ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Segluromet 2.5 mg/850 mg film-coated tablets

Segluromet 2.5 mg/1,000 mg film-coated tablets

Segluromet 7.5 mg/850 mg film-coated tablets

Segluromet 7.5 mg/1,000 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Segluromet 2.5 mg/850 mg film-coated tablets

Each tablet contains 2.5 mg ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 850 mg of metformin hydrochloride.

Segluromet 2.5 mg/1,000 mg film-coated tablets

Each tablet contains 2.5 mg ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 1,000 mg of metformin hydrochloride.

Segluromet 7.5 mg/850 mg film-coated tablets

Each tablet contains 7.5 mg ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 850 mg metformin hydrochloride.

Segluromet 7.5 mg/1,000 mg film-coated tablets

Each tablet contains 7.5 mg ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 1,000 mg metformin hydrochloride.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Segluromet 2.5 mg/850 mg film-coated tablets

Beige, 18 x 10 mm oval, film-coated tablet debossed with “2.5/850” on one side and plain on the other side.

Segluromet 2.5 mg/1,000 mg film-coated tablets

Pink, 19.1 x 10.6 mm oval, film-coated tablet debossed with “2.5/1000” on one side and plain on the other side.

Segluromet 7.5 mg/850 mg film-coated tablets

Dark brown, 18 x 10 mm oval, film-coated tablet debossed with “7.5/850” on one side and plain on the other side.

Segluromet 7.5 mg/1,000 mg film-coated tablets

Red, 19.1 x 10.6 mm oval, film-coated tablet debossed with “7.5/1000” on one side and plain on the other side.

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4. CLINICAL PARTICULARS 4.1 Therapeutic indications

Segluromet is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:

• in patients not adequately controlled on their maximally tolerated dose of metformin alone

• in patients on their maximally tolerated doses of metformin in addition to other medicinal products for the treatment of diabetes

• in patients already being treated with the combination of ertugliflozin and metformin as separate tablets.

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

4.2 Posology and method of administration

Posology

The recommended dose is one tablet twice daily. The dosage should be individualised on the basis of the patient’s current regimen, effectiveness, and tolerability using the recommended daily dose of

5 mg or 15 mg of ertugliflozin, while not exceeding the maximum recommended daily dose of metformin.

In patients with volume depletion, correcting this condition prior to initiation of Segluromet is recommended (see section 4.4).

If a dose is missed, it should be taken as soon as the patient remembers. Patients should not take two doses of Segluromet at the same time.

Adults with normal renal function (glomerular filtration rate [GFR] ≥ 90 ml/min)

For patients inadequately controlled on metformin monotherapy or metformin in combination with other glucose-lowering medicinal products, including insulin

The recommended starting dose of Segluromet should provide ertugliflozin 2.5 mg twice daily (5 mg daily dose) and the dose of metformin similar to the dose already being taken. In patients tolerating a total daily dose of ertugliflozin 5 mg, the dose can be increased to a total daily dose of ertugliflozin 15 mg if additional glycaemic control is needed.

For patients switching from separate tablets of ertugliflozin and metformin

Patients switching from separate tablets of ertugliflozin (5 mg or 15 mg total daily dose) and metformin to Segluromet should receive the same daily dose of ertugliflozin and metformin already being taken or the nearest therapeutically appropriate dose of metformin.

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

Special populations

Renal impairment

A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g., every 3-6 months.

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Initiation of this medicinal product is not recommended in patients with a GFR less than 60 ml/min (see section 4.4).

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering initiation of metformin in patients with GFR < 60 ml/min.

If no adequate strength of Segluromet is available, individual monocomponents should be used instead of the fixed-dose combination.

Hepatic impairment

Segluromet is contraindicated in patients with hepatic impairment (see sections 4.3 and 4.4).

Elderly (≥ 65 years old)

Elderly patients are more likely to have decreased renal function. Because renal function abnormalities can occur after initiating ertugliflozin, and metformin is known to be substantially excreted by the kidneys, Segluromet should be used with caution in the elderly. Regular assessment of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in elderly patients (see section 4.4). Renal function and risk of volume depletion should be taken into account (see sections 4.4 and 4.8).

There is limited experience with Segluromet in patients ≥ 75 years of age.

Paediatric population

The safety and efficacy of Segluromet in children under 18 years of age have not been established. No data are available.

Method of administration

Segluromet should be taken orally twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin. In case of swallowing difficulties, the tablet could be broken or crushed as it is an immediate-release dosage form.

4.3 Contraindications

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

- any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis [DKA]);

- diabetic pre coma;

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- severe renal failure (GFR less than 30 ml/min), end-stage renal disease (ESRD), or patients on dialysis (see section 4.4);

- acute condition with the potential to alter renal function, such as:

- dehydration,

- severe infection,

- shock;

- acute or chronic disease that may cause tissue hypoxia, such as:

- cardiac or respiratory failure,

- recent myocardial infarction,

- shock;

- hepatic impairment;

- acute alcohol intoxication, alcoholism.

4.4 Special warnings and precautions for use

General

Segluromet should not be used in patients with type 1 diabetes mellitus.

Lactic acidosis

Lactic acidosis, a rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe vomiting, diarrhoea, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and non-steroidal anti-inflammatory drugs [NSAIDs]) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (> 5 mmol/l) and an increased anion gap and lactate/pyruvate ratio.

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast-induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Segluromet should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.5).

Renal function

The efficacy of ertugliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.2).

Segluromet should not be initiated in patients with a GFR below 60 ml/min. Segluromet should be discontinued when GFR is persistently below 45 ml/min due to a reduction of efficacy.

GFR should be assessed before treatment initiation and regularly thereafter (see section 4.2). More frequent renal function monitoring is recommended in patients with a GFR below 60 ml/min.

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Metformin is contraindicated in patients with GFR < 30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).

Surgery

Segluromet must be discontinued at the time of surgery under general, spinal, or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.

Hypotension/Volume depletion

Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction. Therefore, symptomatic hypotension may occur after initiating Segluromet (see section 4.8), particularly in patients with impaired renal function (eGFR less than 60 ml/min/1.73 m2 or a CrCl less than 60 ml/min), elderly patients (≥ 65 years), patients on diuretics, or patients on anti-hypertensive therapy with a history of hypotension. Before initiating Segluromet, volume status should be assessed and corrected if indicated. Monitor for signs and symptoms after initiating therapy.

