Synjardy (Tablets) Instructions for Use

Marketing Authorization Holder

Boehringer Ingelheim International, GmbH (Germany)

Manufactured By

Boehringer Ingelheim Pharma, GmbH & Co. KG (Germany)

Or

Boehringer Ingelheim Ellas, A.E. (Greece)

ATC Code

A10BD20 (Metformin and Empagliflozin)

Active Substances

Metformin (Rec.INN registered by WHO)

Empagliflozin (Rec.INN registered by WHO)

Dosage Forms

	Synjardy	Film-coated tablets, 500 mg+5 mg: 30, 60, 90 or 180 pcs.
		Film-coated tablets, 500 mg+12.5 mg: 30, 60, 90 or 180 pcs.
		Film-coated tablets, 850 mg+5 mg: 30, 60, 90 or 180 pcs.
		Film-coated tablets, 850 mg+12.5 mg: 30, 60, 90 or 180 pcs.
		Film-coated tablets, 1000 mg+5 mg: 30, 60, 90 or 180 pcs.
		Film-coated tablets, 1000 mg+12.5 mg: 30, 60, 90 or 180 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets orange-yellow in color, oval, biconvex; on one side of the tablet an engraving of the Boehringer Ingelheim company symbol and “S5”, on the other side – an engraving “500”.

Excipients: corn starch – 30.13 mg, copovidone – 47.2 mg, colloidal anhydrous silicon dioxide – 2.95 mg, magnesium stearate – 4.72 mg.

Film coating composition Opadry^® yellow (02B220011) – 12 mg (hypromellose 2910 – 6 mg, macrogol 400 – 0.6 mg, titanium dioxide – 2.3 mg, yellow iron oxide – 0.7 mg, talc – 2.4 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Hospital pack:
10 pcs. – blisters (9) – cardboard packs (2) – polyethylene film with a label.

Film-coated tablets yellowish-white in color, oval, biconvex; on one side of the tablet an engraving of the Boehringer Ingelheim company symbol and “S5”, on the other side – an engraving “850”.

Excipients: corn starch – 54.721 mg, copovidone – 80.24 mg, colloidal anhydrous silicon dioxide – 5.015 mg, magnesium stearate – 8.024 mg.

Film coating composition Opadry^® yellow (02B220010) – 17 mg (hypromellose 2910 – 8.5 mg, macrogol 400 – 0.85 mg, titanium dioxide – 4.184 mg, yellow iron oxide – 0.066 mg, talc – 3.4 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Hospital pack:
10 pcs. – blisters (9) – cardboard packs (2) – polyethylene film with a label.

Film-coated tablets brownish-yellow in color, oval, biconvex; on one side of the tablet an engraving of the Boehringer Ingelheim company symbol and “S5”, on the other side – an engraving “1000”.

Excipients: corn starch – 65.26 mg, copovidone – 94.4 mg, colloidal anhydrous silicon dioxide – 5.9 mg, magnesium stearate – 9.44 mg.

Film coating composition Opadry^® yellow (02B220012) – 19 mg (hypromellose 2910 – 9.5 mg, macrogol 400 – 0.95 mg, titanium dioxide – 2.156 mg, yellow iron oxide – 2.594 mg, talc – 3.8 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Hospital pack:
10 pcs. – blisters (9) – cardboard packs (2) – polyethylene film with a label.

Film-coated tablets light brownish-violet in color, oval, biconvex; on one side of the tablet an engraving of the Boehringer Ingelheim company symbol and “S12”, on the other side – an engraving “500”.

Excipients: corn starch – 22.63 mg, copovidone – 47.2 mg, colloidal anhydrous silicon dioxide – 2.95 mg, magnesium stearate – 4.72 mg.

Film coating composition Opadry^® pink (02B240004) – 12 mg (hypromellose 2910 – 6 mg, macrogol 400 – 0.6 mg, titanium dioxide – 2.88 mg, black iron oxide – 0.06 mg, red iron oxide – 0.06 mg, talc – 2.4 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Hospital pack:
10 pcs. – blisters (9) – cardboard packs (2) – polyethylene film with a label.

Film-coated tablets pinkish-white in color, oval, biconvex; on one side of the tablet an engraving of the Boehringer Ingelheim company symbol and “S12”, on the other side – an engraving “850”.

Excipients: corn starch – 47.221 mg, copovidone – 80.24 mg, colloidal anhydrous silicon dioxide – 5.015 mg, magnesium stearate – 8.024 mg.

Film coating composition Opadry^® pink (02B240006) – 17 mg (hypromellose 2910 – 8.5 mg, macrogol 400 – 0.85 mg, titanium dioxide – 4.216 mg, black iron oxide – 0.017 mg, red iron oxide – 0.017 mg, talc – 3.4 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Hospital pack:
10 pcs. – blisters (9) – cardboard packs (2) – polyethylene film with a label.

Film-coated tablets dark brownish-violet in color, oval, biconvex; on one side of the tablet an engraving of the Boehringer Ingelheim company symbol and “S12”, on the other side – an engraving “1000”.

Excipients: corn starch – 57.76 mg, copovidone – 94.4 mg, colloidal anhydrous silicon dioxide – 5.9 mg, magnesium stearate – 9.44 mg.

