. In trials with SGLT2 inhibitors, patientswith a history of genital mycotic infections and uncircumcised males were more likely to developgenital mycotic infections (see section 4.8). Patients should be monitored and treated appropriately.

Urinary tract infections

Urinary glucose excretion may be associated with an increased risk of urinary tract infections (seesection 4.8). Temporary interruption of ertugliflozin should be considered when treatingpyelonephritis or urosepsis.

Post-marketing cases of necrotising fasciitis of the perineum, (also known as Fournier’s gangrene),have been reported in female and male patients taking SGLT2 inhibitors. This is a rare but serious andpotentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.

Patients should be advised to seek medical attention if they experience a combination of symptoms ofpain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be awarethat either urogenital infection or perineal abscess may precede necrotising fasciitis. If Fournier’sgangrene is suspected, Steglujan should be discontinued and prompt treatment (including antibioticsand surgical debridement) should be instituted.

Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin havebeen reported (see section 4.8). These reactions include anaphylaxis, angioedema, and exfoliative skinconditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first3 months after initiation of treatment, with some reports occurring after the first dose. If ahypersensitivity reaction is suspected, Steglujan should be discontinued. Other potential causes for theevent should be assessed, and alternative treatment for diabetes initiated.

Bullous pemphigoid

There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitorsincluding sitagliptin. If bullous pemphigoid is suspected, Steglujan should be discontinued.

Elderly patients may be at an increased risk of volume depletion and renal impairment. Patients65 years and older treated with ertugliflozin, had a higher incidence of adverse reactions related tovolume depletion compared to younger patients. In a long-term cardiovascular outcomes study

VERTIS CV, safety and efficacy were similar for patients age 65 years and older compared to patientsyounger than 65 (see sections 4.2 and 4.8).

Cardiac failure

There is no experience in clinical studies with Steglujan in New York Heart Association (NYHA)class IV.

Due to the mechanism of action of ertugliflozin, patients taking Steglujan will test positive for glucosein their urine. Alternative methods should be used to monitor glycaemic control.

Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG areunreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Alternative methodsshould be used to monitor glycaemic control.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Pharmacokinetic drug interaction studies with Steglujan have not been performed; however, suchstudies have been conducted with ertugliflozin and sitagliptin, the individual active substances of

Steglujan.

Ertugliflozin

Ertugliflozin may add to the diuretic effect of diuretics and may increase the risk of dehydration andhypotension (see section 4.4).

Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Ertugliflozin mayincrease the risk of hypoglycaemia when used in combination with insulin and/or an insulinsecretagogue. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reducethe risk of hypoglycaemia when used in combination with Steglujan (see sections 4.2, pct. 4.4, and 4.8).

Effects of other medicinal products on the pharmacokinetics of ertugliflozin

Metabolism by UGT1A9 and UGT2B7 is the primary clearance mechanism for ertugliflozin.

Interaction studies conducted in healthy subjects, using a single dose design, suggest that thepharmacokinetics of ertugliflozin are not altered by sitagliptin, metformin, glimepiride, or simvastatin.

Multiple-dose administration of rifampicin (a uridine 5’-diphospho-glucuronosyltransferase [UGT]and cytochrome P450 [CYP] inducer) decreases ertugliflozin area under the concentration-time curve(AUC) and maximum plasma concentration (Cmax) by 39% and 15%, respectively. This decrease inexposure is not considered clinically relevant and therefore, no dose adjustment is recommended. Aclinically relevant effect with other inducers (e.g., carbamazepine, phenytoin, phenobarbital) is notexpected.

The impact of UGT inhibitors on the pharmacokinetics of ertugliflozin has not been studied clinically,but potential increase in ertugliflozin exposure due to UGT inhibition is not considered to be clinicallyrelevant.

Effects of ertugliflozin on the pharmacokinetics of other medicinal products

Interaction studies conducted in healthy volunteers suggest that ertugliflozin had no clinically relevanteffect on the pharmacokinetics of sitagliptin, metformin, and glimepiride.

Coadministration of simvastatin with ertugliflozin resulted in a 24% and 19% increase in AUC and

Cmax of simvastatin, respectively, and 30% and 16% increase in AUC and Cmax of simvastatin acid,respectively. The mechanism for the small increases in simvastatin and simvastatin acid is unknownand is not perpetrated through organic anion transporting polypeptide (OATP) inhibition byertugliflozin. These increases are not considered to be clinically meaningful.

Sitagliptin

Effects of other medicinal products on sitagliptin

Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. In vitrostudies indicate that the primary enzyme responsible for the limited metabolism of sitagliptin is

CYP3A4, with contribution from CYP2C8.

Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severerenal impairment or ESRD. For this reason, it is possible that potent CYP3A4 inhibitors (i.e.,ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin inpatients with severe renal impairment or ESRD.

Interaction studies conducted in patients with type 2 diabetes or healthy volunteers suggest thatmetformin and ciclosporin had no clinically relevant effect on the pharmacokinetics of sitagliptin.

Effects of sitagliptin on other medicinal products

In drug interaction studies, sitagliptin did not have clinically meaningful effects on thepharmacokinetics of the following: metformin, rosiglitazone, glyburide, simvastatin, warfarin, and oralcontraceptives.

Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mgdigoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin wasincreased on average by 11% and the plasma Cmax on average by 18%. No dose adjustment of digoxinis recommended. However, patients at risk of digoxin toxicity should be monitored for this whensitagliptin and digoxin are administered concomitantly.

There are no data from the use of Steglujan in pregnant women. There are limited data from the use ofertugliflozin in pregnant women. Based on results from animal studies, ertugliflozin may affect renaldevelopment and maturation (see section 5.3). Therefore, Steglujan should not be used duringpregnancy.

There is no information regarding the presence of Steglujan or its individual components in humanmilk, the effects on the breast-fed infant, or the effects on milk production. No studies in lactatinganimals have been conducted with the combined components of Steglujan. Ertugliflozin and sitagliptinare present in the milk of lactating rats. Ertugliflozin caused effects in the offspring of lactating rats.

Pharmacologically mediated effects were observed in juvenile rats treated with ertugliflozin (seesection 5.3). Since human kidney maturation occurs in utero and during the first 2 years of life whenexposure from breast-feeding may occur, a risk to newborns/infants cannot be excluded. Steglujanshould not be used during breast-feeding.

The effect of Steglujan on fertility in humans has not been studied. No effects of ertugliflozin orsitagliptin on fertility were observed in animal studies (see section 5.3).

