Sinjardi film-coated tablets 12.5 mg + 1000 mg blister No. 60

Instructions for Sinjardi film-coated tablets 12.5 mg + 1000 mg blister No. 60

Composition

active ingredient: empagliflozin, metformin hydrochloride;

1 tablet contains 12.5 mg of empagliflozin and 1000 mg of metformin hydrochloride;

excipients: corn starch, copovidone, colloidal anhydrous silicon dioxide, magnesium stearate, film coating Opadry® Purple 02B200006;

composition of the film shell Opadry® Purple 02B200006: hypromellose 2910, macrogol 400, titanium dioxide (E 171), black iron oxide (E 172), red iron oxide (E 172), talc;

Dosage form

Film-coated tablets.

Main physicochemical properties: oval, biconvex, film-coated tablets, purple-brown in color, engraved with the Boehringer Ingelheim company symbol and "S12" on one side and engraved with "1000" on the other side.

Pharmacotherapeutic group

Drugs used in diabetes. Combination of oral hypoglycemic drugs.

ATX code A10B D20.

Pharmacological properties

Pharmacodynamics

Mechanism of action.

SYNJARDI combines two hypoglycemic drugs designed to improve glycemic control in patients with type 2 diabetes mellitus, whose mechanisms of action are complementary: empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin hydrochloride, a member of the biguanide class.

Empagliflozin

Empagliflozin is a reversible potent (IC50 1.3 nmol) and selective competitive inhibitor of sodium-glucose cotransporter 2 (SGLT2). Empagliflozin does not inhibit other glucose transporters that play an important role in glucose delivery to peripheral tissues and is 5000-fold more selective for SGLT2 compared to SGLT1, the main transporter responsible for glucose absorption in the intestine. SGLT2 is expressed at high levels in the kidney, while expression is absent or very low in other tissues. It is responsible, as the main transporter, for the reabsorption of glucose from the tubular lumen back into the bloodstream. In patients with type 2 diabetes and hyperglycemia, more glucose is filtered and absorbed.

Empagliflozin improves glycemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption. The amount of glucose excreted by the kidneys through this glucuretic mechanism depends on the blood glucose concentration and glomerular filtration rate (GFR). Inhibition of SGLT2 in patients with type 2 diabetes mellitus and hyperglycemia results in excess urinary glucose excretion.

In patients with type 2 diabetes mellitus, glucose excretion increased immediately after the first dose of empagliflozin and was maintained over the 24-hour dosing interval. The increase in urinary glucose excretion was maintained at the end of the 4-week treatment period and averaged approximately 78 g/day with empagliflozin 25 mg. The increase in urinary glucose excretion resulted in an immediate decrease in plasma glucose levels in patients with type 2 diabetes. In addition, empagliflozin increases sodium excretion, leading to osmotic diuresis and intravascular volume depletion.

Empagliflozin improves plasma glucose levels both in the fasting and postprandial state. The mechanism of action of empagliflozin is independent of beta-cell function and the insulin pathway, which contributes to a reduced risk of hypoglycemia. Improvements in markers of beta-cell function, including the homeostatic model of β-cell function assessment (HOMA-β), have been observed. In addition, urinary glucose excretion contributes to calorie loss associated with fat loss and weight loss. The glucosuria observed with empagliflozin is accompanied by a modest diuresis, which may contribute to a long-term and modest reduction in blood pressure. The glucosuria, natriuresis, and osmotic diuresis observed with empagliflozin may contribute to improved cardiovascular outcomes.

Metformin

Metformin belongs to the group of biguanides, which have hypoglycemic properties and help reduce blood glucose levels both on an empty stomach and after meals. It does not stimulate insulin production, therefore it does not lead to the development of hypoglycemia.

The action of metformin is due to three mechanisms:

reduction of glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis; increased muscle sensitivity to insulin, improved glucose uptake by peripheral tissues and its utilization; slowing down of glucose absorption in the intestine.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase. Metformin improves the functional activity of all known types of glucose transporters.

Independently of its effect on glycemia, metformin has a beneficial effect on lipid metabolism in humans. This has been demonstrated in controlled medium-term and long-term clinical trials with metformin at therapeutic doses: metformin reduces total cholesterol, low-density lipoprotein cholesterol, and triglycerides.