Film coating composition Opadry^® violet (02B200006) – 19 mg (hypromellose 2910 – 9.5 mg, macrogol 400 – 0.95 mg, titanium dioxide – 3.99 mg, black iron oxide – 0.38 mg, red iron oxide – 0.38 mg, talc – 3.8 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Hospital pack:
10 pcs. – blisters (9) – cardboard packs (2) – polyethylene film with a label.

Clinical-Pharmacological Group

Combined oral hypoglycemic drug

Pharmacotherapeutic Group

Combined hypoglycemic agent for oral administration

Pharmacological Action

Pharmacodynamics

Empagliflozin is a reversible, highly potent, selective and competitive inhibitor of the sodium-glucose cotransporter 2 (SGLT2) with a half maximal inhibitory concentration (IC₅₀) of 1.3 nmol. The selectivity of empagliflozin is 5000 times greater than that of the sodium-glucose cotransporter 1 (SGLT1), which is responsible for glucose absorption in the intestine.

Furthermore, Empagliflozin has been found to be highly selective for other glucose transporters responsible for glucose homeostasis in various tissues.

SGLT2 is the main transporter protein responsible for the reabsorption of glucose from the renal glomeruli back into the bloodstream.

Empagliflozin improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption. The amount of glucose excreted by the kidneys via this mechanism depends on the blood glucose concentration and the glomerular filtration rate (GFR). Inhibition of SGLT2 in patients with T2DM and hyperglycemia leads to the excretion of excess glucose by the kidneys.

Clinical studies have established that in patients with T2DM, renal glucose excretion increased immediately after the first dose of empagliflozin; this effect continued for 24 hours. The increased renal glucose excretion persisted until the end of the 4-week treatment period, averaging about 78 g/day with empagliflozin 25 mg once daily. In patients with T2DM, increased renal glucose excretion led to an immediate reduction in plasma glucose concentration.

Empagliflozin reduces plasma glucose concentration both in the fasting state and postprandially.

The insulin-independent mechanism of action of empagliflozin contributes to a low risk of possible hypoglycemia.

The effect of empagliflozin is independent of the functional state of pancreatic β-cells and insulin metabolism. A positive effect of empagliflozin on surrogate markers of β-cell function, including the HOMA-β index (homeostasis model assessment-β) and the proinsulin-to-insulin ratio, has been noted. Furthermore, the additional renal glucose excretion causes calorie loss, which is accompanied by a reduction in adipose tissue volume and a decrease in body weight.

The glucosuria observed during empagliflozin use is accompanied by a slight increase in diuresis, which may contribute to a moderate reduction in blood pressure.

Metformin is a drug of the biguanide class, the hypoglycemic effect of which is provided by reducing basal and postprandial blood glucose concentrations. Metformin does not stimulate insulin secretion and therefore its use does not lead to hypoglycemia.

Metformin has three mechanisms of action

• Reduction of glucose synthesis in the liver by inhibiting gluconeogenesis and glycogenolysis;
• Increased sensitivity of peripheral receptors to insulin and utilization of glucose by cells;
• Slowing of glucose absorption in the intestine.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin increases the transport capacity of all currently known types of membrane glucose transporters.

Metformin at therapeutic doses has a favorable effect on lipid metabolism: it reduces the concentration of total plasma cholesterol, LDL cholesterol and triglycerides.

Cardiovascular risk

A clinical study evaluated the effect of empagliflozin on the incidence of cardiovascular complications in patients with T2DM and high cardiovascular risk (one or more cardiovascular risk factors were considered, including coronary artery disease, peripheral arterial disease, history of myocardial infarction or history of stroke) receiving standard therapy, which included hypoglycemic drugs and drugs for the treatment of cardiovascular diseases. The primary endpoint was cases of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Additional pre-specified endpoints were cardiovascular mortality, all-cause mortality, development of nephropathy or progressive worsening of nephropathy, hospitalization for heart failure.

Empagliflozin showed a significant reduction in risk for the primary endpoint (cases of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke). Empagliflozin improved overall survival by reducing the risk of cardiovascular death. Empagliflozin reduced the risk of hospitalization for heart failure. The clinical study also showed that Empagliflozin reduced the risk of nephropathy or progressive worsening of nephropathy.

In patients with baseline macroalbuminuria, Empagliflozin was found to lead to sustained normo- or microalbuminuria significantly more often compared to placebo (hazard ratio 1.82 [95% CI 1.40; 2.37]).

Pharmacokinetics

The following points reflect the pharmacokinetic properties of the individual active substances of the drug Synjardy.

Empagliflozin

Absorption

Empagliflozin was rapidly absorbed after oral administration, with the C_max of empagliflozin in plasma reached within 1.5 hours. The plasma concentration of empagliflozin then decreased in two phases.

After administration of empagliflozin 10 mg, the mean steady-state plasma AUC was 1870 nmol×h/L, and the C_max was 259 nmol/L, and after administration of empagliflozin 25 mg – 4740 nmol×h/L and 687 nmol/L, respectively.

The pharmacokinetics of empagliflozin in healthy volunteers and in patients with T2DM were generally similar.