Steglujan has no or negligible influence on the ability to drive and use machines. However, whendriving or using machines, it should be taken into account that dizziness and somnolence have beenreported with sitagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when

Steglujan is used in combination with insulin or an insulin secretagogue and to the elevated risk ofadverse reactions related to volume depletion, such as postural dizziness (see sections 4.2, pct. 4.4, and4.8).

Ertugliflozin and sitagliptin

The safety of concomitantly administered ertugliflozin and sitagliptin has been evaluated in990 patients with type 2 diabetes mellitus treated for 26 weeks in three studies; a factorial study ofertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg once daily compared to theindividual components, a placebo-controlled study of ertugliflozin 5 mg or 15 mg as add-on therapy tositagliptin 100 mg and metformin once daily, and a placebo-controlled study of initial therapy withertugliflozin 5 mg or 15 mg once daily in combination with sitagliptin 100 mg once daily (seesection 5.1). The incidence and type of adverse reactions in these three studies were similar to theadverse reactions seen with the individual monotherapies ertugliflozin and sitagliptin as describedbelow in Table 1.

Ertugliflozin

The safety and tolerability of ertugliflozin were assessed in 7 placebo- or active comparator-controlledstudies with a total of 3 409 patients with type 2 diabetes mellitus treated with ertugliflozin 5 mg or15 mg. In addition, the safety and tolerability of ertugliflozin in patients with type 2 diabetes andestablished atherosclerotic cardiovascular disease were assessed in VERTIS CV (see section 5.1) witha total of 5 493 patients treated with ertugliflozin 5 mg or 15 mg and a mean duration of exposure of2.9 years.

Pool of placebo-controlled trials

The primary assessment of safety was conducted in a pool of three 26-week, placebo-controlled trials.

Ertugliflozin was used as monotherapy in one trial and as add-on therapy in two trials (seesection 5.1). These data reflect exposure of 1 029 patients to ertugliflozin with a mean exposureduration of approximately 25 weeks. Patients received ertugliflozin 5 mg (N=519), ertugliflozin 15 mg(N=510), or placebo (N=515) once daily.

The most commonly reported adverse reactions across the clinical program were urinary tractinfections, vulvovaginal mycotic infection and other female genital mycotic infections. Serious DKAoccurred rarely (see section 4.4).

Sitagliptin

Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported.

Hypoglycaemia has been reported in combination with sulphonylurea (4.7%-13.8%) and insulin(9.6%) (see section 4.4).

Adverse reactions listed below are classified according to frequency and system organ class (SOC),within each frequency grouping, adverse reactions are presented in the order of decreasingseriousness. Frequency categories are defined according to the following convention: very common(≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to< 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data).

Table 1: Adverse reactions from placebo- and active comparator-controlled clinical trials andpost-marketing experience

System organ class Adverse reaction

Frequency

Very common Urinary tract infections†,1

Vulvovaginal mycotic infection and other femalegenital mycotic infections*,†,1

Common Balanitis candida and other male genital mycoticinfections*,†,1

Not known Necrotising fasciitis of the perineum (Fournier’sgangrene)*,a

Rare Thrombocytopenia2

Not known Hypersensitivity reactions including anaphylacticresponses*,a,2

Common Hypoglycaemia*,†,1,2

Rare DKA*,†,1

Common Headache2

Uncommon Dizziness2

Common Volume depletion*,†,1

Not known Interstitial lung diseasea,2

System organ class Adverse reaction

Frequency

Uncommon Constipation2

Fatal and non-fatal haemorrhagic and necrotising

Not known pancreatitis*,a,2

Acute pancreatitisa,*,b,2

Not known Vomitinga,2

Not known

Uncommon Pruritusa,2

Not known Exfoliative skin conditions including

Stevens-Johnson syndromea,*,2

Not known Angioedemaa,*,2

Not known Bullous pemphigoida,*,2

Not known Cutaneous vasculitisa,*,2

Not known Rasha,*,1,2

Not known Urticariaa,*,2

Not known Arthropathya,2

Not known Back paina,2

Not known Arthralgiaa,2

Not known Myalgiaa,2

Common Increased urination‡,1

Uncommon Dysuria1, Blood creatinine increased/Glomerularfiltration rate decreased†,1

Not known Acute renal failurea,2

Not known Impaired renal functiona,2

Common Vulvovaginal pruritus1

Common Thirst§,1

Common Serum lipids changed¶,1, Haemoglobinincreased**,1, BUN increased¶¶,11 Adverse reaction with ertugliflozin.2 Adverse reaction with sitagliptin.

* See section 4.4.† See subsections below for additional information.

‡ Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.§ Includes: thirst and polydipsia.¶ Mean percent changes from baseline for ertugliflozin 5 mg and 15 mg versus placebo, respectively,were low-density lipoprotein cholesterol (LDL-C) 5.8% and 8.4% versus 3.2%; total cholesterol2.8% and 5.7% versus 1.1%; however, high-density lipoprotein cholesterol (HDL-C) 6.2% and7.6% versus 1.9%. Median percent changes from baseline for ertugliflozin 5 mg and 15 mg versusplacebo, respectively, were triglycerides -3.9% and -1.7% versus 4.5%.

** The proportion of subjects having at least 1 increase in haemoglobin > 2.0 g/dL was higher in theertugliflozin 5 mg and 15 mg groups (4.7% and 4.1%, respectively) compared to the placebo group(0.6%).

¶¶ The proportion of subjects having any occurrence of blood urea nitrogen (BUN) values ≥50%increase and value >upper limit of normal (ULN) was numerically higher in the ertugliflozin 5 mggroup and higher in the 15 mg group (7.9% and 9.8%, respectively) relative to the placebo group(5.1%).

a Adverse reactions were identified through post-marketing surveillance.b See Sitagliptin cardiovascular outcomes study (TECOS) below.

Ertugliflozin

Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction andadverse reactions related to volume depletion. In the pool of placebo-controlled studies, the incidenceof adverse events related to volume depletion (dehydration, dizziness postural, presyncope, syncope,hypotension and orthostatic hypotension) was low (< 2%) and not notably different across theertugliflozin and placebo groups. In the subgroup analyses in the broader pool of phase 3 studies,subjects with eGFR < 60 mL/min/1.73 m2, subjects ≥ 65 years of age and subjects on diuretics had ahigher incidence of volume depletion in the ertugliflozin groups relative to the comparator group (seesections 4.2 and 4.4). In subjects with eGFR < 60 mL/min/1.73 m2, the incidence was 5.1%, 2.6% and0.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and the comparator group and for subjects with eGFR45 to < 60 mL/min/1.73 m2, the incidence was 6.4%, 3.7% and 0% respectively.