Clinical efficacy and safety

Treatment with empagliflozin, in combination with metformin and other antidiabetic agents (pioglitazone, sulfonylureas, DPP-4 inhibitors and insulin) or without them, resulted in clinically meaningful improvements in HbA1c, fasting plasma glucose (FPG), body weight, systolic and diastolic blood pressure. Empagliflozin 25 mg increased the proportion of patients achieving the target HbA1c of less than 7% and reduced the number of patients requiring glycemic therapy compared with empagliflozin 10 mg and placebo. The higher the baseline HbA1c, the greater the reduction with the drug.

In addition, empagliflozin, as an add-on to standard therapy, reduces cardiovascular mortality and cardiovascular disease in patients with type 2 diabetes.

Cardiovascular prognosis

The double-blind, placebo-controlled study EMPA-REG OUTCOME compared the efficacy of empagliflozin 10 mg and 25 mg and placebo as an adjunct to standard therapy in patients with type 2 diabetes and established cardiovascular disease.

Empagliflozin was superior to placebo in preventing death from cardiovascular disease, non-fatal myocardial infarction, or non-fatal stroke. The effect was driven by a significant reduction in cardiovascular mortality without significant changes in non-fatal myocardial infarction or non-fatal stroke. The reduction in cardiovascular mortality was comparable for empagliflozin 10 mg and 25 mg (see graph below) and was supported by an improvement in overall survival (Table 1).

The efficacy in preventing cardiovascular mortality has not been definitively established in patients receiving empagliflozin concomitantly with DPP-4 inhibitors and in patients of black race, as the representation of these groups in the EMPA-REG OUTCOME study was limited.

Table 1. Treatment effect by main evaluation criteria, their components and mortalitya

a Data obtained from treated (TS) patients (i.e. patients who received at least one dose of study drug).

b Combined doses of empagliflozin 10 mg and 25 mg.

* Since the study results were included in the interim analysis, a two-sided confidence interval of 95.02% is used, which corresponds to a p value of < 0.0498 for significance.

Heart failure requiring hospitalization

In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of developing heart failure requiring hospitalization compared with placebo (empagliflozin group - 2.7%; placebo group - 4.1%; HR 0.65, 95% CI 0.50; 0.85).

Nephropathy

In the EMPA-REG OUTCOME study, the HR for time to first episode of nephropathy was 0.61 (95% CI 0.53; 0.70) in the empagliflozin group (12.7%) compared with the placebo group (18.8%).

In addition, empagliflozin increased the risk (HR 1.82; 95% CI 1.40; 2.37) of developing persistent normo- or microalbuminuria (49.7%) in patients with macroalbuminuria at baseline compared with placebo (28.8%).

Pharmacokinetics

Sinjardi drug

Results of bioequivalence studies in healthy volunteers indicate that the combination tablet formulation SYNJARDI (empagliflozin/metformin hydrochloride) 12.5 mg/1000 mg is bioequivalent to the corresponding doses of empagliflozin and metformin as separate tablets taken simultaneously.

Administration of empagliflozin/metformin 12.5 mg/1000 mg after food resulted in a 9% decrease in AUC and a 28% decrease in Cmax in the empagliflozin group compared to the fasted state. In the metformin group, AUC was decreased by 12% and Cmax was decreased by 26% compared to the fasted state. The observed effect of food on empagliflozin and metformin is not considered clinically relevant. However, since metformin is recommended to be administered with food, the drug

Empagliflozin

Absorption

The pharmacokinetics of empagliflozin have been described in detail in healthy volunteers and patients with type 2 diabetes. After oral administration, empagliflozin was rapidly absorbed, with peak plasma concentrations occurring at a mean tmax of 1.5 hours post-dose. Plasma concentrations then declined in a biphasic manner, with a rapid distribution phase and a relatively slow terminal phase. Mean steady-state plasma AUC and Cmax were 1870 nmol/h and 259 nmol/l for empagliflozin 10 mg and 4740 nmol/h and 687 nmol/l for empagliflozin 25 mg once daily. Systemic exposure to empagliflozin increased in a dose-proportional manner. The pharmacokinetic parameters of empagliflozin at rest after single-dose administration were similar, indicating linear pharmacokinetics with respect to time. There were no clinically relevant differences in the pharmacokinetics of empagliflozin between healthy volunteers and patients with type 2 diabetes.