In healthy volunteers, the pharmacokinetics of empagliflozin 5 mg administered twice daily and empagliflozin 10 mg administered once daily were comparable. The total exposure of empagliflozin (AUC_ss) over a 24-hour period with the drug administered 5 mg twice daily and 10 mg once daily was similar. The C_max of empagliflozin administered 5 mg twice daily was lower compared to the C_max of empagliflozin administered 10 mg once daily, but in the former case a higher basal plasma concentration of empagliflozin (C_min) was noted.

Food intake does not have a clinically significant effect on the pharmacokinetics of empagliflozin.

Distribution

The V_d at steady-state plasma concentration was approximately 73.8 L. After oral administration of labeled empagliflozin [¹⁴C] to healthy volunteers, binding to erythrocytes was approximately 36.8%, and to plasma proteins – 86.2%.

Metabolism

The main pathway of empagliflozin metabolism in humans is glucuronidation involving the uridine-5′-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9 and UGT2B7. The most frequently detected metabolites of empagliflozin are three glucuronic conjugates (2-O-, 3-O- and 6-O-glucuronide). The systemic influence of each metabolite is small (less than 10% of the total influence of empagliflozin).

Elimination

T_1/2 was approximately 12.4 hours. With empagliflozin administered once daily, steady-state plasma concentration was achieved after the fifth dose. After oral administration of labeled empagliflozin [¹⁴C] to healthy volunteers, approximately 95.6% of the dose was excreted (41.2% via the intestine and 54.4% via the kidneys). The majority of the labeled empagliflozin was excreted unchanged via the intestine. Only half of the labeled empagliflozin was excreted unchanged by the kidneys.

Pharmacokinetics in special patient groups

Renal impairment. In patients with mild (60<GFR<90 ml/min/1.73 m²), moderate (30<GFR<60 ml/min/1.73 m²), severe (GFR<30 ml/min/1.73 m²) renal impairment and in patients with end-stage renal disease, empagliflozin AUC values increased by approximately 18%, 20%, 66% and 48%, respectively, compared to patients with normal renal function. In patients with moderate renal impairment and in patients with end-stage renal disease, the C_max of empagliflozin in plasma was similar to the corresponding values in patients with normal renal function. In patients with mild and severe renal impairment, the C_max of empagliflozin in plasma was approximately 20% higher than in patients with normal renal function. Data from a population pharmacokinetic analysis showed that the total clearance of empagliflozin decreased as GFR decreased, leading to increased drug exposure.

Hepatic impairment. In patients with mild, moderate and severe hepatic impairment (according to Child-Pugh classification), empagliflozin AUC values increased by approximately 23%, 47% and 75%, respectively, and C_max values by approximately 4%, 23% and 48%, respectively (compared to patients with normal liver function).

BMI, sex, race and age did not have a clinically significant effect on the pharmacokinetics of empagliflozin.

Children and adolescents under 18 years. Pharmacokinetic studies of empagliflozin in children and adolescents under 18 years of age have not been conducted.

Metformin

Absorption

After oral administration, Metformin is absorbed from the gastrointestinal tract quite completely. The proportion of unabsorbed metformin found in stool is 20-30%. The absorption process of metformin is characterized by saturation. It is assumed that the pharmacokinetics of its absorption is nonlinear. C_max (approximately 2 µg/ml or 15 µmol) in plasma is reached within 2.5 hours. When used at recommended doses, the C_ss of metformin in plasma is achieved within 24-48 hours and generally does not exceed 1 µg/ml. The absolute bioavailability in healthy volunteers is 50-60%. When taken with food, the absorption of metformin is reduced and delayed.

Distribution

Metformin is rapidly distributed into tissues and practically does not bind to plasma proteins. C_max in blood is lower than C_max in plasma and is reached in approximately the same time. Metformin penetrates into erythrocytes. Erythrocytes probably represent a secondary distribution compartment for metformin. The mean V_d is 63-276 L.

Metabolism and Elimination

It is metabolized to a very small extent; no metabolites have been detected in the body.

It is excreted primarily by the kidneys unchanged. The clearance of metformin in healthy volunteers is more than 400 ml/min (4 times greater than CC), indicating the presence of active tubular secretion. T_1/2 is approximately 6.5 hours.

Pharmacokinetics in special patient groups

Renal impairment. In case of renal impairment, the clearance of metformin decreases in proportion to CC, respectively, T_1/2 increases, the plasma concentration of metformin increases, and the risk of its accumulation increases.

Children and adolescents under 18 years. With a single dose of 500 mg in children and adolescents under 18 years of age, the pharmacokinetic parameters of metformin were similar to those in healthy adults.

With multiple administration of 500 mg twice daily for 7 days in children and adolescents under 18 years of age, the C_max and AUC_0-t of metformin were reduced by approximately 33% and 40%, respectively, compared to adult patients with diabetes mellitus who received Metformin 500 mg twice daily for 14 days. Since the dose of metformin is individually adjusted based on glycemic control indicators, the obtained data have limited clinical significance.

Indications

The drug Synjardy is indicated for the treatment of type 2 diabetes mellitus in adult patients as an adjunct to diet and exercise to improve glycemic control.