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

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

Diabetic ketoacidosis

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

The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue, or sleepiness. 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 Segluromet should be discontinued immediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. In both cases, treatment with Segluromet may be restarted once the patient’s condition has stabilised.

Before initiating Segluromet, factors in the patient history that may predispose to ketoacidosis should be considered.

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) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery, or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.

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

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The safety and efficacy of Segluromet in patients with type 1 diabetes have not been established and Segluromet should not be used for treatment of patients with type 1 diabetes. Limited data from clinical trials suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors.

Lower limb amputations

An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. Like for all diabetic patients it is important to counsel patients on routine preventative foot care.

Hypoglycaemia with concomitant use of insulin and insulin secretagogues

Ertugliflozin may increase the risk of hypoglycaemia when used in combination with insulin and/or an insulin secretagogue, which are known to cause hypoglycaemia (see section 4.8). Therefore, a lower dose of insulin or insulin secretagogue may be required to minimise the risk of hypoglycaemia when used in combination with Segluromet (see sections 4.2 and 4.5).

Genital mycotic infections

Ertugliflozin 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). Patients should be monitored and treated appropriately.

Urinary tract infections

Urinary glucose excretion may be associated with an increased risk of urinary tract infections.

The incidence of urinary tract infections was not notably different in the ertugliflozin 5 mg and 15 mg groups (4.0% and 4.1%) and the placebo group (3.9%). Most of the events were mild or moderate and no serious case was reported. Temporary interruption of ertugliflozin should be considered when treating pyelonephritis or urosepsis.

Elderly patients

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. The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Segluromet is expected to have diminished efficacy in elderly patients with renal impairment (see sections 4.2 and 4.8). Assess renal function more frequently in elderly patients.

Cardiac failure

Experience in New York Heart Association (NYHA) class I-II is limited, and there is no experience in clinical studies with ertugliflozin in NYHA class III-IV.

Urine laboratory assessments

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

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

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

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic drug interaction studies with Segluromet have not been performed; however, such studies have been conducted with ertugliflozin and metformin, the individual active substances of Segluromet.

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Ertugliflozin

Pharmacodynamic interactions

Diuretics

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

Insulin and insulin secretagogues

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

Pharmacokinetic interactions

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 the pharmacokinetics of ertugliflozin are not altered by sitagliptin, metformin, glimepiride, or simvastatin.

Multiple-dose administration of rifampin (a UGT and CYP inducer) decreases ertugliflozin AUC and Cmax by 39% and 15%, respectively. This decrease in exposure is not considered clinically relevant and therefore, no dose adjustment is recommended. A clinically relevant effect with other inducers (e.g., carbamazepine, phenytoin, phenobarbital) is not expected.

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 clinically relevant.

Effects of ertugliflozin on the pharmacokinetics of other medicinal products

Interaction studies conducted in healthy volunteers suggest that ertugliflozin had no clinically relevant effect 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 unknown and is not perpetrated through OATP inhibition by ertugliflozin. These increases are not considered to be clinically meaningful.

Metformin

Concomitant use not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Segluromet must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.4).

Combinations requiring precautions for use

Some medicinal products can adversely affect renal function, which may increase the risk of lactic acidosis, e.g., NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors,

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angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2.

Coadministration of metformin with

· Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.

· Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.

· Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.

· Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are coadministered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.

Glucocorticoids (given by systemic and local routes), beta 2 agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Segluromet in pregnant women.

A limited amount of data suggests the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or post-natal development (see section 5.3).

There are limited data from the use of ertugliflozin in pregnant women. Based on results from animal studies, ertugliflozin may affect renal development and maturation (see section 5.3).Therefore, Segluromet should not be used during pregnancy.

Breast-feeding

There is no information regarding the presence of ertugliflozin in human milk, the effects on the breast-fed infant, or the effects on milk production. Metformin is present in human breast milk. Ertugliflozin and metformin are 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 (see section 5.3). Since human kidney maturation occursin utero and during the first 2 years of life when exposure from breast-feeding may occur, a risk to newborns/infants cannot be excluded. Segluromet should not be used during breast-feeding.

Fertility

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

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4.7 Effects on ability to drive and use machines

Segluromet has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when Segluromet is used in combination with insulin or an insulin secretagogue and to the elevated risk of adverse reactions related to volume depletion, such as postural dizziness (see sections 4.2, 4.4, and 4.8).

4.8 Undesirable effects

Summary of the safety profile

Ertugliflozin and Metformin

The safety of concomitantly administered ertugliflozin and metformin has been evaluated in

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

Ertugliflozin

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 (see

section 5.1). These data reflect exposure of 1,029 patients to ertugliflozin with a mean exposure duration of approximately 25 weeks. Patients received ertugliflozin 5 mg (N=519), ertugliflozin 15 mg (N=510), or placebo (N=515) once daily.

The most commonly reported adverse reactions across the clinical program were vulvovaginal mycotic infection, and other female genital mycotic infections. Serious diabetic ketoacidosis occurred rarely. See “Description of selected adverse reactions” for frequencies and see section 4.4.

Tabulated list of adverse reactions

Adverse reactions listed below are classified according to frequency and system organ class (SOC). 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

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Vascular disorders

1 Adverse reaction with ertugliflozin.

2 Adverse reaction with metformin. * See Section 4.4.

†   See subsections below for additional information.

‡ Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption, which may very

rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anaemia).

§ Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.

¶ Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.

# Includes: thirst and polydipsia.

Þ Mean percent changes from baseline for ertugliflozin 5 mg and 15 mg versus placebo, respectively, were LDL-C 5.8% and 8.4% versus 3.2%; total cholesterol 2.8% and 5.7% versus 1.1%; however, HDL-C 6.2% and 7.6% versus 1.9%. Median percent changes from baseline for ertugliflozin 5 mg and 15 mg versus placebo, respectively, were triglycerides -3.9% and -1.7% versus 4.5%.

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

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

Description of selected adverse reactions

Volume depletion (ertugliflozin)

Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of placebo-controlled studies, the incidence of adverse events related to volume depletion (dehydration, dizziness postural, presyncope, syncope, hypotension, and orthostatic hypotension) was low (< 2%) and not notably different across the ertugliflozin 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 a higher incidence of volume depletion in the ertugliflozin groups relative to the comparator group (see sections 4.2 and 4.4). In subjects with eGFR < 60 mL/min/1.73 m2, the incidence was 5.1%, 2.6%, and 0.5% for ertugliflozin 5 mg, ertugliflozin 15 mg, and the comparator group and for subjects with eGFR 45 to < 60 mL/min/1.73 m2, the incidence was 6.4%, 3.7%, and 0% respectively.