The pharmacokinetics of empagliflozin 5 mg twice daily and empagliflozin 10 mg once daily were compared to those in healthy volunteers. The total exposure (AUCSS) of empagliflozin over 24 hours with empagliflozin 5 mg twice daily was similar to that with empagliflozin 10 mg once daily. As expected, empagliflozin 5 mg twice daily resulted in lower Cmax and higher trough plasma concentrations (Cmin) of empagliflozin compared to empagliflozin 10 mg once daily.

Administration of empagliflozin 25 mg after a high-calorie, high-fat meal resulted in a slight decrease in exposure; AUC was decreased by approximately 16% and Cmax by approximately 37% compared to administration in the fasted state. This effect of food on the pharmacokinetics of empagliflozin is not considered clinically relevant. Empagliflozin can be taken without regard to food. Similar results were obtained when SYNJARDI (empagliflozin/metformin) combination tablets were administered with a high-calorie and high-fat meal.

Distribution

The apparent volume of distribution at rest is 73.8 L based on a pharmacokinetic analysis in subjects. Following oral administration of [14C]-empagliflozin solution to healthy volunteers, erythrocyte partitioning was approximately 37% and plasma protein binding was 86%.

Biotransformation

No significant metabolites of empagliflozin were detected in human plasma. The most abundant metabolites were three glucuronide conjugates (2-, 3-, and 6-O-glucuronide). The systemic exposure of each metabolite accounted for less than 10% of the total drug-related material. In vitro studies indicate that the major route of metabolism of empagliflozin in humans is glucuronidation by uridine 5'-diphosphoglucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.

Breeding

Based on pharmacokinetic analysis in subjects, the apparent terminal half-life of empagliflozin is 12.4 hours and the apparent oral clearance is 10.6 L/h. The inter-subject variation and final change in oral clearance of empagliflozin were 39.1% and 35.8%, respectively. With once-daily dosing, steady-state plasma concentrations of empagliflozin were achieved by the 5th dose. Based on the half-life, up to 22% accumulation (based on plasma AUC) was observed at rest. Following oral administration of [14C]-empagliflozin to healthy volunteers, approximately 96% of the drug-related radioactivity was excreted in the feces (41%) or urine (54%). Unchanged parent drug accounted for the majority of the drug-related radioactivity excreted in the feces. Unchanged parent drug accounted for approximately half of the drug-related radioactivity excreted in the urine.

Special patient groups

Kidney dysfunction

In patients with mild, moderate or severe renal impairment (creatinine clearance <30 - <90 mL/min) and patients with renal insufficiency/end-stage renal disease (ESRD), the AUC of empagliflozin increased by approximately 18%, 20%, 66% and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and renal insufficiency/ESRD compared to subjects with normal renal function. Peak plasma levels of empagliflozin were approximately 20% higher in patients with mild and severe renal impairment compared to subjects with normal renal function. Based on pharmacokinetic analysis in subjects, the apparent oral clearance of empagliflozin decreased with decreasing creatinine clearance, resulting in enhanced drug exposure.

Liver dysfunction

In subjects with mild, moderate, and severe hepatic impairment according to Child-Pugh classification, empagliflozin AUC increased by approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.

Body mass index

Body mass index (BMI) had no clinically relevant effect on the pharmacokinetics of empagliflozin. AUC was 5.82%, 10.4%, and 17.3% lower in patients with a BMI of 30, 35, and 45 kg/m2, respectively, compared to patients with a BMI of 25 kg/m2.

Sex

Gender had no clinically significant effect on the pharmacokinetics of empagliflozin.

The AUC was 13.5% higher in patients of the Mongoloid race with a body mass index of 25 kg/m2 compared to patients of other races with a body mass index of 25 kg/m2.

Elderly patients

Age had no clinically significant effect on the pharmacokinetics of empagliflozin.

Children

A paediatric study investigated the pharmacokinetics and pharmacodynamics of empagliflozin (5 mg, 10 mg and 25 mg) in children and adolescents ≥ 10 - < 18 years of age with type 2 diabetes. The pharmacokinetic and pharmacodynamic data obtained were consistent with those in adults.

Metformin

Absorption

After an oral dose of metformin, the maximum concentration (Tmax) is reached after 2.5 hours. The absolute bioavailability of metformin hydrochloride tablets of 500 mg or 850 mg in healthy volunteers is approximately 50-60%. After oral administration, the unabsorbed fraction excreted in the feces was 20-30%. After oral administration, the absorption of metformin hydrochloride is saturable and incomplete. The pharmacokinetics of metformin hydrochloride absorption are considered non-linear. When the recommended doses and regimen of metformin are followed, plasma concentrations at rest are achieved within 24-48 hours and are generally less than 1 μg/ml. In controlled clinical studies, maximum plasma levels of metformin (Cmax) did not exceed 5 μg/ml, even at maximum doses.