• In case of inadequate glycemic control on metformin monotherapy at the maximum tolerated dose;
• In combination with other hypoglycemic agents in case of inadequate glycemic control on their combined use with metformin;
• In patients who were previously treated with combination therapy of empagliflozin and metformin as separate drugs.

ICD codes

Dosage Regimen

Adult patients with normal renal function (eGFR ≥ 90 ml/min)

The recommended dose is 1 tablet 2 times/day.

The dosing regimen of the drug should be adjusted individually based on the nature of the current hypoglycemic therapy, its effectiveness and tolerability.

The maximum recommended daily dose of Synjardy is 25 mg of empagliflozin and 2000 mg of metformin.

Synjardy should be taken with meals to reduce gastrointestinal adverse reactions caused by metformin.

For patients with inadequate glycemic control on metformin monotherapy or in combination with other hypoglycemic agents, Synjardy should usually be prescribed so that the dose of empagliflozin is 5 mg 2 times/day (daily dose 10 mg), and the dose of metformin remains the same as before. In patients who tolerate a daily empagliflozin dose of 10 mg well and require improved glycemic control, it can be increased to 25 mg.

For patients previously treated with empagliflozin monotherapy, Synjardy is prescribed so that the daily dose of empagliflozin is the same as before.

For patients previously treated with a combination of empagliflozin and metformin as two separate drugs, Synjardy should be prescribed so that the doses of empagliflozin and metformin are the same as before.

When Synjardy is used in combination with a sulfonylurea derivative and/or insulin, a lower dose of the sulfonylurea derivative and/or insulin may be required to reduce the risk of hypoglycemia.

Patients with renal impairment

No dose adjustment is required for patients with mild renal impairment. However, in such patients, eGFR must be monitored before prescribing the drug and at least once a year throughout the entire period of therapy. In patients at increased risk of further progression of renal impairment and in elderly patients, renal function should be monitored more frequently, for example, every 3-6 months.

If none of the Synjardy dosages are suitable, the combined drug should be discontinued and therapy with two separate drugs, empagliflozin and metformin, should be continued.

Table 1. Dosages for patients with renal impairment

Elderly patients

Metformin is excreted by the kidneys; due to possible decreased renal function, the dose of metformin must be adjusted with regular monitoring of renal function parameters (determination of plasma creatinine concentration at least 2-4 times a year).

Children and adolescents

Use in children and adolescents under 18 years of age is contraindicated due to insufficient data on efficacy and safety.

Patients with hepatic impairment

Use of Synjardy in patients with hepatic impairment is contraindicated.

Actions in case of missing one or more doses of the drug

If a dose is missed, the patient should take the drug as soon as they remember. A double dose should not be taken on the same day.

Adverse Reactions

In clinical studies, the most frequently reported adverse event was hypoglycemia, which depended on the type of background therapy used in the respective studies, urinary and genital tract infections, and increased urination.

In clinical studies using empagliflozin in combination with metformin, no additional adverse reactions were observed compared to the adverse reactions noted with the individual components.

Adverse reactions are presented in the table below (adverse reactions were classified by organ system and according to MedDRA preferred terms) with their absolute frequency.

Frequency categories are defined as follows: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000) or very rare (<1/10000); adverse reactions with unknown frequency (cannot be estimated from the available data) are also highlighted.

Table 2. Adverse reactions reported in patients receiving empagliflozin monotherapy or a combination of empagliflozin and metformin (pooled analysis of placebo-controlled and post-marketing studies)

¹ Adverse reactions recorded during empagliflozin monotherapy.
² Adverse reactions recorded during metformin monotherapy.
³ Long-term treatment with metformin was accompanied by reduced vitamin B₁₂ absorption, which in very rare cases could lead to clinically significant vitamin B₁₂ deficiency, for example, megaloblastic anemia.
⁴ Gastrointestinal symptoms such as decreased appetite, diarrhea, nausea, vomiting, and abdominal pain most often appeared at the very beginning of therapy and resolved spontaneously in most cases.

Description of selected adverse reactions

Hypoglycemia

The frequency of hypoglycemia depended on the concomitant hypoglycemic therapy used and was comparable for empagliflozin and placebo when used in combination with metformin, in combination with linagliptin and metformin, for the combination of empagliflozin with metformin in previously untreated patients compared to patients receiving Empagliflozin and Metformin as separate drugs and as an add-on to standard therapy. When empagliflozin was prescribed in combination with sulfonylurea derivatives + Metformin (Empagliflozin 10 mg: 16.1%, Empagliflozin 25 mg: 11.5%, placebo: 8.4%) or in combination with insulin + Metformin (Empagliflozin 10 mg: 31.3%, Empagliflozin 25 mg: 36.2%, placebo: 34.7%), the frequency of hypoglycemia was higher than with placebo.

Severe hypoglycemia (requiring medical intervention)

The proportion of patients with severe hypoglycemia was low (less than 1%) and comparable for empagliflozin and placebo when used in combination with metformin, and for the combination of empagliflozin with metformin in previously untreated patients compared to patients receiving Empagliflozin and Metformin as separate drugs and as an add-on to standard therapy. The frequency of severe hypoglycemia cases was 0.5%, 0% and 0.5% with empagliflozin 10 mg, empagliflozin 25 mg and placebo, respectively, against the background of metformin therapy in combination with insulin. No cases of severe hypoglycemia were observed when empagliflozin was used against the background of metformin therapy in combination with sulfonylurea drugs, or against the background of metformin therapy in combination with linagliptin.