Hypoglycaemia (ertugliflozin)

In the pool of placebo-controlled studies, the incidence of documented hypoglycaemia was increased for ertugliflozin 5 mg and 15 mg (5.0% and 4.5%) compared to placebo (2.9%). In this population, the

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incidence of severe hypoglycaemia was 0.4% in each group. When ertugliflozin was used as monotherapy, the incidence of hypoglycaemic events in the ertugliflozin groups was 2.6% in both groups and 0.7% in the placebo group. When used as add-on to metformin, the incidence of hypoglycaemic events was 7.2% in the ertugliflozin 5 mg group, 7.8% in the ertugliflozin 15 mg group and 4.3% in the placebo group.

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

In patients with moderate renal impairment taking insulins, SU, or meglitinides as background medication, documented hypoglycaemia was 36%, 27% and 36% for ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively (see sections 4.2, 4.4, and 4.5).

Diabetic ketoacidosis (ertugliflozin)

Across the clinical program for ertugliflozin, ketoacidosis was identified in 3 of 3,409 (0.1%) ertugliflozin-treated patients and 0.0% of comparator-treated patients (see section 4.4).

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

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

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.

Genital mycotic infections (ertugliflozin)

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%, and 3.0% of females treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. In females, discontinuation due to genital mycotic infections occurred in 0.6% and 0% of patients treated with ertugliflozin and placebo, respectively (see section 4.4).

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

4.9 Overdose

In the event of an overdose with Segluromet, employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status.

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Ertugliflozin

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

Metformin

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

5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering

drugs, ATC code: A10BD23.

Mechanism of action

Segluromet combines two antihyperglycaemic agents with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: ertugliflozin, a SGLT2 inhibitor, and metformin hydrochloride, a member of the biguanide class.

Ertugliflozin

SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Ertugliflozin is a potent, selective, and reversible inhibitor of SGLT2. By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Metformin

Metformin is an antihyperglycaemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and post -prandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycaemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation. Unlike sulphonylureas, metformin does not produce hypoglycaemia in either patients with type 2 diabetes or normal subjects, except in special circumstances (see section 4.5), and does not cause hyperinsulinaemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacodynamic effects

Ertugliflozin

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) in patients with type 2 diabetes mellitus, providing 87% and 96% of maximal inhibition, respectively.

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Clinical efficacy and safety

Ertugliflozin in combination with metformin

The efficacy and safety of ertugliflozin in combination with metformin have been studied in

4 multi-centre, randomised, double-blind, placebo- and active comparator-controlled, Phase 3 clinical studies involving 3,643 patients with type 2 diabetes. Across the four studies, the racial distribution ranged from 66.2% to 80.3% White, 10.6% to 20.3% Asian, 1.9% to 10.3% Black, and 4.5% to 7.4% other. Hispanic or Latino patients comprised 15.6% to 34.5% of the population. The mean age of the patients across these four studies ranged from 55.1 to 59.1 years (range 21 years to 86 years); 15.6% to 29.9% of patients were ≥65 years of age and 0.6% to 3.8% were ≥75 years of age.

Ertugliflozin as add-on combination therapy with metformin

A total of 621 patients with type 2 diabetes inadequately controlled on metformin monotherapy (≥ 1,500 mg/day) participated in a randomised, double-blind, multi -centre, 26-week, placebo-controlled study to evaluate the efficacy and safety of ertugliflozin in combination with metformin. Patients were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo administered once daily in addition to continuation of background metformin therapy (see Table 2).

Table 2: Results at Week 26 from a placebo-controlled study for ertugliflozin used in combination with metformin*

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

† Least squares means adjusted for treatment, time, prior antihyperglycaemic medication (metformin monotherapy or metformin + another AHA), baseline eGFR (continuous), menopausal status randomisation stratum (men, premenopausal women, women who are perimenopausal or < 3 years postmenopausal, women who are ³ 3 years postmenopausal) 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 regression model using multiple imputation for missing data values).

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 in combination with sitagliptin 100 mg compared to the individual components. Patients with type 2 diabetes inadequately controlled on metformin monotherapy (≥ 1,500 mg/day) were randomised to one of five active-treatment arms: ertugliflozin 5 mg or 15 mg, sitagliptin 100 mg, or sitagliptin 100 mg in combination with 5 mg or 15 mg ertugliflozin administered once daily in addition to continuation of background metformin therapy (see Table 3).

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Table 3: Results at Week 26 from a factorial study with ertugliflozin and sitagliptin as add-on combination therapy with metformin compared to individual components alone*

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

† Least squares means adjusted for treatment, 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 ratio comparisons 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 randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo administered once daily in addition to continuation of background metformin and sitagliptin therapy (see Table 4).

Table 4: Results at Week 26 from an add-on study of ertugliflozin in combination with metformin and sitagliptin*

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

†   Least squares means adjusted for treatment, time, prior antihyperglycaemic medication.

‡   p£ 0.001 compared to placebo.

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

A total of 1,326 patients with type 2 diabetes inadequately controlled on metformin monotherapy participated in a randomised, double-blind, multi-centre, 52-week, active comparator-controlled study to evaluate the efficacy and safety of ertugliflozin in combination with metformin. These patients, who were receiving metformin monotherapy (≥ 1,500 mg/day), were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or glimepiride administered once daily in addition to continuation of background metformin therapy. Glimepiride was initiated at 1 mg/day and titrated up to a maximum dose of 6 or 8 mg/day (depending on maximum approved dose in each country) or a maximum tolerated dose or down-titrated to avoid or manage hypoglycaemia. The mean daily dose of glimepiride was 3.0 mg (see Table 5).

Table 5: Results at Week 52 from an active-controlled study comparing ertugliflozin to glimepiride as add-on therapy in patients inadequately controlled on metformin*

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

† Least squares means adjusted for treatment, time, prior antihyperglycaemic medication (monotherapy or dual therapy),

baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.

‡ Non-inferiority is declared when the upper bound of the two-sided 95% confidence interval (CI) for the mean difference is

less than 0.3%.

§ p< 0.001 compared to glimepiride.