Food reduces the extent and slightly delays the absorption of metformin. Following a dose of 850 mg metformin hydrochloride, a 40% decrease in peak plasma concentration, a 25% decrease in AUC (area under the curve), and a 35-minute delay in time to peak plasma concentration were observed. The clinical significance of these decreases is unknown.

Distribution

Plasma protein binding is negligible. Metformin is distributed into erythrocytes. Peak blood concentrations are lower than those in plasma and are reached at approximately the same time. Erythrocytes are likely to be a secondary distribution compartment. The mean volume of distribution (Vd) ranged from 63 to 276 liters.

Biotransformation

Metformin is excreted unchanged in the urine. Metabolites have not been identified in humans.

Breeding

Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.

As renal function deteriorates, renal clearance decreases in proportion to creatinine clearance, and thus the terminal elimination half-life is prolonged, leading to increased metformin plasma levels.

Special patient groups

Children

Single-dose study: After single doses of metformin hydrochloride 500 mg, the pharmacokinetic profile in children was comparable to that observed in healthy adult patients.

Multiple-dose study: After repeated doses of 500 mg twice daily for 7 days, peak plasma concentration (Cmax) and systemic exposure (AUC0-t) in children were reduced by approximately 33% and 40%, respectively, compared to adult diabetic patients receiving repeated doses of 500 mg twice daily for 14 days. Since the dose is individualized based on glycemic control, the clinical relevance of these data is considered limited.

Indication

Treatment of type 2 diabetes mellitus in adults as an adjunct to diet therapy and exercise regimen:

if the maximum tolerated dose of metformin alone is not sufficient; if metformin in combination with other antidiabetic medicinal products does not provide adequate glycaemic control; if patients are already receiving therapy with a combination of empagliflozin and metformin as separate medicinal products.

For the results of studies on the use of combinations, the effect on glycemic control and cardiovascular diseases, see the sections “Special instructions for use”, “Interaction with other medicinal products and other types of interactions” and “Pharmacological properties”.

Contraindication

Hypersensitivity to the active substances or to any of the excipients;

any type of metabolic acidosis (lactic acidosis, diabetic ketoacidosis) (see section "Special warnings and precautions for use");

diabetic precoma;

severe renal failure (GFR < 30 ml/min) (see sections “Special instructions” and “Method of administration and dosage”);

acute conditions that may alter renal function, such as dehydration, severe infection, shock (see sections "Adverse reactions" and "Special precautions for use");

acute or chronic diseases that may cause tissue hypoxia: heart or respiratory failure, recent myocardial infarction, shock (see section "Special instructions for use");

hepatic failure, acute alcohol intoxication, alcoholism (see sections “Method of administration and dosage” and “Interaction with other medicinal products and other types of interactions”).

Interaction with other medicinal products and other types of interactions

Drug interaction studies with SYNJARDI have not been conducted. The data presented reflect the known information for each active substance individually.

Empagliflozin

Pharmacodynamic interactions

Diuretics

Empagliflozin may enhance the diuretic effect of thiazide and loop diuretics and increase the risk of dehydration and hypotension (see section 4.4).

Insulin and insulin secretagogues

Insulin and insulin secretagogues such as sulfonylureas increase the risk of hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogues may be required to reduce the risk of hypoglycemia when used in combination with empagliflozin (see sections 4.2 and 4.8).

Pharmacokinetic interactions

Effects of other medicinal products on empagliflozin

In vitro data indicate that the major metabolic pathway of empagliflozin in humans is glucuronidation by uridine-5'-diphosphoglucuronosyltransferases UGT1A3, UGT1A8, UGT1A9 and UGT2B7. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1 and OATP1B3, but not OAT1 and OCT2. Empagliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein.

Co-administration of empagliflozin with probenecid, an inhibitor of the uridine diphosphate glucuronosyltransferase (UGT) and OAT3 enzymes, resulted in a 26% increase in the peak plasma concentration (Cmax) of empagliflozin and a 53% increase in the area under the concentration-time curve (AUC). These changes were not considered clinically relevant.