Urinary tract infections

The frequency of urinary tract infections when using empagliflozin 10 mg in combination with metformin was higher (8.8%) than when using empagliflozin 25 mg in combination with metformin (6.6%) or placebo in combination with metformin (7.8%). As with placebo, urinary tract infections were more frequently noted in patients with a history of chronic and recurrent urinary tract infections. The severity of urinary tract infections was similar in patients taking Empagliflozin and placebo. Urinary tract infections were reported more frequently in women receiving Empagliflozin 10 mg in combination with metformin than in women receiving placebo; this was not observed with empagliflozin 25 mg in combination with metformin. The frequency of urinary tract infections in men was low and similar across treatment groups.

Genital infections

The frequency of adverse events such as candidal vaginitis, vulvovaginitis, balanitis and other genital infections was higher with empagliflozin 10 mg in combination with metformin (4.0%) and empagliflozin 25 mg in combination with metformin (3.9%) than with placebo or placebo in combination with metformin (1.3%). These frequency differences were less noticeable in men. Genital adverse reactions were mild to moderate in severity.

Increased urination

The frequency of increased urination (symptoms such as pollakiuria, polyuria, nocturia were assessed) was higher with empagliflozin 10 mg in combination with metformin (3.0%) and empagliflozin 25 mg in combination with metformin (2.9%) than with placebo in combination with metformin (1.4%). The frequency of nocturia was comparable in the group of patients taking Empagliflozin in combination with metformin and in the group of patients taking placebo in combination with metformin (less than 1%). The intensity of increased urination was mild or moderate.

Hypovolemia

The frequency of hypovolemia (which manifested as decreased BP, orthostatic arterial hypotension, dehydration, syncope) with empagliflozin in combination with metformin was low or comparable to placebo (Empagliflozin 10 mg in combination with metformin (0.6%), Empagliflozin 25 mg in combination with metformin (0.3%), placebo in combination with metformin (0.1%). The glucosuric effect of empagliflozin is accompanied by osmotic diuresis, which may affect the hydration status of patients aged 75 years and older. One case of hypovolemia was reported in a patient aged ≥75 years receiving Empagliflozin 25 mg as an add-on to metformin therapy.

Decreased eGFR and increased blood creatinine concentration

The overall frequency of decreased eGFR and increased blood creatinine concentration were similar with empagliflozin and placebo with metformin (increased blood creatinine concentration: Empagliflozin 10 mg 0.5%, Empagliflozin 25 mg 0.1%, placebo 0.4%; decreased eGFR: Empagliflozin 10 mg 0.1%, Empagliflozin 25 mg 0%, placebo 0.2%). An initial transient increase in blood creatinine concentration was observed (mean change from baseline after 12 weeks: Empagliflozin 10 mg – 0.02 mg/dl, Empagliflozin 25 mg – 0.02 mg/dl) and an initial transient decrease in estimated eGFR (mean change from baseline after 12 weeks: Empagliflozin 10 mg – 1.46 ml/min/1.73 m², Empagliflozin 25 mg – 2.05 ml/min/1.73 m²). In long-term studies, these changes were usually reversible upon continued treatment or after discontinuation of the drug.

Contraindications

• Hypersensitivity to empagliflozin, metformin or any of the excipients of the drug;
• Type 1 diabetes mellitus;
• Diabetic ketoacidosis;
• Diabetic precoma, coma;
• Renal failure with eGFR <45 ml/min/1.73 m²;
• Acute conditions with a risk of renal function impairment: dehydration (with diarrhea or vomiting), severe infectious diseases, shock;
• Clinically significant manifestations of acute or chronic diseases that can lead to tissue hypoxia (including acute heart failure, chronic heart failure with unstable hemodynamic parameters, respiratory failure, acute myocardial infarction);
• Hepatic failure;
• Lactic acidosis;
• Acute alcohol intoxication, chronic alcoholism;
• Pregnancy;
• Lactation period (breastfeeding);
• Age 85 years and older;
• Children under 18 years of age (due to insufficient data on efficacy and safety);
• Use within 48 hours before and 48 hours after radioisotope or X-ray studies with the administration of iodine-containing contrast agent;
• Adherence to a hypocaloric diet (less than 1000 kcal/day);
• Extensive surgical operations and trauma, when insulin therapy is indicated.

With caution

• Gastrointestinal diseases leading to fluid loss;
• History of diabetic ketoacidosis;
• Moderate renal impairment (eGFR 45-59 ml/min/1.73 m²);
• Use in combination with sulfonylurea derivatives or insulin;
• Chronic heart failure with stable hemodynamic parameters;
• Diet with very low carbohydrate content;
• Alcohol abuse;
• History of pancreatic diseases (pancreatitis or pancreatic surgery) or low secretory activity of pancreatic β-cells;
• With combination therapy with insulin – in case of insulin dose reduction;
• Concomitant use with antihypertensive drugs, diuretics and NSAIDs;
• In case of urinary tract infections;
• Age over 75 years.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of Synjardy or its components in pregnant women are limited. The use of Synjardy during pregnancy or in women planning pregnancy is contraindicated.