Fasting plasma glucose

In three placebo-controlled studies, ertugliflozin resulted in statistically significant reductions in FPG. For ertugliflozin 5 mg and 15 mg, respectively, the placebo-corrected reductions in FPG were 1.92 and 2.44 mmol/l as monotherapy, 1.48 and 2.12 mmol/l as add-on to metformin, and 1.40 and 1.74 mmol/l as add-on to metformin and sitagliptin.

The combination of ertugliflozin and sitagliptin on a background of metformin resulted in significantly greater reductions in FPG compared to sitagliptin or ertugliflozin alone. The combination of ertugliflozin 5 or 15 mg and sitagliptin resulted in incremental FPG reductions of 0.46 and

0.65 mmol/l compared to the ertugliflozin alone or 1.02 and 1.28 mmol/l compared to sitagliptin alone, respectively.

Efficacy in patients with baseline HbA1c ≥ 9%

In the study of ertugliflozin in combination with metformin in patients with baseline HbA1c from 7.0-10.5%, the placebo-corrected reductions in HbA1c for the subgroup of patients in the study with baseline HbA1c ≥ 9% were 1.31% and 1.43% with ertugliflozin 5 mg and 15 mg, respectively.

In the study of patients inadequately controlled on metformin with baseline HbA1c from 7.5-11.0%, among the subgroup of patients with a baseline HbA1c ≥ 10%, the combination of ertugliflozin 5 mg or 15 mg with sitagliptin resulted in reductions of HbA1c of 2.35% and 2.66%, respectively, compared to 2.10%, 1.30%, and 1.82% for ertugliflozin 5 mg, ertugliflozin 15 mg, and sitagliptin alone, respectively.

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Blood pressure

As add-on to metformin, ertugliflozin 5 mg and 15 mg resulted in statistically significant placebo-corrected reductions in SBP of 3.7 mmHg and 4.5 mmHg, respectively. As add-on to metformin and sitagliptin, ertugliflozin 5 mg and 15 mg resulted in statistically significant placebo-corrected reductions in SBP of 2.9 mmHg and 3.9 mmHg, respectively.

In a 52-week, active-controlled study versus glimepiride, reductions from baseline in SBP were

2.2 mmHg and 3.8 mmHg for ertugliflozin 5 mg and 15 mg, respectively, while subjects treated with glimepiride had an increase in SBP from baseline of 1.0 mmHg.

Subgroup analysis

In patients with type 2 diabetes treated with ertugliflozin in combination with metformin, clinically meaningful reductions in HbA1c were observed in subgroups defined by age, sex, race, ethnicity, geographic region, baseline BMI, baseline HbA1c, and duration of type 2 diabetes mellitus.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Segluromet in all subsets of the paediatric population in the treatment of type 2 diabetes (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Segluromet

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

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, with 5 mg ertugliflozin once daily treatment, and 1,193 ng∙hr/ml and 268 ng/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 post-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 from 1 mg to 100 mg. The absolute oral bioavailability of ertugliflozin following administration of a 15-mg dose is approximately 100%.

Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin Cmax by 29% and prolongs Tmax by 1 hour, but does not alter AUC as compared with the fasted state. The observed effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and

ertugliflozin may be administered with or without food. In Phase 3 clinical trials, ertugliflozin was administered without regard to meals.

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

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

Distribution

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 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.

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

Biotransformation

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

Elimination

The mean systemic plasma clearance following an intravenous 100 µg dose was 11 l/hr. The mean elimination half-life in type 2 diabetic patients with normal renal function was estimated to be

17 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-related radioactivity was eliminated in faeces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged ertugliflozin in urine and 34% 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 eGFR), following a single-dose administration of 15 mg ertugliflozin, 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). 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 population

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 a clinically meaningful effect on the pharmacokinetics of ertugliflozin.

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Drug Interactions

In vitroassessment of ertugliflozin

Inin 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 and ertugliflozin glucuronides did not inhibit the activity of UGTs 1A6, 1A9 or 2B7in vitro. Ertugliflozin was a weak inhibitor of UGTs 1A1 and 1A4in vitro at higher concentrations that are not clinically relevant. Ertugliflozin glucuronides had no effect on these isoforms. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered drugs eliminated by these enzymes.

Ertugliflozin or ertugliflozin glucuronides do not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 transporters or transporting polypeptides OATP1B1 and OATP1B3 at clinically relevant concentrationsin vitro. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are substrates of these transporters.

Metformin

Absorption

The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady-state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 µg/ml. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.

Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850-mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654 ± 358 l. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes.

Biotransformation

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours.

Special populations

Renal impairment

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in eGFR (see sections 4.3 and 4.4).

Hepatic impairment

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

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Effects of age, body weight, gender and race

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

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

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

5.3 Preclinical safety data

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

General toxicity

Ertugliflozin

Repeat-dose oral toxicity studies were conducted in mice, rats, and dogs for up to 13, 26, and

39 weeks, respectively. Signs of toxicity that were considered adverse were generally observed at exposures greater than or equal to 77 times the human unbound exposure (AUC) at the maximum recommended human dose (MRHD) of 15 mg/day. Most toxicity was consistent with pharmacology related to urinary glucose loss and included decreased body weight and body fat, increased food consumption, diarrhoea, dehydration, decreased serum glucose and increases in other serum parameters reflective of increased protein metabolism, gluconeogenesis and electrolyte imbalances, and urinary changes such as polyuria, glucosuria, and calciuria. Microscopic changes related to glucosuria and/or calciuria observed only in rodents included dilatation of renal tubules, hypertrophy of 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) at the MRHD of 15 mg/day.

Carcinogenesis

Ertugliflozin

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 to

40 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 doses of 1.5, 5, and 15 mg/kg/day. Ertugliflozin-related neoplastic findings included an increased incidence of benign adrenal medullary pheochromocytoma in male rats at 15 mg/kg/day. This finding was attributed to carbohydrate malabsorption leading to altered calcium homeostasis and was not considered 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).