In the pool of placebo-controlled studies, the incidence of documented hypoglycaemia was increasedfor ertugliflozin 5 mg and 15 mg (5% and 4.5%) compared to placebo (2.9%). In this population, theincidence of severe hypoglycaemia was 0.4% in each group. When ertugliflozin was used asmonotherapy, the incidence of hypoglycaemic events in the ertugliflozin groups was 2.6% in bothgroups and 0.7% in the placebo group. When used as add-on to metformin, the incidence ofhypoglycaemic events was 7.2% in the ertugliflozin 5 mg group, 7.8% in the ertugliflozin 15 mggroup and 4.3% in the placebo group.

When ertugliflozin was added to metformin and compared to sulphonylurea, the incidence ofhypoglycaemia was higher for the sulphonylurea (27%) compared to ertugliflozin (5.6% and 8.2% forertugliflozin 5 mg and 15 mg, respectively).

In the VERTIS CV sub-studies, when ertugliflozin was added to insulin with or without metformin,the incidences of documented hypoglycaemia were 39.4%, 38.9% and 37.5% for ertugliflozin 5 mg,ertugliflozin 15 mg and placebo, respectively. When ertugliflozin was added to a sulphonylurea, theincidences of hypoglycaemia were 7.3%, 9.3% and 4.2% for ertugliflozin 5 mg, ertugliflozin 15 mgand placebo, respectively. When ertugliflozin was added to metformin and a sulphonylurea, theincidences of hypoglycaemia were 20%, 26.5% and 14.5% for ertugliflozin 5 mg, ertugliflozin 15 mgand placebo, respectively.

In patients with moderate renal impairment taking insulins, sulphonylurea, or meglitinides asbackground medicinal products, documented hypoglycaemia was 36%, 27% and 36% for ertugliflozin5 mg, ertugliflozin 15 mg, and placebo, respectively (see sections 4.2, pct. 4.4, and 4.5).

In VERTIS CV, ketoacidosis was identified in 19 (0.3%) ertugliflozin-treated patients and in 2 (0.1%)placebo-treated patients. Across 7 other phase 3 clinical trials in the ertugliflozin developmentprogram, ketoacidosis was identified in 3 (0.1%) ertugliflozin-treated patients and 0 (0%) ofcomparator-treated patients (see section 4.4).

Blood creatinine increased/Glomerular filtration rate decreased and renal-related events

Initial increases in mean creatinine and decreases in mean eGFR in patients treated with ertugliflozinwere generally transient during continuous treatment. Patients with moderate renal impairment atbaseline had larger mean changes that did not return to baseline at Week 26; these changes reversedafter treatment discontinuation.

In VERTIS CV, treatment with ertugliflozin was associated with an initial decrease in mean eGFR (at

Week 6, -2.7, -3.8 and -0.4 mL/min/1.73 m2 in the ertugliflozin 5 mg, ertugliflozin 15 mg and placebogroups, respectively) followed by a return toward baseline. Long-term, continued treatment withertugliflozin was associated with a slower decline in eGFR compared to placebo (up to week 260).

In VERTIS CV, the incidences of renal-related adverse reactions (e.g., acute kidney injury, renalimpairment, acute prerenal failure) were 4.2%, pct. 4.3% and 4.7% in patients treated with ertugliflozin5 mg, ertugliflozin 15 mg and placebo respectively in the overall population and were 9.7%, 10% and10.2% in patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo respectively inpatients with an eGFR from 30 to less than 60 mL/min/1.73 m2.

Genital mycotic infections

In the pool of three placebo-controlled clinical trials, female genital mycotic infections (e.g., genitalcandidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginalmycotic infection, vulvovaginitis) occurred in 9.1%, 12%, and 3% of females treated with ertugliflozin5 mg, ertugliflozin 15 mg, and placebo, respectively. In females, discontinuation due to genitalmycotic infections occurred in 0.6% and 0% of patients treated with ertugliflozin and placebo,respectively (see section 4.4).

In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genitalinfection, genital infection fungal) occurred in 3.7%, 4.2%, and 0.4% of males treated withertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. Male genital mycotic infectionsoccurred more commonly in uncircumcised males. In males, discontinuations due to genital mycoticinfections occurred in 0.2% and 0% of patients treated with ertugliflozin and placebo, respectively. Inrare instances, phimosis was reported and sometimes circumcision was performed (see section 4.4).

Urinary tract infections

In VERTIS CV, urinary tract infections occurred in 12.2%, 12% and 10.2% of patients treated withertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. The incidences of serious urinarytract infections were 0.9%, 0.4%, and 0.8% with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo,respectively.

Across 7 other phase 3 clinical trials in the ertugliflozin development program, the incidences ofurinary tract infections were 4% and 4.1% for ertugliflozin 5 mg and 15 mg groups and 3.9% forplacebo. Most of the events were mild or moderate, and no serious cases were reported.

Sitagliptin

In addition to the adverse reactions described in the table above, adverse experiences reportedregardless of causal relationship to medication and occurring in at least 5% and more commonly inpatients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis.

Additional adverse experiences reported regardless of causal relationship to medication that occurredmore frequently in patients treated with sitagliptin (not reaching the 5% level, but occurring with anincidence of > 0.5% higher with sitagliptin than that in the control group) included osteoarthritis andpain in extremity.

Some adverse reactions were observed more frequently in studies of combination use of sitagliptinwith other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These includedhypoglycaemia (frequency very common with the combination of sulphonylurea and metformin),influenza (common with insulin (with or without metformin)), nausea and vomiting (common withmetformin), flatulence (common with metformin or pioglitazone), constipation (common with thecombination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or thecombination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin),and dry mouth (uncommon with insulin (with or without metformin)).

TECOS (trial evaluating cardiovascular outcomes with sitagliptin)

The cardiovascular safety study with sitagliptin (TECOS) included 7 332 patients treated withsitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2),and 7 339 patients treated with placebo in the intention-to-treat population. Both treatments wereadded to usual care targeting regional standards for haemoglobin A1c (HbA1c) and cardiovascular(CV) risk factors. The overall incidence of serious adverse events in patients receiving sitagliptin wassimilar to that in patients receiving placebo.

In the intention-to-treat population, among patients who were using insulin and/or a sulphonylurea atbaseline, the incidence of severe hypoglycaemia was 2.7% in sitagliptin-treated patients and 2.5% inplacebo-treated patients; among patients who were not using insulin and/or a sulphonylurea atbaseline, the incidence of severe hypoglycaemia was 1% in sitagliptin-treated patients and 0.7% inplacebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3% insitagliptin-treated patients and 0.2% in placebo-treated patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of an overdose with Steglujan, employ the usual supportive measures (e.g., removeunabsorbed material from the gastrointestinal tract, employ clinical monitoring including obtaining anelectrocardiogram, 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 andmultiple doses up to 100 mg daily for 2 weeks. No potential acute symptoms and signs of overdosewere identified. Removal of ertugliflozin by haemodialysis has not been studied.