Breastfeeding

Metformin passes into breast milk in small amounts. It is contraindicated during breastfeeding. It is not known whether Empagliflozin passes into breast milk. Data obtained from preclinical animal studies indicate that empagliflozin passes into breast milk. A risk to the breastfed child cannot be excluded. The use of empagliflozin during breastfeeding is contraindicated.

Use in Hepatic Impairment

Use of the drug in patients with hepatic impairment is contraindicated.

Use in Renal Impairment

Use of the drug is contraindicated in renal failure with eGFR <45 ml/min/1.73 m².

The drug should be used with caution in moderate renal impairment (eGFR 45-59 ml/min/1.73 m²).

Pediatric Use

Use of the drug under 18 years of age is contraindicated (due to insufficient data on efficacy and safety).

Geriatric Use

Use of the drug is contraindicated at 85 years of age and older.

The drug should be used with caution in patients over 75 years of age.

Special Precautions

Use of Synjardy is contraindicated in patients with type 1 diabetes mellitus.

Diabetic ketoacidosis

Cases of diabetic ketoacidosis (DKA), a serious and life-threatening condition requiring urgent hospitalization, including fatal outcomes, have been reported with the use of empagliflozin. In some of these cases, the manifestations of diabetic ketoacidosis were atypical and expressed only as a moderate increase in blood glucose concentration, not more than 14 mmol/L (250 mg/dl).

The risk of developing diabetic ketoacidosis should be considered in case of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, disorientation, unexplained fatigue or drowsiness.

If such symptoms develop, patients should be examined immediately to rule out ketoacidosis regardless of blood glucose concentration. If ketoacidosis is suspected, Synjardy should be discontinued, the patient should be examined and treatment should be initiated immediately.

A higher risk of developing diabetic ketoacidosis when taking Synjardy is possible in patients on a very low carbohydrate diet (as this combination may further increase ketone body formation), patients with acute illness, patients with pancreatic diseases suggesting insulin deficiency (e.g., type 1 diabetes mellitus, history of pancreatitis or pancreatic surgery), with insulin dose reduction (including ineffective insulin pump operation), patients who abuse alcohol, patients with severe dehydration and patients with a history of ketoacidosis. In such patients, Synjardy should be used with caution. In patients receiving Synjardy, monitoring for ketoacidosis and temporary discontinuation of Synjardy should be considered in clinical situations predisposing to the development of ketoacidosis (e.g., prolonged fasting due to acute illness or surgery). In such cases, ketone monitoring should be considered even if Synjardy has been discontinued.

Resumption of therapy with SGLT2 inhibitors is not recommended in patients who developed diabetic ketoacidosis while taking them, unless another causative factor for this complication has been clearly identified and excluded.

Lactic Acidosis

Lactic acidosis is a very rare but serious metabolic complication, typically manifesting as impaired renal function, cardiorespiratory disease, or sepsis. Acute renal impairment is accompanied by the accumulation of metformin, which increases the risk of developing lactic acidosis.

In case of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), metformin intake should be temporarily discontinued and a doctor should be contacted.

Medications that can significantly impair renal function (such as antihypertensive drugs, diuretics, and NSAIDs) should be prescribed with caution in patients taking Metformin.

Other concomitant risk factors for the development of lactic acidosis include excessive alcohol consumption, hepatic insufficiency, poor glycemic control, ketosis, prolonged fasting, and any conditions accompanied by hypoxia, as well as the concomitant use of medications that can cause lactic acidosis.

Patients should be informed about the risk of developing lactic acidosis.

Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia followed by coma. If suspicious symptoms occur, the patient should discontinue the drug and immediately consult a doctor.

Changes in laboratory parameters are diagnostically significant – decreased blood pH (<7.35), increased plasma lactate concentration (>5 mmol/L), increased anion gap, and an increased lactate/pyruvate ratio. If lactic acidosis is suspected, the drug should be discontinued, and the patient should be hospitalized immediately.

Use of Iodinated Contrast Media

Intravascular use of iodinated contrast media during radiological examinations can lead to renal failure and, consequently, to the accumulation of metformin and the risk of lactic acidosis. Metformin intake must be discontinued 48 hours before or during a radiological examination using iodinated contrast media and should not be resumed earlier than 48 hours after the end of the examination and only after renal function has been re-evaluated and found to be normal.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Cases of necrotizing fasciitis of the perineum (also known as Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection, have been reported in both male and female patients using SGLT2 inhibitors, including Empagliflozin. Serious outcomes included hospitalization, multiple surgical interventions, and death.

If a patient taking Synjardy develops symptoms such as pain or tenderness, redness, swelling in the genital or perineal area, fever, or malaise, they should be examined for the presence of necrotizing fasciitis. If necrotizing fasciitis is suspected, the use of Synjardy should be discontinued, and urgent therapy with broad-spectrum antibiotics should be initiated, and, if necessary, debridement and removal of necrotic tissues should be performed.

Effect on Renal Function

According to its mechanism of action, the efficacy of empagliflozin depends on renal function. It is recommended to determine the GFR before starting therapy and regularly thereafter.