Metformin

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

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Mutagenesis

Ertugliflozin

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

Metformin

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

Reproductive toxicology

Ertugliflozin

In the rat fertility and embryonic development study, male and female rats were administered ertugliflozin 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 AUC comparisons). Ertugliflozin did not adversely affect developmental outcomes in rats and rabbits at maternal exposures that were 239 and 1,069 times, respectively, the human exposure at the maximum clinical dose of 15 mg/day, based on AUC. At a maternally toxic dose in rats (250 mg/kg/day), lower foetal viability and a higher incidence of a visceral malformation were observed at maternal exposure that 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 were observed 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 of

15 mg/day, based on AUC). Sexual maturation was delayed in both sexes at 250 mg/kg/day (estimated

620 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, a period of renal development corresponding to the late second and third trimesters of human pregnancy, increased kidney weights, dilatation of the renal pelvis and tubules, and renal tubular mineralization 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 effects of delayed puberty were observed at an exposure 817 times the MHRD of 15 mg/day based on AUC. The effects on kidney and bone did not fully reverse after the 1-month recovery period.

Metformin

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons. Metformin did not adversely affect developmental outcomes when administered to rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the exposure at the maximum recommended human dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of foetal concentrations demonstrated a partial placental barrier to metformin.

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6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Tablet core

Povidone K29-32 (E1201)

Microcrystalline cellulose (E460)

Crospovidone (E1202)

Sodium lauryl sulfate (E487)

Magnesium stearate (E470b)

Film coating

Segluromet 2.5 mg/850 mg film-coated tablets and Segluromet 7.5 mg/850 mg film-coated tablets

Hypromellose (E464)

Hydroxypropyl cellulose (E463)

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Iron oxide black (E172)

Carnauba wax (E903)

Film coating

Segluromet 2.5 mg/1,000 mg film-coated tablets and Segluromet 7.5 mg/1,000 mg film-coated tablets

Hypromellose (E464)

Hydroxypropyl cellulose (E463)

Titanium dioxide (E171)

Iron oxide red (E172)

Carnauba wax (E903)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Alu/PVC/PA/Alu blisters.

Packs of 14, 28, 56, 60, 168, and 180 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.

6.6 Special precautions for disposal

No special requirements.

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7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd.

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

Segluromet 2.5 mg/850 mg film-coated tablets

EU/1/18/1265/001

EU/1/18/1265/002

EU/1/18/1265/003

EU/1/18/1265/004

EU/1/18/1265/005

EU/1/18/1265/006

EU/1/18/1265/007

Segluromet 2.5 mg/1,000 mg film-coated tablets

EU/1/18/1265/008

EU/1/18/1265/009

EU/1/18/1265/010

EU/1/18/1265/011

EU/1/18/1265/012

EU/1/18/1265/013

EU/1/18/1265/014

Segluromet 7.5 mg/850 mg film-coated tablets

EU/1/18/1265/015

EU/1/18/1265/016

EU/1/18/1265/017

EU/1/18/1265/018

EU/1/18/1265/019

EU/1/18/1265/020

EU/1/18/1265/021

Segluromet 7.5 mg/1,000 mg film-coated tablets

EU/1/18/1265/022

EU/1/18/1265/023

EU/1/18/1265/024

EU/1/18/1265/025

EU/1/18/1265/026

EU/1/18/1265/027

EU/1/18/1265/028

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY}

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

23

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

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A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Merck Sharp & Dohme B.V.

Waarderweg 39

2031 BN Haarlem

Netherlands

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

· Periodic safety update reports

The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

· Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

· At the request of the European Medicines Agency;

· Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

25

ANNEX III

LABELLING AND PACKAGE LEAFLET

26

A. LABELLING

27

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON FOR SEGLUROMET 2.5 mg/850 mg

1. NAME OF THE MEDICINAL PRODUCT

Segluromet 2.5 mg/850 mg film-coated tablets

ertugliflozin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 2.5 mg of ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 850 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets

28 film-coated tablets

30x1 film-coated tablets

56 film-coated tablets

60 film-coated tablets

168 film-coated tablets

180 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

28

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd.

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1265/001 (14 film-coated tablets)

EU/1/18/1265/002 (28 film-coated tablets)

EU/1/18/1265/003 (30x1 film-coated tablets)

EU/1/18/1265/004 (56 film-coated tablets)

EU/1/18/1265/005 (60 film-coated tablets)

EU/1/18/1265/006 (168 film-coated tablets)

EU/1/18/1265/007 (180 film-coated tablets)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Segluromet 2.5 mg/850 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:

SN:

NN:

29

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER FOR SEGLUROMET 2.5 mg/850 mg

1. NAME OF THE MEDICINAL PRODUCT

Segluromet 2.5 mg/850 mg tablets

ertugliflozin/metformin hydrochloride

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

30

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON FOR SEGLUROMET 2.5 mg/1000 mg

1. NAME OF THE MEDICINAL PRODUCT

Segluromet 2.5 mg/1000 mg film-coated tablets

ertugliflozin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 2.5 mg of ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 1000 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets

28 film-coated tablets

30x1 film-coated tablets

56 film-coated tablets

60 film-coated tablets

168 film-coated tablets

180 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

31

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd.

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1265/008 (14 film-coated tablets)

EU/1/18/1265/009 (28 film-coated tablets)

EU/1/18/1265/010 (30x1 film-coated tablets)

EU/1/18/1265/011 (56 film-coated tablets)

EU/1/18/1265/012 (60 film-coated tablets)

EU/1/18/1265/013 (168 film-coated tablets)

EU/1/18/1265/014 (180 film-coated tablets)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Segluromet 2.5 mg/1000 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:

SN:

NN:

32

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER FOR SEGLUROMET 2.5 mg/1000 mg

1. NAME OF THE MEDICINAL PRODUCT

Segluromet 2.5 mg/1000 mg tablets

ertugliflozin/metformin hydrochloride

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

33

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON FOR SEGLUROMET 7.5 mg/850 mg

1. NAME OF THE MEDICINAL PRODUCT

Segluromet 7.5 mg/850 mg film-coated tablets

ertugliflozin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 7.5 mg of ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 850 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets

28 film-coated tablets

30x1 film-coated tablets

56 film-coated tablets

60 film-coated tablets

168 film-coated tablets

180 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

34

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd.