The effect of UGT induction (induction by rifampicin or phenytoin) on empagliflozin has not been studied. Use with known inducers of UGT enzymes is not recommended due to the potential risk of reduced efficacy. If concomitant use with inducers of UGT enzymes is necessary, monitoring of glycemic control is appropriate to assess the effect on SYNJARDI.

An in vitro interaction study with gemfibrozil, an inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that the Cmax of empagliflozin increased by 15% and the AUC decreased by 59% after co-administration. These changes were not considered clinically relevant.

Inhibition of OATP1B1/1B3 transporters when co-administered with rifampicin resulted in a 75% increase in Cmax and a 35% increase in AUC of empagliflozin. These changes were not considered clinically relevant.

The exposure of empagliflozin to verapamil, a P-gp inhibitor, was similar to that of empagliflozin alone, indicating that P-gp inhibition has no clinically relevant effect on empagliflozin.

Interaction studies indicate that the pharmacokinetics of empagliflozin are not affected by co-administration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide.

Effects of empagliflozin on other medicinal products

Empagliflozin does not inhibit, inactivate or induce CYP450 isoforms in in vitro studies. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9 or UGT2B7. Drug-drug interactions involving major CYP450 or UGT isoforms with empagliflozin and co-administered substrates of these enzymes are considered unlikely.

Empagliflozin does not inhibit P-gp at therapeutic doses. Based on in vitro studies, empagliflozin is unlikely to cause interactions with active substances that are P-gp substrates. Co-administration of digoxin, a P-gp substrate, with empagliflozin resulted in an increase in AUC and Cmax of digoxin of up to 6% and 14%, respectively. These changes were not considered clinically relevant.

Empagliflozin does not inhibit human uptake transporters such as OAT3, OATP1B1 and OATP1B3 in vitro at clinically relevant concentrations, i.e. drug-drug interactions with substrates of these uptake transporters are considered unlikely.

Results of interaction studies in healthy volunteers indicate that empagliflozin has no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics, and oral contraceptives.

Metformin

Combinations that are not recommended for use

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis (especially in cases of starvation, malnutrition, or liver failure).

Organic cation transporters (OCTs)

Metformin is a substrate of two transporters – OCT1 and OCT2.

Concomitant use of metformin:

with OCT1 inhibitors (such as verapamil) may reduce the efficacy of metformin; with OCT1 inducers (such as rifampicin) may increase the gastrointestinal absorption and efficacy of metformin; with OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal elimination of metformin and therefore lead to increased plasma metformin concentrations; with OCT1 and OCT2 inhibitors (such as crizotinib, olaparib) may alter the efficacy and renal elimination of metformin.

Metformin plasma concentrations may increase when these drugs are co-administered with metformin, therefore caution should be exercised, especially in patients with renal impairment. If necessary, the metformin dose may be adjusted, as OCT inhibitors/inducers may alter the efficacy of metformin (see sections 4.4 and 4.8).

Metformin should be discontinued prior to or for the duration of the studies. Treatment should not be resumed until 48 hours after the studies if renal function has been re-evaluated and is stable, see sections 4.2 and 4.4.

Combinations to be used with caution

Some medicinal products may adversely affect renal function, which may lead to an increased risk of lactic acidosis (e.g. NSAIDs, including cyclooxygenase II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, particularly loop diuretics). When such medicinal products are used in combination with metformin, renal function should be closely monitored.

Glucocorticoids (systemically and locally administered), beta-2-agonists and diuretics have their own hyperglycaemic properties. The patient should be informed of this and blood glucose levels should be monitored more frequently, especially at the beginning of treatment with such drugs. If necessary, the dose of the antihyperglycaemic drug should be adjusted during therapy with the other drug, as well as when it is discontinued.

Insulin and insulin secretagogues

Insulin and insulin secretagogues such as sulfonylureas increase the risk of hypoglycemia. Therefore, a reduction in the dose of insulin or insulin secretagogues may be required to reduce the risk of hypoglycemia when used concomitantly with metformin (see sections 4.2 and 4.8).

Application features

Lactic acidosis

Lactic acidosis is a very rare but serious metabolic complication that most often occurs in the setting of acute renal failure, cardiorespiratory disease, or sepsis. Metformin accumulation occurs in acute renal failure and increases the risk of lactic acidosis.

In case of dehydration (due to severe diarrhea or vomiting, fever, or decreased fluid intake), metformin should be temporarily discontinued and a doctor should be consulted.