Sitagliptin

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin wereadministered. Minimal increases in QTc, not considered to be clinically relevant, were observed in onestudy at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinicalstudies. In phase 1 multiple-dose studies, there were no dose-related clinical adverse reactionsobserved with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mgper day for periods of up to 28 days.

Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5% of the dose was removedover a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinicallyappropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose loweringdrugs, ATC code: A10BD24.

Steglujan combines two antihyperglycaemic agents with complementary mechanisms of action toimprove glycaemic control in patients with type 2 diabetes: ertugliflozin, a SGLT2 inhibitor, andsitagliptin phosphate, a DPP-4 inhibitor.

Ertugliflozin

SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerularfiltrate back into the circulation. Ertugliflozin is a potent, selective, and reversible inhibitor of SGLT2.

By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renalthreshold for glucose, and thereby increases urinary glucose excretion.

Sitagliptin

Sitagliptin is a member of a class of oral anti-hyperglycaemic agents called DPP-4 inhibitors. Theimprovement in glycaemic control observed with this medicinal product may be mediated byenhancing the levels of active incretin hormones. Incretin hormones, including glucagon-likepeptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by theintestine throughout the day, and levels are increased in response to a meal. The incretins are part of anendogenous system involved in the physiologic regulation of glucose homeostasis. When bloodglucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and releasefrom pancreatic beta cells by intracellular signalling pathways involving cyclic adenosinemonophosphate (AMP). Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulinbiosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In addition,

GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations,along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease inblood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when bloodglucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by

GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced asglucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagonresponse to hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, whichrapidly hydrolyses the incretin hormones to produce inactive products. Sitagliptin prevents thehydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the activeforms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release anddecreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes withhyperglycaemia, these changes in insulin and glucagon levels lead to lower HbA1c and lower fastingand post-prandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinctfrom the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels arelow and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. Sitagliptinis a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-relatedenzymes DPP-8 or DPP-9 at therapeutic concentrations.

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations,whereas metformin alone increased active and total GLP-1 concentrations to similar extents.

Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.

Sitagliptin, but not metformin, increased active GIP concentrations.

Ertugliflozin

Urinary glucose excretion and urinary volume

Dose-dependent increases in the amount of glucose excreted in urine were observed in healthysubjects and in patients with type 2 diabetes mellitus following single- and multiple-doseadministration of ertugliflozin. Dose-response modelling indicates that ertugliflozin 5 mg and 15 mgresult in near maximal urinary glucose excretion (UGE) in patients with type 2 diabetes mellitus,providing 87% and 96% of maximal inhibition, respectively.

The glycaemic efficacy and safety of ertugliflozin in combination with sitagliptin have been studied in3 multi-centre, randomised, double-blind, placebo- and active comparator-controlled, phase 3 clinicalstudies involving 1 985 patients with type 2 diabetes. Across the 3 studies, the racial distributionranged from 72.9% to 90.4% White, 0% to 20.3% Asian, 1.9% to 4.5% Black and 4.8% to 5.4%

Other. Hispanic or Latino patients comprised 15.6% to 36.1% of the population. The mean age of thepatients across these 3 studies ranged from 55.1 to 59.1 years (range 21 years to 85 years). Across the3 studies, 16.2% to 29.9% of patients were ≥ 65 years of age and 2.3% to 2.8% were ≥ 75 years of age.

Factorial study with ertugliflozin and 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 ertugliflozin 5 mg or 15 mg incombination with sitagliptin 100 mg compared to the individual components. Patients with type 2diabetes inadequately controlled on metformin monotherapy (≥ 1 500 mg/day) were randomised to oneof five active-treatment arms: ertugliflozin 5 mg or 15 mg, sitagliptin 100 mg, or sitagliptin 100 mg incombination with 5 mg or 15 mg ertugliflozin administered once daily in addition to continuation ofbackground metformin therapy (see Table 2).

Table 2: Results at week 26 from a factorial study with ertugliflozin and sitagliptin as add-oncombination therapy with metformin compared to individual components alone*

Ertugliflozin Ertugliflozin Sitagliptin Ertugliflozin Ertugliflozin5 mg 15 mg 100 mg 5 mg + 15 mg +

Sitagliptin Sitagliptin100 mg 100 mg

HbA1c (%) N = 250 N = 248 N = 247 N = 243 N = 244

Baseline (mean) 8.6 8.6 8.5 8.6 8.6

Change from baseline (LS mean†) -1.0 -1.1 -1.1 -1.5 -1.5

Difference from

Sitagliptin -0.4‡ (-0.6, -0.3) -0.5‡ (-0.6, -0.3)

Ertugliflozin 5 mg -0.5‡ (-0.6, -0.3)

Ertugliflozin 15 mg -0.4‡ (-0.6, -0.3)(LS mean†, 95% CI)

Patients [N (%)] with HbA1c66 (26.4) 79 (31.9) 81 (32.8) 127 (52.3)§ 120 (49.2)§< 7%

Body weight (kg) N = 250 N = 248 N = 247 N = 243 N = 244

Baseline (mean) 88.6 88.0 89.8 89.5 87.5

Change from baseline (LS mean†) -2.7 -3.7 -0.7 -2.5 -2.9

Difference from Sitagliptin -1.8‡ (-2.5, -1.2) -2.3‡ (-2.9, -1.6)(LS mean†, 95% CI)

* N includes all randomised, treated patients who had at least one measurement of the outcomevariable.

† Least squares means adjusted for time, baseline eGFR and the interaction of time by treatment.‡ p< 0.001 compared to control group.§ p< 0.001 compared to corresponding dose of ertugliflozin or sitagliptin (based on adjusted odds ratiocomparisons from a logistic regression model using multiple imputation for missing data values).

Ertugliflozin as add-on combination therapy with metformin and sitagliptin

A total of 463 patients, with type 2 diabetes inadequately controlled on metformin (≥ 1 500 mg/day)and sitagliptin 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 randomisedto ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo administered once daily in addition tocontinuation of background metformin and sitagliptin therapy (see Table 3).