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1265/015 (14 film-coated tablets)

EU/1/18/1265/016 (28 film-coated tablets)

EU/1/18/1265/017 (30x1 film-coated tablets)

EU/1/18/1265/018 (56 film-coated tablets)

EU/1/18/1265/019 (60 film-coated tablets)

EU/1/18/1265/020 (168 film-coated tablets)

EU/1/18/1265/021 (180 film-coated tablets)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Segluromet 7.5 mg/850 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:

SN:

NN:

35

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER FOR SEGLUROMET 7.5 mg/850 mg

1. NAME OF THE MEDICINAL PRODUCT

Segluromet 7.5 mg/850 mg tablets

ertugliflozin/metformin hydrochloride

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

36

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON FOR SEGLUROMET 7.5 mg/1000 mg

1. NAME OF THE MEDICINAL PRODUCT

Segluromet 7.5 mg/1000 mg film-coated tablets

ertugliflozin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 7.5 mg of ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 1000 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets

28 film-coated tablets

30x1 film-coated tablets

56 film-coated tablets

60 film-coated tablets

168 film-coated tablets

180 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

37

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd.

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1265/022 (14 film-coated tablets)

EU/1/18/1265/023 (28 film-coated tablets)

EU/1/18/1265/024 (30x1 film-coated tablets)

EU/1/18/1265/025 (56 film-coated tablets)

EU/1/18/1265/026 (60 film-coated tablets)

EU/1/18/1265/027 (168 film-coated tablets)

EU/1/18/1265/028 (180 film-coated tablets)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Segluromet 7.5 mg/1000 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:

SN:

NN:

38

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER FOR SEGLUROMET 7.5 mg/1000 mg

1. NAME OF THE MEDICINAL PRODUCT

Segluromet 7.5 mg/1000 mg tablets

ertugliflozin/metformin hydrochloride

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

39

B. PACKAGE LEAFLET

40

Package leaflet: Information for the patient

Segluromet 2.5 mg/850 mg film-coated tablets

Segluromet 2.5 mg/1,000 mg film-coated tablets

Segluromet 7.5 mg/850 mg film-coated tablets

Segluromet 7.5 mg/1,000 mg film-coated tablets

ertugliflozin/metformin hydrochloride

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

· Keep this leaflet. You may need to read it again.

· If you have any further questions, ask your doctor, pharmacist, or nurse.

· This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

· If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Segluromet is and what it is used for

2. What you need to know before you take Segluromet

3. How to take Segluromet

4. Possible side effects

5. How to store Segluromet

6. Contents of the pack and other information

1. What Segluromet is and what it is used for

What Segluromet is

Segluromet contains two active substances, ertugliflozin and metformin.

· Ertugliflozin belongs to a group of medicines called sodium glucose co-transporter-2 (SGLT2) inhibitors.

· Metformin belongs to a group of medicines called biguanides.

What Segluromet is used for

· Segluromet lowers blood sugar levels in adult patients (aged 18 years and older) with type 2 diabetes.

· Segluromet can be used instead of taking both ertugliflozin and metformin as separate tablets.

· Segluromet can be used alone or with some other medicines that lower blood sugar.

· You need to keep following your food and exercise plan while taking Segluromet.

How Segluromet works

· Ertugliflozin works by blocking the SGLT2 protein in your kidneys. This causes blood sugar to be removed in your urine.

· Metformin works by inhibiting sugar (glucose) production in the liver.

What is type 2 diabetes?

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

41

2. What you need to know before you take Segluromet

Do not take Segluromet:

· if you are allergic to ertugliflozin or metformin or any of the other ingredients of this medicine (listed in section 6).

· if you have severely reduced kidney function or need dialysis.

· if you have uncontrolled diabetes, with, for example, severe hyperglycaemia (high blood glucose), nausea, vomiting, diarrhoea, rapid weight loss, lactic acidosis (see “Risk of lactic acidosis” below) or ketoacidosis. Ketoacidosis is a condition in which substances called ‘ketone bodies’ accumulate in the blood and which can lead to diabetic pre-coma. Symptoms include stomach pain, fast and deep breathing, sleepiness, or your breath developing an unusual fruity smell.

· if you have a severe infection or are dehydrated.

· if you have recently had a heart attack or have severe circulatory problems, such as ‘shock’ or breathing difficulties.

· if you have liver problems.

· if you drink alcohol to excess (either regularly or from time to time).

Do not take Segluromet if any of the above apply to you. If you are not sure, talk to your doctor before taking Segluromet.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before and while taking Segluromet, if you:

· have kidney problems.

· have or have had yeast infections of the vagina or penis.

· have ever had serious heart disease or if you have had a stroke.

· have type 1 diabetes. Segluromet should not be used to treat this condition.

· take other diabetes medicines; you are more likely to get low blood sugar with certain medicines.

· might be at risk of dehydration (for example, if you are taking medicines that increase urine production [diuretics] lower blood pressure or if you are over 65 years old). Ask about ways to prevent dehydration.

· experience rapid weight loss, feeling sick or being sick, stomach pain, excessive thirst, fast and deep breathing, confusion, unusual sleepiness or tiredness, a sweet smell to your breath, a sweet or metallic taste in your mouth or a different odour to your urine or sweat, contact a doctor or the nearest hospital straight away. These symptoms could be a sign of “diabetic ketoacidosis” – a problem you can get with diabetes because of increased levels of “ketone bodies” in your urine or blood, seen in tests. The risk of developing diabetic ketoacidosis may be increased with prolonged fasting, excessive alcohol consumption, dehydration, sudden reductions in insulin dose, or a higher need of insulin due to major surgery or serious illness.

When this medicine is used in combination with insulin or medicines that increase insulin release from the pancreas, low blood sugar (hypoglycaemia) can occur. Your doctor may reduce the dose of your insulin or other medicine.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Risk of lactic acidosis

Segluromet may cause a very rare, but very serious side effect called lactic acidosis, particularly if your kidneys are not working properly. The risk of developing lactic acidosis is also increased with uncontrolled diabetes, serious infections, prolonged fasting or alcohol intake, dehydration (see further information below), liver problems and any medical conditions in which a part of the body has a reduced supply of oxygen (such as acute severe heart disease).

If any of the above apply to you, talk to your doctor for further instructions.

42

Stop taking Segluromet for a short time if you have a condition that may be associated with dehydration (significant loss of body fluids) such as severe vomiting, diarrhoea, fever, exposure to heat or if you drink less fluid than normal. Talk to your doctor for further instructions.

Stop taking Segluromet and contact a doctor or the nearest hospital immediately if you experience some of the symptoms of lactic acidosis, as this condition may lead to coma. Symptoms of lactic acidosis include:

· vomiting

· stomach ache (abdominal pain)

· muscle cramps

· a general feeling of not being well with severe tiredness

· difficulty in breathing

· reduced body temperature and heartbeat

Lactic acidosis is a medical emergency and must be treated in a hospital.