Synjardy is contraindicated in patients with GFR <45 ml/min/1.73 m², and the use of the drug should be discontinued in the presence of conditions affecting renal function.

Cardiac Function

Experience with the drug in patients with chronic heart failure of NYHA class I-II is limited, and Empagliflozin has never been used in clinical studies involving patients with chronic heart failure of NYHA class III-IV. It is reported that in the EMPA-REG OUTCOME study, 10.1% of patients had heart failure at its initiation. The reduction in mortality from acute cardiovascular disorders achieved among them was comparable to that in the overall study participant group.

In patients with chronic heart failure with stable hemodynamic parameters, Synjardy can be used provided that cardiac and renal function are regularly monitored. Synjardy is contraindicated in patients with acute and chronic heart failure with unstable hemodynamic parameters because it contains Metformin.

Liver Injury

Reports of liver injury in patients receiving Empagliflozin were obtained during clinical studies. A causal relationship between the use of empagliflozin and liver injury has not been established.

Increase in Hematocrit

Cases of increased hematocrit levels during therapy with empagliflozin have been observed.

Elderly Patients

Patients aged 75 years and older have an increased risk of hypovolemia. Therefore, Synjardy should be used with caution in such patients. Experience in patients over 85 years of age is limited, therefore the use of Synjardy in patients over 85 years of age is contraindicated.

Since Metformin is excreted by the kidneys, and elderly individuals tend to have reduced renal function, the use of Synjardy in the elderly should be accompanied by regular monitoring of renal function.

Use in Patients at Risk of Hypovolemia

According to the mechanism of action, taking SGLT2 inhibitors may lead to a moderate decrease in BP. Therefore, the drug should be used with caution in cases where a decrease in BP is undesirable, for example, in patients with cardiovascular diseases; patients taking antihypertensive drugs (with a history of arterial hypotension), as well as in patients over 75 years of age.

If a patient taking Synjardy develops conditions that may lead to fluid loss (e.g., gastrointestinal diseases), the patient’s condition, BP, as well as hematocrit and electrolyte balance should be carefully monitored. Temporary discontinuation of the drug may be required until fluid balance is restored.

Urinary Tract Infections

The frequency of adverse reactions such as urinary tract infections was comparable when using empagliflozin 25 mg in combination with metformin and placebo in combination with metformin, and higher when using empagliflozin 10 mg in combination with metformin. Complicated urinary tract infections, including pyelonephritis and urosepsis, were observed in patients taking Empagliflozin in post-marketing studies. In case of development of complicated urinary tract infections, temporary discontinuation of therapy is necessary.

Surgical Interventions

Synjardy should be discontinued 48 hours before a planned surgical intervention performed under general, spinal, or epidural anesthesia. The use of the drug can be resumed no earlier than 48 hours after surgery or after resuming oral nutrition, and only provided that the results of the re-evaluation of renal function indicate no deterioration.

Urine Laboratory Test Results

According to the mechanism of action, glucose is detected in the urine of patients taking Synjardy.

Increased Frequency of Lower Limb Amputations

In long-term clinical studies of another SGLT2 inhibitor, an increased frequency of lower limb amputations (mostly toes) was observed. It is not known whether therapy with other SGLT2 inhibitors causes this complication. Patients with diabetes, including those receiving Synjardy, should be strongly recommended to practice constant preventive foot care.

Effect on Ability to Drive and Use Machines

No studies on the effect of Synjardy on the ability to drive and use machines have been conducted. However, due to the possible development of hypoglycemia (which may manifest as headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, palpitations, sweating, panic attacks), especially when taking Synjardy in combination with sulfonylurea derivatives and/or insulin, caution should be exercised when driving and operating machinery.

Overdose

Symptoms

During controlled clinical studies, a single dose of empagliflozin 800 mg (32 times the maximum daily dose) was well tolerated by healthy volunteers.

When metformin was used in doses up to 85 g, hypoglycemia was not observed, but in some cases, this led to the development of lactic acidosis. Significant overdose of metformin or the presence of concomitant risk factors can lead to lactic acidosis. Lactic acidosis is a medical emergency; treatment in such cases should be carried out in a hospital.

Treatment

In case of overdose, it is recommended to remove the unabsorbed drug from the gastrointestinal tract, implement clinical monitoring, and provide symptomatic treatment. The most effective method for removing lactate and metformin is hemodialysis; the possibility of removing empagliflozin by hemodialysis has not been studied.

Drug Interactions

No drug interaction studies have been conducted with Synjardy. However, pharmacokinetic studies on drug interactions of the components of Synjardy: empagliflozin and metformin have been conducted.

Empagliflozin

Diuretics

Empagliflozin may enhance the diuretic effect of thiazide and loop diuretics, which in turn may increase the risk of dehydration and arterial hypotension.

Insulin and Insulin Secretagogues

When empagliflozin is used concomitantly with insulin and insulin secretagogues, such as sulfonylurea derivatives, the risk of hypoglycemia may increase. Therefore, the doses of insulin and insulin secretagogues should be reduced when used in combination with empagliflozin to reduce the risk of hypoglycemia.