Table 3: Results at week 26 from an add-on study of ertugliflozin in combination withmetformin and sitagliptin*

Ertugliflozin Ertugliflozin Placebo5 mg 15 mg

HbA1c (%) N = 156 N = 153 N = 153

Baseline (mean) 8.1 8.0 8.0

Change from baseline (LS mean†) -0.8 -0.9 -0.1

Difference from placebo (LS mean†, 95% -0.7‡ (-0.9, -0.5) -0.8‡ (-0.9, -0.6)

CI)

Patients [N (%)] with HbA1c < 7% 50 (32.1)§ 61 (39.9)§ 26 (17.0)

Body weight (kg) N = 156 N = 153 N = 153

Baseline (mean) 87.6 86.6 86.5

Change from baseline (LS mean†) -3.3 -3.0 -1.3

Difference from placebo (LS mean†, 95% -2.0‡ (-2.6, -1.4) -1.7‡ (-2.3, -1.1)

CI)

* N includes all randomised, treated patients who had at least one measurement of the outcomevariable.

† Least squares means adjusted for time, prior antihyperglycaemic medicinal products, baseline eGFR,and the interaction of time by treatment.

‡ p< 0.001 compared to placebo.§ p< 0.001 compared to placebo (based on adjusted odds ratio comparisons from a logistic regressionmodel using multiple imputation for missing data values).

Combination therapy of ertugliflozin and sitagliptin

A total of 291 patients with type 2 diabetes inadequately controlled on diet and exercise participated ina randomised, double-blind, multi-centre, placebo-controlled 26-week study to evaluate the efficacyand safety of ertugliflozin in combination with sitagliptin. These patients, who were not receiving anybackground antihyperglycaemic treatment, were randomised to ertugliflozin 5 mg or ertugliflozin15 mg in combination with sitagliptin (100 mg) or to placebo, once daily (see Table 4).

Table 4: Results at week-26 from a combination therapy study of ertugliflozin and sitagliptin*

Ertugliflozin Ertugliflozin Placebo5 mg 15 mg+ Sitagliptin + Sitagliptin

HbA1c (%) N = 98 N = 96 N = 96

Baseline (mean) 8.9 9.0 9.0

Change from baseline (LS mean†) -1.6 -1.7 -0.4

Difference from placebo (LS mean† -1.2‡ (-1.5, -0.8) -1.2‡ (-1.6, -0.9)and 95% CI)

Patients [N (%)] with HbA1c < 7% 35 (35.7)§ 30 (31.3)§ 8 (8.3)

Body weight (kg) N = 98 N = 96 N = 97

Baseline (mean) 90.8 91.3 95.0

Change from baseline (LS mean†) -2.9 -3.0 -0.9

Difference from placebo (LS mean†, -2.0‡ (-3.0, -1.0) -2.1‡ (-3.1, -1.1)95% CI)

* N includes all patients who received at least one dose of study medication and had at least onemeasurement of the outcome variable.

† Least squares means adjusted for time, and the interaction of time by treatment.‡ p< 0.001 compared to placebo.§ p< 0.001 compared to placebo (based on adjusted odds ratio comparisons from a logisticregression model using multiple imputation for missing data values).

In three placebo-controlled studies, ertugliflozin resulted in statistically significant reductions infasting plasma glucose (FPG). For ertugliflozin 5 mg and 15 mg, respectively, the placebo-correctedreductions in FPG were 1.92 and 2.44 mmol/L as monotherapy, 1.48 and 2.12 mmol/L as add-on tometformin, and 1.40 and 1.74 mmol/L as add-on to metformin and sitagliptin.

The combination of ertugliflozin and sitagliptin resulted in significantly greater reductions in FPGcompared to sitagliptin or ertugliflozin alone or placebo. The combination of ertugliflozin 5 or 15 mgand sitagliptin resulted in incremental FPG reductions of 0.46 to 0.65 mmol/L compared to theertugliflozin alone or 1.02 to 1.28 mmol/L compared to sitagliptin alone. The placebo-correctedreductions of ertugliflozin 5 or 15 mg in combination with sitagliptin were 2.16 and 2.56 mmol/L.

Efficacy in patients with baseline HbA1c ≥ 10%

In the study of patients inadequately controlled on metformin with baseline HbA1c from 7.5-11%,among the subgroup of patients with a baseline HbA1c ≥ 10%, the combination of ertugliflozin 5 mgor 15 mg with sitagliptin resulted in reductions of HbA1c of 2.35% and 2.66%, respectively, comparedto 2.10%, 1.30%, and 1.82% for ertugliflozin 5 mg, ertugliflozin 15 mg, and sitagliptin alone,respectively.

Post-prandial glucose

When used in monotherapy, ertugliflozin 5 and 15 mg resulted in statistically significant placebo-corrected reductions in 2-hour post-prandial glucose (PPG) of 3.83 and 3.74 mmol/L.

The combination of ertugliflozin 5 or 15 mg with sitagliptin resulted in statistically significantplacebo-corrected reductions in 2-hour PPG of 3.46 and 3.87 mmol/L.

After 26-weeks of treatment, the combination of ertugliflozin 5 mg or 15 mg and sitagliptin 100 mgresulted in statistically significant reductions in systolic blood pressure (SBP) compared to sitagliptinalone (-2.8 and -3.0 mmHg for E5/S100 and E15/S100 respectively) or placebo (-4.4 and -6.4 mmHgfor E5/S100 and E15/S100, respectively). Additionally, when added on to background metformin andsitagliptin therapy, ertugliflozin 5 mg and 15 mg resulted in statistically significant placebo subtractedreductions in SBP of 2.9 and 3.9 mmHg, respectively.

In patients with type 2 diabetes treated with ertugliflozin in combination with sitagliptin, theimprovement in HbA1c was similar across subgroups defined by age, sex, and race, and duration oftype 2 diabetes mellitus.

Cardiovascular outcomes

Ertugliflozin cardiovascular outcomes study (VERTIS CV)

The effect of ertugliflozin on cardiovascular risk in adult patients with type 2 diabetes mellitus andestablished atherosclerotic cardiovascular disease was evaluated in the VERTIS CV study, amulti-centre, multi-national, randomised, double-blind, placebo-controlled, event-driven trial. Thestudy compared the risk of experiencing a major adverse cardiovascular event (MACE) betweenertugliflozin and placebo when these were added to and used concomitantly with standard of caretreatments for diabetes and atherosclerotic cardiovascular disease.

A total of 8 246 patients were randomised (placebo N=2 747, ertugliflozin 5 mg N=2 752, ertugliflozin15 mg N=2 747) and followed for a median of 3 years. The mean age was 64 years and approximately70% were male.

All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1cgreater 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 weretreated with one (32%) or more (67%) antidiabetic medicinal products including metformin (76%),insulin (47%), sulphonylureas (41%), DPP-4 inhibitors (11%) and GLP-1 receptor agonists (3%).