If you need to have major surgery you must stop taking Segluromet during and for some time after the procedure. Your doctor will decide when you must stop and when to restart your treatment with Segluromet.

During treatment with Segluromet, your doctor will check your kidney function at least once a year or more frequently if you are elderly and/or if you have worsening kidney function.

Foot care

Like for all diabetic patients it is important to check your feet regularly and adhere to any other advice regarding foot care given by your health care professional.

Urine glucose

Because of how Segluromet works, your urine will test positive for sugar (glucose) while you are on this medicine.

Children and adolescents

Children and adolescents below 18 years should not take this medicine. It is not known if this medicine is safe and effective when used in children and adolescents under 18 years of age.

Other medicines and Segluromet

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

You may need more frequent blood glucose and kidney function tests, or your doctor may need to adjust the dose of Segluromet. In particular, tell your doctor:

· if you are taking medicines which increase urine production (diuretics).

· if you are taking other medicines that lower the sugar in your blood, such as insulin or medicines that increase insulin release from the pancreas.

· if you are taking medicines used to treat pain and inflammation (NSAID and COX-2-inhibitors, such as ibuprofen and celecoxib).

· if you are taking certain medicines for the treatment of high blood pressure (ACE inhibitors and

angiotensin II receptor antagonists).

If any of the above apply to you (or you are not sure), tell your doctor.

If you need to have an injection of a contrast medium that contains iodine into your bloodstream, for example, in the context of an X-ray or scan, you must stop taking Segluromet before or at the time of the injection. Your doctor will decide when you must stop and when to restart your treatment with Segluromet.

43

Segluromet with alcohol

Avoid excessive alcohol intake while taking Segluromet since this may increase the risk of lactic acidosis (see section “Warnings and precautions”).

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

It is not known if Segluromet can harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant. You should not use Segluromet if you are pregnant.

It is not known if Segluromet passes into breast milk. Talk with your doctor about the best way to feed your baby if you take this medicine. You should not use Segluromet if you are breast-feeding.

Driving and using machines

This medicine has no or negligible influence on the ability to drive and use machines. Taking this medicine in combination with insulin or medicines that increase insulin release from the pancreas 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 Segluromet.

3. How to take Segluromet

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

How much to take

· The recommended dose of Segluromet is one tablet twice a day.

· The dose of Segluromet that you take will depend on your condition and the amount of ertugliflozin and metformin needed to control your blood sugar.

· Your doctor will prescribe the right dose for you. Do not change your dose unless your doctor has told you to.

Taking this medicine

· Swallow the tablet; if you have difficulties in swallowing the tablet can be broken or crushed.

· Take one tablet twice daily. Try to take it at the same time each day; this will help you remember to take it.

· It is best to take your tablet with a meal. This will lower your chance of having an upset stomach.

· You need to keep following your food and exercise plan while taking Segluromet.

If you take more Segluromet than you should

If you take too much Segluromet, talk to a doctor or pharmacist straight away.

If you forget to take Segluromet

If you forget a dose, take it as soon as you remember. However, if it is nearly time for your next dose, skip the missed dose and go back to your regular schedule.

Do not take a double dose (two doses at the same time) to make up for a forgotten dose.

If you stop taking Segluromet

Do not stop taking this medicine without talking to your doctor. Your blood sugar levels may increase if you stop the medicine.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

44

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Contact a doctor or the nearest hospital straight away if you have any of the following serious side effects:

Lactic acidosis (very rare, may affect up to 1 in 10,000 people)

Segluromet may cause a very rare, but very serious side effect called lactic acidosis (see section “Warnings and precautions”). If this happens, you must stop taking Segluromet and contact a doctor or the nearest hospital immediately, as lactic acidosis may lead to coma.

Diabetic ketoacidosis (rare, may affect up to 1 in 1,000 people)

These are the signs of diabetic ketoacidosis (see also section “Warnings and precautions”):

· increased levels of “ketone bodies” in your urine or blood

· rapid weight loss

· feeling sick or being sick

· stomach pain

· excessive thirst

· fast and deep breathing

· confusion

· unusual sleepiness or tiredness

· a sweet smell to your breath, a sweet or metallic taste in your mouth or a different odour to your

urine or sweat

This may occur regardless of blood glucose level. Your doctor may decide to temporarily or permanently stop your treatment with Segluromet.

If you notice any of the side effects above, contact a doctor or the nearest hospital straight away.

Contact your doctor as soon as possible if you notice the following side effects:

Dehydration (losing too much water from your body; common, may affect up to 1 in 10 people)

Symptoms of dehydration include:

· 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 medicines that increase your urine production (diuretics) or lower blood pressure

· are 65 years or older

Low blood sugar (hypoglycaemia; common)

Your doctor will tell you how to treat low blood sugar and what to do if you have any of the symptoms or signs below. The doctor may lower the dose of your insulin or other diabetes medicine. Signs and symptoms of low blood sugar may include:

· headache

· drowsiness

· irritability

· hunger

· dizziness

· confusion

· sweating

· feeling jittery

45

· weakness

· fast heart beat

If you notice any of the side effects above, contact your doctor as soon as possible.

Other side effects include:

Very common

· vaginal yeast infection (thrush)

· feeling sick (nausea)

· vomiting

· diarrhoea

· stomach ache

· loss of appetite

Common

· yeast infections of the penis

· changes in urination, including urgent need to urinate more often, in larger amounts, or at night

· thirst

· vaginal itching

· change in taste

· blood tests may show changes in the amount of urea in your blood

· blood tests may show changes in the amount of total and bad cholesterol (called LDL - a type of fat in your blood)

· blood tests may show changes in the amount of red blood cells in your blood (called haemoglobin)

Uncommon (may affect up to 1 in 100 people)

· blood tests may show changes related to kidney function (such as ‘creatinine’)

· painful urination

Very rare

· decreased vitamin B12 levels. This may cause anaemia (low levels of red blood cells).

· liver function test disorders

· hepatitis (a liver problem)

· hives

· redness of the skin

· itching

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Segluromet

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP.

The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not use this medicine if the packaging is damaged or shows signs of tampering.