In Vitro Drug Interaction Assessment

Empagliflozin does not inhibit, inactivate, or induce CYP450 isoenzymes. The main pathway of empagliflozin metabolism in humans is glucuronidation involving uridine 5′-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The ability of empagliflozin, at therapeutic doses, to reversibly inhibit or inactivate the major CYP450 isoenzymes or UGT1A1 is low. A drug interaction between empagliflozin and drugs that are substrates of CYP450 isoenzymes and UGT1A1 is considered unlikely.

Empagliflozin is a substrate for P-glycoprotein (Pgp) and Breast Cancer Resistance Protein (BCRP), but at therapeutic doses, it does not inhibit these proteins. Based on in vitro study data, the ability of empagliflozin to interact with drugs that are substrates for P-glycoprotein (Pgp) is considered unlikely. Empagliflozin is a substrate for organic anion transporters: OAT3, OATP1B1, and OATP1B3, but is not a substrate for organic anion transporters 1 (OAT1) and organic cation transporters 2 (OCT2). However, drug interactions of empagliflozin with drugs that are substrates for the aforementioned transporter proteins are considered unlikely.

The interaction of empagliflozin with inducers of UGT family enzymes has not been studied. Concomitant use of empagliflozin with inducers of UGT family enzymes is not recommended due to the potential risk of reduced efficacy of empagliflozin.

In Vivo Drug Interaction Assessment

The pharmacokinetics of empagliflozin are not altered in healthy volunteers when used concomitantly with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide, and hydrochlorothiazide. When empagliflozin was used concomitantly with gemfibrozil, rifampicin, and probenecid, an increase in the AUC of empagliflozin by 59%, 35%, and 53%, respectively, was noted, but these changes were not considered clinically significant.

Empagliflozin does not have a clinically significant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torasemide, and oral contraceptive drugs.

Metformin

Concomitant Use Contraindicated

Iodinated contrast media. Against the background of functional hepatic insufficiency in patients with diabetes, radiological examination using iodinated contrast media can cause the development of lactic acidosis. Treatment with Synjardy must be discontinued depending on renal function 48 hours before or during a radiological examination using iodinated contrast media and not resumed earlier than 48 hours after, provided that renal function was found to be normal during the examination.

Concomitant Use Not Recommended

Alcohol. Acute alcohol intoxication increases the risk of developing lactic acidosis, especially in case of insufficient nutrition, adherence to a low-calorie diet, or hepatic insufficiency. During drug intake, alcohol and medications containing ethanol should be avoided.

Substrates of Organic Cation Transporter 1 and 2 (OCT1 and OCT2). Metformin is a substrate of organic cations OCT1 and OCT2. When used concomitantly with metformin

• OCT1 inhibitors (such as verapamil) may reduce the hypoglycemic effect of metformin;
• OCT1 inducers (such as rifampicin) may increase the absorption of metformin in the gastrointestinal tract and enhance its hypoglycemic effect;
• OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin and lead to an increase in its plasma concentration;
• OCT1 and OCT2 inhibitors (such as crizotinib, olaparib) may reduce the hypoglycemic effect of metformin.

Combinations Requiring Caution

Danazol simultaneous use of danazol is not recommended to avoid its hyperglycemic effect. If treatment with danazol is necessary and after its discontinuation, adjustment of the metformin dose under blood glucose control is required.

Chlorpromazine when taken in large doses (100 mg/day) increases blood glucose concentration by reducing insulin release. When treating with antipsychotics and after their discontinuation, adjustment of the metformin dose under blood glucose control is required.

Glucocorticosteroids (GCS) systemic and local action reduce glucose tolerance, increase blood glucose concentration, sometimes causing ketosis. When treating with GCS and after their discontinuation, adjustment of the metformin dose under blood glucose control is required.

Diuretics simultaneous use of loop diuretics may lead to the development of lactic acidosis due to possible functional renal failure.

Injected Beta₂-Adrenergic Agonists increase blood glucose concentration due to stimulation of β₂-adrenergic receptors. In this case, blood glucose control is necessary. If necessary, insulin administration is recommended.

When using the above-mentioned drugs concomitantly, more frequent monitoring of blood glucose levels may be required, especially at the beginning of treatment. If necessary, the dose of metformin can be adjusted during treatment and after its discontinuation.

Antihypertensive drugs, except for ACE inhibitors, may reduce blood glucose concentration. If necessary, the dose of metformin should be adjusted.

Nifedipine increases the absorption and C_max of metformin.

Insulin and Insulin Secretagogues

Insulin and insulin secretagogues, such as sulfonylurea derivatives, may increase the risk of hypoglycemia. Therefore, it is necessary to reduce the doses of insulin and insulin secretagogues when used in combination with metformin to reduce the risk of hypoglycemia.

The hypoglycemic effect of metformin may be reduced by phenothiazides, glucagon, estrogens, oral contraceptives, phenytoin, sympathomimetics, nicotinic acid, isoniazid, calcium channel blockers, levothyroxine sodium.

Simultaneous use with cimetidine reduces the excretion rate of metformin, which may lead to the development of lactic acidosis.

In healthy volunteers, no changes in their pharmacokinetic parameters were observed with simultaneous use of metformin and propranolol, as well as with the use of metformin and ibuprofen.

Metformin may reduce the effect of indirect anticoagulants.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not take the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.