Almost all patients (99%) had established atherosclerotic cardiovascular disease at baseline.

Approximately 24% patients had a history of heart failure. The primary endpoint in VERTIS CV wasthe time to first occurrence of MACE (cardiovascular death, non-fatal myocardial infarction (MI) ornon-fatal stroke).

Ertugliflozin demonstrated non-inferiority versus placebo for MACE (see Table 5). Results for theindividual 5 mg and 15 mg doses were consistent with results for the combined dose groups.

In patients treated with ertugliflozin, the rate of hospitalisation for heart failure was lower than inpatients treated with placebo (see Table 5 and Figure 1).

Table 5: Analysis of MACE and its components and hospitalisation for heart failure from the

VERTIS CV study*

Placebo (N=2 747) Ertugliflozin (N=5 499)

Endpoint† N (%) Event rate N (%) Event rate Hazard ratio(per 100 (per 100 vs Placeboperson- person- (CI)‡years) years)

MACE (CV death, non- 327 (11.9) 4.0 653 (11.9) 3.9 0.97fatal MI, or non-fatal (0.85, 1.11)stroke)

Non-fatal MI 148 (5.4) 1.6 310 (5.6) 1.7 1.04(0.86, 1.27)

Non-fatal stroke 78 (2.8) 0.8 157 (2.9) 0.8 1.00(0.76, 1.32)

CV death 184 (6.7) 1.9 341 (6.2) 1.8 0.92(0.77, 1.11)

Hospitalisation for 99 (3.6) 1.1 139 (2.5) 0.7 0.70heart failure#(0.54, 0.90)

N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction.

* Intent-to-treat analysis set.† MACE was evaluated in subjects who took at least one dose of study medication and, for subjectswho discontinued study medication prior to the end of the study, events that occurred more than365 days after the last dose of study medication were censored. Other endpoints were evaluated usingall randomised subjects and events that occurred any time after the first dose of study medication untilthe last contact date. The total number of first events was analysed for each endpoint.‡ For MACE a 95.6% CI is presented, for other endpoints a 95% CI is presented.# Not evaluated for statistical significance as it was not a part of the prespecified sequential testingprocedure.

Figure 1: Time to first occurrence of hospitalisation for heart failure

Sitagliptin cardiovascular outcomes study (TECOS)

The TECOS was a randomised study in 14 671 patients in the intention-to-treat population with an

HbA1c of ≥ 6.5 to 8.0% with established CV disease who received sitagliptin (7 332) 100 mg daily (or50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2) or placebo (7 339) added tousual care targeting regional standards for HbA1c and CV risk factors. Patients with an eGFR< 30 mL/min/1.73 m2 were not to be enrolled in the study. The study population included2 004 patients ≥ 75 years of age and 3 324 patients with renal impairment(eGFR < 60 mL/min/1.73 m2).

Over the course of the study, the overall estimated mean (SD) difference in HbA1c between thesitagliptin and placebo groups was 0.29% (0.01), 95% CI (-0.32, -0.27); p< 0.001. The primarycardiovascular endpoint was a composite of the first occurrence of cardiovascular death, non-fatalmyocardial infarction, non-fatal stroke, or hospitalisation for unstable angina. Secondarycardiovascular endpoints included the first occurrence of cardiovascular death, non-fatal myocardialinfarction, or non-fatal stroke; first occurrence of the individual components of the primary composite;all-cause mortality; and hospital admissions for congestive heart failure.

After a median follow up of 3 years, sitagliptin, when added to usual care, did not increase the risk ofmajor adverse cardiovascular events or the risk of hospitalisation for heart failure compared to usualcare without sitagliptin in patients with type 2 diabetes (see Table 6).

Table 6: Rates of composite cardiovascular outcomes and key secondary outcomes

Sitagliptin 100 mg Placebo

Incidence Incidencerate per rate per100 100patient- patient- Hazard ratio

N (%) years* N (%) years* (95% CI) p-value†

Analysis in the intention-to-treat population

Number of patients 7,332 7,339

Primary composite endpoint(Cardiovascular death, non-fatalmyocardial infarction, non-fatalstroke, or hospitalisation for 851unstable angina) 839 (11.4) 4.1 (11.6) 4.2 0.98 (0.89-1.08) < 0.001

Secondary composite endpoint(Cardiovascular death, non-fatalmyocardial infarction, or non- 746fatal stroke) 745 (10.2) 3.6 (10.2) 3.6 0.99 (0.89-1.10) < 0.001

Secondary outcome

Cardiovascular death 366380 (5.2) 1.7 (5.0) 1.7 1.03 (0.89-1.19) 0.711

All myocardial infarction (fatal 316and non-fatal) 300 (4.1) 1.4 (4.3) 1.5 0.95 (0.81-1.11) 0.487

All stroke (fatal and non-fatal) 183178 (2.4) 0.8 (2.5) 0.9 0.97 (0.79-1.19) 0.760

Hospitalisation for unstable 129angina 116 (1.6) 0.5 (1.8) 0.6 0.90 (0.70-1.16) 0.419

Death from any cause 537547 (7.5) 2.5 (7.3) 2.5 1.01 (0.90-1.14) 0.875

Hospitalisation for heart failure‡ 229228 (3.1) 1.1 (3.1) 1.1 1.00 (0.83-1.20) 0.983

*Incidence rate per 100 patient-years is calculated as 100 × (total number of patients with ≥ 1 eventduring eligible exposure period per total patient-years of follow-up).

† Based on a Cox model stratified by region. For composite endpoints, the p-values correspond to a testof non-inferiority seeking to show that the hazard ratio is less than 1.3. For all other endpoints, thep-values correspond to a test of differences in hazard rates.

‡The analysis of hospitalisation for heart failure was adjusted for a history of heart failure at baseline.

The European Medicines Agency has waived the obligation to submit the results of studies with

Steglujan in all subsets of the paediatric population in the treatment of type 2 diabetes (see section 4.2for information on paediatric use).

Steglujan

Steglujan has been shown to be bioequivalent to coadministration of corresponding doses ofertugliflozin and sitagliptin tablets.

The effects of a high-fat meal on the pharmacokinetics of ertugliflozin and sitagliptin whenadministered as Steglujan tablets are comparable to those reported for the individual tablets.

Administration of Steglujan with food decreased ertugliflozin Cmax by 29% and had no meaningfuleffect on ertugliflozin AUCinf, or on sitagliptin AUCinf and Cmax.