46

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information What Segluromet contains

· The active substances are ertugliflozin and metformin.

o Each Segluromet 2.5 mg/850 mg film-coated tablet contains 2.5 mg ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 850 mg of metformin hydrochloride.

o Each Segluromet 2.5 mg/1,000 mg film-coated tablet contains 2.5 mg ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 1,000 mg of metformin hydrochloride.

o Each Segluromet 7.5 mg/850 mg film-coated tablet contains 7.5 mg ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 850 mg of metformin hydrochloride.

o Each Segluromet 7.5 mg/1,000 mg film-coated tablet contains 7.5 mg ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 1,000 mg of metformin hydrochloride.

· The other ingredients are:

o Tablet core: povidone (E1201), microcrystalline cellulose (E460), crospovidone (E1202), sodium lauryl sulfate (E487), magnesium stearate (E470b).

· Film coating:

o Segluromet 2.5 mg/850 mg tablets and Segluromet 7.5 mg/850 mg tablets: hypromellose (E464), hydroxypropyl cellulose (E463), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172), iron oxide black (E172), carnauba wax (E903).

o Segluromet 2.5 mg/1,000 mg tablets and Segluromet 7.5 mg/1,000 mg tablets: hypromellose (E464), hydroxypropyl cellulose (E463), titanium dioxide (E171), iron oxide red (E172), carnauba wax (E903).

What Segluromet looks like and contents of the pack

· Segluromet 2.5 mg/850 mg film-coated tablets (tablets) are beige, 18 x 10 mm oval, film-coated tablets debossed with “2.5/850” on one side and plain on the other side.

· Segluromet 2.5 mg/1,000 mg film-coated tablets (tablets) are pink, 19.1 x 10.6 mm oval, film-coated tablets debossed with “2.5/1000” on one side and plain on the other side.

· Segluromet 7.5 mg/850 mg film-coated tablets (tablets) are dark brown, 18 x 10 mm oval, film-coated tablets debossed with “7.5/850” on one side and plain on the other side.

· Segluromet 7.5 mg/1,000 mg film-coated tablets (tablets) are red, 19.1 x 10.6 mm oval, film-coated tablets debossed with “7.5/1000” on one side and plain on the other side.

Segluromet is available in Alu/PVC/PA/Alu blisters. The pack sizes are 14, 28, 56, 60, 168, and

180 film-coated tablets in non-perforated blisters and 30x1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder Manufacturer

Merck Sharp & Dohme Ltd. Merck Sharp & Dohme BV

Hertford Road, Hoddesdon Waarderweg 39

Hertfordshire 2031 BN, Haarlem

EN11 9BU The Netherlands

United Kingdom

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

47

België/Belgique/Belgien MSD Belgium BVBA/SPRL

Tél/Tel: 0800 38 693 (+32(0)27766211)

dpoc_belux@merck.com

България

Мерк Шарп и Доум България ЕООД Teл.: + 359 2 819 3737 info-msdbg@merck.com

Česká republika

Merck Sharp & Dohme s.r.o.

Tel.: +420 233 010 111

dpoc_czechslovak@merck.com

Danmark

MSD Danmark ApS

Tlf: +45 4482 4000

dkmail@merck.com

Deutschland

MSD SHARP & DOHME GMBH

Tel: 0800 673 673 673 (+49 (0) 89 4561 2612) e-mail@msd.de

Eesti

Merck Sharp & Dohme OÜ Tel: + 372 6144 200 msdeesti@merck.com

Ελλάδα

MSD Α.Φ.Β.Ε.Ε.

Τηλ: + 30 210 98 97 300

dpoc_greece@merck.com

España

Merck Sharp & Dohme de España, S.A. Tel: +34 91 321 06 00 msd_info@merck.com

France

MSD France

Tél: + 33 (0) 1 80 46 40 40

Hrvatska

Merck Sharp & Dohme d.o.o. Tel: + 385 1 6611 333 croatia_info@merck.com

Ireland

Merck Sharp & Dohme Ireland (Human Health) Limited

Tel: +353 (0)1 2998700 medinfo_ireland@merck.com

Lietuva

UAB Merck Sharp & Dohme Tel: + 370 5 2780247 msd_lietuva@merck.com

Luxembourg/Luxemburg MSD Belgium BVBA/SPRL Tél/Tel: +32(0)27766211 dpoc_belux@merck.com

Magyarország

MSD Pharma Hungary Kft. Tel.: + 36 1 888-5300 hungary_msd@merck.com

Malta

Merck Sharp & Dohme Cyprus Limited Tel: 8007 4433 (+356 99917558) malta_info@merck.com

Nederland

Merck Sharp & Dohme BV

Tel: 0800 9999 000 (+ 31 23 515 3153)

medicalinfo.nl@merck.com

Norge

MSD (Norge) AS

Tlf: + 47 32 20 73 00

msdnorge@msd.no

Österreich

Merck Sharp & Dohme Ges.m.b.H. Tel: +43 (0) 1 26 044 msd-medizin@merck.com

Polska

MSD Polska Sp. z o.o.

Tel.: +48 22 549 51 00

msdpolska@merck.com

Portugal

Merck Sharp & Dohme, Lda Tel: + 351 21 4465700 clic@merck.com

România

Merck Sharp & Dohme Romania S.R.L. Tel: +40 21 529 29 00 msdromania@merck.com

Slovenija

Merck Sharp & Dohme, inovativna zdravila d.o.o.

Tel: + 386 1 5204201

msd_slovenia@merck.com

48

Ísland

Vistor hf.

Sími: + 354 535 7000

Italia

MSD Italia S.r.l.

Tel: +39 06 361911

medicalinformation.it@merck.com

Κύπρος

Merck Sharp & Dohme Cyprus Limited Τηλ: 800 00 673

+357 22866700

cyprus_info@merck.com

Latvija

SIA Merck Sharp & Dohme Latvija Tel: + 371 67 364224 msd_lv@merck.com

Slovenská republika

Merck Sharp & Dohme, s.r.o.

Tel: + 421 (2) 58282010

dpoc_czechslovak@merck.com

Suomi/Finland

MSD Finland Oy

Puh/Tel: + 358 (0)9 804650

info@msd.fi

Sverige

Merck Sharp & Dohme (Sweden) AB Tfn: + 46 (0)77 570 04 88 medicinskinfo@merck.com

United Kingdom

Merck Sharp & Dohme Limited Tel: +44 (0) 1992 467272 medicalinformationuk@merck.com

This leaflet was last revised in {MM/YYYY}

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu.