Emforix (Tablets) Instructions for Use

Marketing Authorization Holder

Grotex, LLC (Russia)

ATC Code

A10BK03 (Empagliflozin)

Active Substance

Empagliflozin (Rec.INN registered by WHO)

Dosage Forms

	Emforix	Film-coated tablets 10 mg: 10 or 30 pcs.
		Film-coated tablets 25 mg: 10 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex.

Excipients : lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, film coating: hypromellose (hydroxypropylcellulose), hypromellose 2910 (hydroxypropyl methylcellulose), talc, titanium dioxide.

10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.

Film-coated tablets white or almost white, round, biconvex.

Excipients : lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, film coating: hypromellose (hydroxypropylcellulose), hypromellose 2910 (hydroxypropyl methylcellulose), talc, titanium dioxide.

10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.

Clinical-Pharmacological Group

Hypoglycemic drug for oral administration – sodium-glucose cotransporter 2 inhibitor

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; sodium-glucose cotransporter 2 (SGLT2) inhibitors

Pharmacological Action

Hypoglycemic agent for oral administration. Inhibitor of sodium-glucose cotransporter 2 with a half-maximal inhibitory concentration (IC₅₀) of 1.3 nmol. The selectivity of empagliflozin for sodium-glucose cotransporter 2 is 5000 times greater than its selectivity for sodium-glucose cotransporter 1, 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.

Sodium-glucose cotransporter 2 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 by reducing renal glucose reabsorption. The amount of glucose excreted by the kidneys via this mechanism depends on blood glucose concentration and GFR. Inhibition of sodium-glucose cotransporter 2 in patients with type 2 diabetes and hyperglycemia leads to the excretion of excess glucose by the kidneys.

Empagliflozin (at doses of 10 mg and 25 mg) reduces plasma glucose concentration both when taken on an empty stomach and after a meal.

The mechanism of action of empagliflozin is independent of the functional state of pancreatic β-cells and insulin metabolism, which contributes to a low risk of possible hypoglycemia. A positive effect of empagliflozin on surrogate markers of β-cell function was noted, including the HOMA-β index and the proinsulin-to-insulin ratio. Furthermore, the additional excretion of glucose by the kidneys causes calorie loss, which is accompanied by a reduction in adipose tissue volume and a decrease in body weight.

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

Clinical studies have proven a statistically significant reduction in glycated hemoglobin (HbA_1c), a decrease in fasting plasma glucose concentration, as well as a reduction in blood pressure and body weight.

Empagliflozin contributes to a reduction in cardiovascular death and reduces the risk of hospitalization for heart failure. It reduces the risk of nephropathy or progressive worsening of nephropathy.

In patients with baseline macroalbuminuria, Empagliflozin led to sustained normo- or microalbuminuria significantly more often compared to placebo.

Pharmacokinetics

After oral administration, Empagliflozin is rapidly absorbed from the gastrointestinal tract, with the maximum plasma concentration (C_max) of empagliflozin reached within 1.5 hours. The plasma concentration of empagliflozin then decreases in a biphasic manner: with a rapid distribution phase and a relatively slow terminal phase. After administration of the drug at a dose of 25 mg once daily, the mean steady-state AUC was 4740 nmol×h/L, and C_max was 687 nmol/L. Food intake does not have a clinically significant effect on the pharmacokinetics of empagliflozin.

The pharmacokinetics of empagliflozin in healthy volunteers and patients with type 2 diabetes were generally similar.

At steady state, the apparent volume of distribution (V_d) was approximately 73.8 L. Plasma protein binding is 86%.

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

The elimination half-life (T_1/2) is approximately 12.4 hours. With once-daily administration of empagliflozin, steady-state plasma concentration (C_ss) was achieved after the fifth dose. After oral administration of radiolabeled empagliflozin [¹⁴C] in healthy volunteers, approximately 96% of the dose was excreted (via the intestine – 41%, via the kidneys – 54%). The majority of the radiolabeled substance was excreted unchanged via the intestine. Only half of the radiolabeled substance was excreted unchanged by the kidneys.

In patients with renal impairment, the C_max of empagliflozin in plasma increased by approximately 20% compared to patients with normal renal function. Data from population pharmacokinetic analysis showed that the total clearance of empagliflozin decreased with decreasing GFR, leading to increased exposure.

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

Indications

For the treatment of type 2 diabetes mellitus in adult patients with inadequate glycemic control in addition to diet and exercise: as monotherapy; as part of combination therapy with other hypoglycemic agents, including insulin.

The drug is indicated for patients with type 2 diabetes and high cardiovascular risk in combination with standard therapy for cardiovascular diseases to reduce: overall mortality by reducing cardiovascular mortality; cardiovascular mortality or hospitalization for heart failure.

ICD codes

Dosage Regimen

Take orally once daily in the morning, with or without food.

Swallow the tablet whole with water; do not split or chew.

The recommended starting dose is 10 mg once daily.