Ertugliflozin

General introduction

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

The steady state mean plasma AUC and Cmax were 398 ng∙hr/mL and 81 ng/mL, respectively, with5 mg ertugliflozin once daily treatment, and 1 193 ng∙hr/mL and 268 ng/mL, respectively, with 15 mgertugliflozin once daily treatment. Steady-state is reached after 4 to 6 days of once-daily dosing withertugliflozin. Ertugliflozin does not exhibit time-dependent pharmacokinetics and accumulates inplasma up to 10-40% following multiple dosing.

Following single-dose oral administration of 5 mg and 15 mg of ertugliflozin, peak plasmaconcentrations (median time to maximum plasma concentration [Tmax]) of ertugliflozin occur at 1 hourpost-dose 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 from1 mg to 100 mg. The absolute oral bioavailability of ertugliflozin following administration of a 15-mgdose is approximately 100%.

Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin Cmax by29% and prolongs Tmax by 1 hour but does not alter AUC as compared with the fasted state. Theobserved effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, andertugliflozin may be administered with or without food. In phase 3 clinical trials, ertugliflozin wasadministered without regard to meals.

Ertugliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)transporters.

The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 86 L.

Plasma protein binding of ertugliflozin is 93.6% and is independent of ertugliflozin plasmaconcentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepaticimpairment. The blood-to-plasma concentration ratio of ertugliflozin is 0.66.

Ertugliflozin is not a substrate of organic anion transporters (OAT1, OAT3), organic cationtransporters (OCT1, OCT2), or organic anion transporting polypeptides (OATP1B1, OATP1B3) invitro.

Metabolism is the primary clearance mechanism for ertugliflozin. The major metabolic pathway forertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation to two glucuronides that arepharmacologically inactive at clinically relevant concentrations. CYP-mediated (oxidative)metabolism of ertugliflozin is minimal (12%).

The mean systemic plasma clearance following an intravenous 100 µg dose was 11 L/hr. The meanelimination half-life in type 2 diabetic patients with normal renal function was estimated to be17 hours based on the population pharmacokinetic analysis. Following administration of an oral[14C]-ertugliflozin solution to healthy subjects, approximately 41% and 50% of the drug-relatedradioactivity was eliminated in faeces and urine, respectively. Only 1.5% of the administered dose wasexcreted as unchanged ertugliflozin in urine and 34% as unchanged ertugliflozin in faeces, which islikely due to biliary excretion of glucuronide metabolites and subsequent hydrolysis to parent.

In a phase 1 clinical pharmacology study in patients with type 2 diabetes and mild, moderate, or severerenal impairment (as determined by eGFR), following a single-dose administration of 15 mgertugliflozin, the mean increases in AUC of ertugliflozin were ≤ 1.7-fold, compared to subjects withnormal 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 differentrenal function groups. The 24-hour urinary glucose excretion declined with increasing severity of renalimpairment (see section 4.4). The plasma protein binding of ertugliflozin was unaffected in patientswith renal impairment.

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

No studies with ertugliflozin 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 aclinically meaningful effect on the pharmacokinetics of ertugliflozin.

Sitagliptin

Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed,with median Tmax occurring 1 to 4 hours post-dose. Mean plasma AUC of sitagliptin was 8.52 M*hrand Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87%. Sincecoadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, Steglujanmay be administered with or without food.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was notestablished for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hrincreased in a less than dose-proportional manner).

The mean volume of distribution at steady state following a single 100-mg intravenous dose ofsitagliptin to healthy subjects is approximately 198 L. The fraction of sitagliptin reversibly bound toplasma proteins is low (38%).

Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.

Approximately 79% of sitagliptin is excreted unchanged in the urine.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted asmetabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected tocontribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that theprimary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contributionfrom CYP2C8.

In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6,1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.

Following administration of an oral [14C]-sitagliptin dose to healthy subjects, approximately 100% ofthe administered radioactivity was eliminated in faeces (13%) or urine (87%) within one week ofdosing. The apparent terminal t1/2 following a 100-mg oral dose of sitagliptin was approximately12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance wasapproximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.

Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved inthe renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has notbeen established. Sitagliptin is also a substrate of P-gp, which may also be involved in mediating therenal elimination of sitagliptin. However, ciclosporin, a P-gp inhibitor, did not reduce the renalclearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or peptide transporter 1/2(PEPT1/2) transporters. In vitro, sitagliptin did not inhibit OAT3 (IC50=160 M) or p-glycoprotein (upto 250 M) mediated transport at therapeutically relevant plasma concentrations. In a clinical studysitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be amild inhibitor of P-gp.

No drug interactions studies have been performed with Steglujan and other medicinal products;however, such studies have been conducted with the individual active substances.

In vitro assessment of ertugliflozin

In in vitro studies, ertugliflozin and ertugliflozin glucuronides did not inhibit or inactivate CYPs 1A2,2C9, 2C19, 2C8, 2B6, 2D6, or 3A4, and did not induce CYPs 1A2, 2B6, or 3A4. Ertugliflozin andertugliflozin glucuronides did not inhibit the activity of UGTs 1A6, 1A9 or 2B7 in vitro. Ertugliflozinwas a weak inhibitor of UGTs 1A1 and 1A4 in vitro at higher concentrations that are not clinicallyrelevant. Ertugliflozin glucuronides had no effect on these isoforms. Overall, ertugliflozin is unlikelyto affect the pharmacokinetics of concurrently administered medicinal products eliminated by theseenzymes.

Ertugliflozin or ertugliflozin glucuronides do not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3transporters or transporting polypeptides OATP1B1 and OATP1B3 at clinically relevantconcentrations in vitro. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrentlyadministered medicinal products that are substrates of these transporters.

In vitro assessment of sitagliptin

In vitro data suggest that sitagliptin does not inhibit or induce CYP450 isoenzymes. In clinical studies,sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin,rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity forcausing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and OCT. Sitagliptin may be amild inhibitor of P-gp in vivo.

In vitro transport studies showed that sitagliptin is a substrate for P-gp and OAT3. OAT3 mediatedtransport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningfulinteractions is considered to be low. Concomitant administration of OAT3 inhibitors has not beenevaluated in vivo.

The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients withtype 2 diabetes.

In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role inthe clearance of sitagliptin. Metabolism may play a more significant role in the elimination ofsitagliptin in the setting of severe renal impairment or ESRD.

Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased modestly inpatients with GFR ≥ 45 to < 90 mL/min. Because increases of this magnitude are not clinicallyrelevant, dose adjustment in these patients is not necessary.

No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment(Child-Pugh score  9). There is no clinical experience in patients with severe hepatic impairment(Child-Pugh score > 9). However, because sitagliptin is primarily renally eliminated, severe hepaticimpairment is not expected to affect the pharmacokinetics of sitagliptin.