Medicinal products that may cause acute deterioration of renal function (e.g. antihypertensives, diuretics, non-steroidal anti-inflammatory drugs (NSAIDs)) should be used with caution in patients receiving metformin. Other risk factors for the development of lactic acidosis include alcohol abuse, hepatic insufficiency, poorly controlled diabetes mellitus, ketosis, prolonged fasting, any conditions associated with hypoxia, and concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or caregivers should be informed of the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia, followed by coma. If the above symptoms occur, patients should discontinue metformin and seek immediate medical attention. Diagnostic laboratory signs of lactic acidosis include decreased blood pH (< 7.35), increased plasma lactate (> 5 mmol/L), and increased anion gap and lactate/pyruvate ratio.

Diabetic ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported with SGLT2 inhibitors (including empagliflozin). In a few cases, DKA presented atypically, with only a modest increase in blood glucose [below 14 mmol/L (250 mg/dL)]. It is unknown whether increasing the dose of empagliflozin affects the likelihood of DKA.

The risk of DKA should be considered in the event of nonspecific symptoms such as nausea, vomiting, loss of appetite, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or drowsiness. Patients should be evaluated immediately for ketoacidosis if these symptoms occur, regardless of blood glucose levels.

Empagliflozin should be discontinued immediately in patients with suspected or diagnosed DKA.

If the patient is hospitalized for major surgical procedures or in case of serious acute illness, treatment should be interrupted. In these patients, ketone monitoring is recommended. Blood ketone measurements are preferred over urine. Empagliflozin treatment can be resumed when ketone levels return to normal and the patient's condition stabilizes.

Before initiating empagliflozin, the patient's medical history should be reviewed for factors that may indicate a predisposition to ketoacidosis.

Patients at high risk of ketoacidosis include patients with low beta-cell function (e.g., type 2 diabetes with low C-peptide, latent autoimmune diabetes in adults, or a history of pancreatitis); patients with conditions that result in restricted food intake or severe dehydration; patients whose insulin dose is being reduced; and patients with increased insulin requirements due to acute illness, surgery, or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.

SYNJARDI should not be used to treat patients with type 1 diabetes mellitus. Data from a clinical trial program in patients with type 1 diabetes mellitus showed an increased incidence of DKA in patients treated with empagliflozin 10 mg and 25 mg as add-on to insulin compared to placebo.

Use of iodinated contrast agents

Intravascular administration of iodinated contrast media may cause contrast-induced nephropathy. This may lead to metformin accumulation and increase the risk of lactic acidosis. Therefore, metformin treatment should be discontinued prior to or for the duration of the investigation. Treatment should not be resumed until 48 hours after the investigation and only if renal function has been re-evaluated and has been shown to be stable (see sections 4.2 and 4.5).

Kidney function

GFR should be assessed before initiating therapy and regularly thereafter (see section 4.2). SYNJARDI is contraindicated in patients with a GFR < 30 mL/min.

The drug should be temporarily discontinued in the presence of conditions that alter renal function (see section "Contraindications").

Cardiac function

Patients with heart failure are at increased risk of hypoxia and renal failure. SYNJARDI can be used in patients with stable chronic heart failure with monitoring of cardiac and renal function. SYNJARDI is contraindicated in patients with acute and unstable heart failure due to the metformin content (see section 4.3).

Operations

Metformin treatment should be discontinued for the duration of surgery under general, spinal or epidural anaesthesia. Treatment should not be resumed until 48 hours after surgery or resumption of oral nutrition and only after renal function has been re-evaluated and confirmed to be stable.

Risk of decreased interstitial fluid volume

As a consequence of the action of SGLT2 inhibitors, the osmotic diuresis associated with drug-induced glucosuria may lead to a small decrease in blood pressure (see section 5.1). Empagliflozin should be used with caution in patients who may be at risk from a decrease in blood pressure due to empagliflozin, such as patients with a history of cardiovascular disease, patients (with a history of hypotension) receiving antihypertensive therapy, or patients aged 75 years or older.

In the event of conditions that may lead to fluid loss (e.g., gastrointestinal disease), patients receiving SYNJARDI are advised to be closely monitored for the degree of volume depletion (e.g., physical examination, blood pressure, laboratory tests including hematocrit) and electrolytes. Temporary interruption of SYNJARDI therapy should be considered until fluid loss is corrected.

Elderly patients

The effect of empagliflozin on urinary glucose excretion is related to osmotic diuresis, which may affect hydration status. Patients aged