For patients tolerating 10 mg daily who require additional glycemic control, the dose may be increased to the maximum recommended dose of 25 mg once daily.

Assess renal function before initiation; the drug is contraindicated in patients with an estimated glomerular filtration rate (eGFR) persistently below 45 mL/min/1.73 m².

Discontinue use if eGFR falls below 45 mL/min/1.73 m² during therapy.

When used in combination with insulin or a sulfonylurea, a lower dose of the concomitant medication may be required to reduce the risk of hypoglycemia.

Monitor for signs and symptoms of volume depletion, particularly in elderly patients, those with renal impairment, or those on diuretics or antihypertensive agents.

In patients at risk for ketoacidosis, consider temporary discontinuation during acute medical illness, prolonged fasting, or planned surgical procedures.

Do not use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Adverse Reactions

Infections and infestations: frequent – vaginal candidiasis, vulvovaginitis, balanitis and other genital infections, urinary tract infections (including pyelonephritis and urosepsis).

Metabolism and nutrition disorders: very frequent – hypoglycemia (when used in combination with sulfonylurea derivatives or insulin); frequent – thirst, increased plasma lipid concentration; infrequent – hypovolemia; rare – diabetic ketoacidosis.

Skin and subcutaneous tissue disorders: frequent – generalized pruritus, skin rash.

Allergic reactions infrequent – urticaria; frequency unknown – angioedema.

Renal and urinary disorders frequent – increased urine output; infrequent – dysuria, decreased GFR, increased plasma creatinine concentration.

Investigations infrequent – increased hematocrit.

Contraindications

Type 1 diabetes mellitus; diabetic ketoacidosis; renal failure with GFR <45 ml/min/1.73 m²; pregnancy, breastfeeding period; use in combination with glucagon-like peptide-1 (GLP-1) analogues (due to lack of efficacy and safety data); age under 18 years; age over 85 years; hypersensitivity to empagliflozin.

With caution

Patients at risk of hypovolemia (use of antihypertensive drugs with a history of arterial hypotension); in gastrointestinal diseases leading to fluid loss; age over 75 years; use in combination with sulfonylurea derivatives or insulin; infections of the genitourinary system; low-carbohydrate diet; history of diabetic ketoacidosis; low secretory activity of pancreatic beta cells.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and breastfeeding.

Use in Renal Impairment

Contraindication: renal failure with GFR <45 ml/min/1.73 m².

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Contraindication: age over 85 years.

Special Precautions

Cases of diabetic ketoacidosis, 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 were atypical and expressed 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 such nonspecific symptoms as nausea, vomiting, lack of appetite, abdominal pain, severe thirst, difficulty breathing, disorientation, unmotivated fatigue, or drowsiness. If such symptoms develop, patients should be immediately examined for ketoacidosis regardless of blood glucose concentration. If ketoacidosis is suspected, the use of empagliflozin should be discontinued, the patient should be examined, and treatment should be initiated immediately.

Patients at potentially higher risk of developing diabetic ketoacidosis include patients on a very low-carbohydrate diet (in which case this combination may further increase ketone production in the body), patients with acute illnesses, patients with pancreatic diseases suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), when reducing the insulin dose (including ineffective insulin pump operation), patients who abuse alcohol, patients with severe dehydration, and patients with a history of ketoacidosis. Caution should be exercised when reducing the insulin dose. In patients receiving Empagliflozin, monitoring for ketoacidosis and temporary discontinuation of empagliflozin should be considered in clinical situations predisposing to the development of ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).

It is recommended to monitor renal function before starting treatment and periodically during treatment (at least once a year), as well as before prescribing concomitant therapy that may adversely affect renal function. Patients with renal failure (GFR <45 ml/min/1.73 m²) are contraindicated to take empagliflozin.

Patients aged 75 years and older have an increased risk of dehydration. Adverse reactions caused by hypovolemia were more frequently observed in such patients.

Use with caution in cases where a decrease in blood pressure 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 receiving Empagliflozin develops conditions that may lead to fluid loss (e.g., gastrointestinal diseases), careful monitoring of the patient’s condition, blood pressure, as well as monitoring of hematocrit and electrolyte balance should be carried out. Temporary discontinuation of empagliflozin may be required until fluid balance is restored.

In case of development of complicated urinary tract infections, temporary discontinuation of empagliflozin therapy is necessary.

According to the mechanism of action, glucose is detected in the urine of patients receiving Empagliflozin.

Effect on ability to drive vehicles and operate machinery

During treatment, patients should exercise caution when driving vehicles and operating machinery, as hypoglycemia may develop when using empagliflozin (especially in combination with sulfonylurea derivatives and/or insulin).

Drug Interactions

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 drugs that enhance its secretion, such as sulfonylurea derivatives, may increase the risk of hypoglycemia. Therefore, when empagliflozin is used concomitantly with insulin and drugs that enhance its secretion, a reduction in their dose may be required to avoid the risk of hypoglycemia.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.