No dose adjustment is required based on age. Age did not have a clinically meaningful impact on thepharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of phase 1 and phase 2data. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations ofsitagliptin compared to younger subjects.

Paediatric

No studies with sitagliptin have been performed in paediatric patients.

Other patient characteristics

No dose adjustment is necessary based on gender, race, or body mass index (BMI). Thesecharacteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on acomposite analysis of phase 1 pharmacokinetic data and on a population pharmacokinetic analysis ofphase 1 and phase 2 data.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, acute toxicity, repeated dose toxicity, genotoxicity, and carcinogenic potential.

Ertugliflozin

Repeat-dose oral toxicity studies were conducted in mice, rats, and dogs for up to 13, 26, and39 weeks, respectively. Signs of toxicity that were considered adverse were generally observed atexposures greater than or equal to 77 times the human unbound exposure (AUC) at the maximumrecommended human dose (MRHD) of 15 mg/day. Most toxicity was consistent with pharmacologyrelated to urinary glucose loss and included decreased body weight and body fat, increased foodconsumption, diarrhoea, dehydration, decreased serum glucose and increases in other serumparameters reflective of increased protein metabolism, gluconeogenesis and electrolyte imbalances,and urinary changes such as polyuria, glucosuria, and calciuria. Microscopic changes related toglucosuria and/or calciuria observed only in rodents included dilatation of renal tubules, hypertrophyof zona glomerulosa in adrenal glands (rats), and increased trabecular bone (rats). Except for emesis,there were no adverse toxicity findings in dogs at 379 times the human unbound exposure (AUC) atthe MRHD of 15 mg/day.

In the 2-year mouse carcinogenicity study, ertugliflozin was administered by oral gavage at doses of 5,15, and 40 mg/kg/day. There were no ertugliflozin-related neoplastic findings at doses up to40 mg/kg/day (approximately 41 times human unbound exposure at the MRHD of 15 mg/day based on

AUC). In the 2-year rat carcinogenicity study, ertugliflozin was administered by oral gavage at dosesof 1.5, 5, and 15 mg/kg/day. Ertugliflozin-related neoplastic findings included an increased incidenceof benign adrenal medullary pheochromocytoma in male rats at 15 mg/kg/day. This finding wasattributed to carbohydrate malabsorption leading to altered calcium homeostasis and was notconsidered relevant to human risk. The no-observed-effect level (NOEL) for neoplasia was5 mg/kg/day (approximately 16 times human unbound exposure at the MRHD of 15 mg/day).

Ertugliflozin was not mutagenic or clastogenic with or without metabolic activation in the microbialreverse mutation, in vitro cytogenetic (human lymphocytes), and in vivo rat micronucleus assays.

In the rat fertility and embryonic development study, male and female rats were administeredertugliflozin at 5, 25, and 250 mg/kg/day. No effects on fertility were observed at 250 mg/kg/day(approximately 386 times human unbound exposure at the MRHD of 15 mg/day based on AUCcomparisons). Ertugliflozin did not adversely affect developmental outcomes in rats and rabbits atmaternal exposures that were 239 and 1 069 times, respectively, the human exposure at the maximumclinical dose of 15 mg/day, based on AUC. At a maternally toxic dose in rats (250 mg/kg/day), lowerfetal viability and a higher incidence of a visceral malformation were observed at maternal exposurethat was 510 times the maximum clinical dose of 15 mg/day.

In the pre- and post-natal development study, decreased post-natal growth and development wereobserved in rats administered ertugliflozin gestation day 6 through lactation day 21 at≥ 100 mg/kg/day (estimated 239 times the human exposure at the maximum clinical dose of15 mg/day, based on AUC). Sexual maturation was delayed in both sexes at 250 mg/kg/day (estimated620 times the MRHD at 15 mg/day, based on AUC).

When ertugliflozin was administered to juvenile rats from post-natal day (PND) 21 to PND 90, aperiod of renal development corresponding to the late second and third trimesters of humanpregnancy, increased kidney weights, dilatation of the renal pelvis and tubules, and renal tubularmineralization were seen at an exposure 13 times the maximum clinical dose of 15 mg/day, based on

AUC. Effects on bone (shorter femur length, increased trabecular bone in the femur) as well as effectsof delayed puberty were observed at an exposure 817 times the MRHD of 15 mg/day based on AUC.

The effects on kidney and bone did not fully reverse after the 1 month recovery period.

Sitagliptin

Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the humanexposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teethabnormalities were observed in rats at exposure levels 67 times the clinical exposure level; theno-effect level for this finding was 58-fold based on the 14-week rat study. The relevance of thesefindings for humans is unknown. Transient treatment-related physical signs, some of which suggestneural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling,decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration wasalso observed histologically at doses resulting in systemic exposure levels of approximately 23 timesthe human exposure level. A no-effect level for these findings was found at an exposure 6-fold theclinical exposure level.

Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was notcarcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas atsystemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown tocorrelate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in ratswas likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin(19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situationin humans.

No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to andthroughout mating.

In a pre-/post-natal development study performed in rats sitagliptin showed no adverse effects.

Reproductive toxicity studies showed a slight treatment-related increased incidence of foetal ribmalformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levelsmore than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than29 times the human exposure levels. Because of the high safety margins, these findings do not suggesta relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk oflactating rats (milk/plasma ratio: 4:1).

Microcrystalline cellulose (E460)

Calcium hydrogen phosphate (anhydrous)

Croscarmellose sodium

Sodium stearyl fumarate (E487)

Magnesium stearate (E470b)

Propyl gallate

Hypromellose (E464)

Hydroxypropyl cellulose (E463)

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Iron oxide black (E172)

Carnauba wax (E903)

Not applicable.

2 years

This medicinal product does not require any special storage conditions.

Alu/PVC/PA/Alu blisters

Packs of 14, 28, 30, 84, 90 and 98 film-coated tablets in non-perforated blisters.

Packs of 30x1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

Steglujan 5 mg/100 mg film-coated tablets

EU/1/18/1266/001

EU/1/18/1266/002

EU/1/18/1266/003

EU/1/18/1266/004

EU/1/18/1266/005

EU/1/18/1266/006

EU/1/18/1266/013

Steglujan 15 mg/100 mg film-coated tablets

EU/1/18/1266/007

EU/1/18/1266/008

EU/1/18/1266/009

EU/1/18/1266/010

EU/1/18/1266/011

EU/1/18/1266/012

EU/1/18/1266/014

Date of first authorisation: 23 March 2018

Date of latest renewal: 05 December 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.