Jardins, 25 mg 30 pcs.

Empagliflozin is a reversible, highly active, selective and competitive inhibitor of the type 2 sodium-dependent glucose transporter with a concentration required to inhibit 50% of the enzyme activity (IC₅₀) equal to 1.3 nmol. The selectivity of empagliflozin to the sodium-dependent glucose transporter type 2 is 5000 times greater than the selectivity to the sodium-dependent glucose transporter type 1, responsible for glucose absorption in the intestine.

Empagliflozin was also found to be highly selective against other glucose transporters responsible for glucose homeostasis in various tissues.

The sodium-dependent glucose transporter type 2 is the main glucose transporter protein responsible for 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 glucose reabsorption in the kidneys. The amount of glucose excreted by the kidneys through this mechanism depends on blood glucose concentration and GFR. Inhibition of the type 2 sodium-dependent glucose transporter in patients with DM 2 and hyperglycemia results in excretion of excess glucose by the kidneys.

In a 4-week clinical trial, it was found that in patients with DM 2, renal glucose excretion increased immediately after the first dose of empagliflozin; this effect lasted for 24 hours. Increased renal glucose excretion persisted until the end of treatment, averaging approximately 78 g/day when empagliflozin was administered at a dose of 25 mg once daily. In patients with DM 2, increased renal excretion of glucose led to an immediate decrease in plasma glucose concentrations.

Empagliflozin (10 mg and 25 mg doses) decreases plasma glucose concentrations both when taken on an empty stomach and after meals.

The mechanism of action of empagliflozin does not depend on the functional state of pancreatic β-cells and insulin metabolism, which promotes low risk of possible hypoglycemia. A positive effect of empagliflozin on surrogate markers of β-cell function, including the NOMA-β index (homeostasis-β assessment model) and the proinsulin/insulin ratio, has been noted. In addition, additional glucose excretion by the kidneys causes caloric loss, which is accompanied by a decrease in adipose tissue volume and body weight.

Glucosuria seen during empagliflozin administration is accompanied by a slight increase in diuresis, which may contribute to a moderate decrease in BP.

In clinical trials using empagliflozin as monotherapy; combination therapy with metformin; combination therapy with metformin in patients with newly diagnosed DM2; combination therapy with metformin and sulfonylurea derivatives; combination therapy with pioglitazone ± metformin; combination therapy with linagliptin in patients with newly diagnosed DMD 2; combination therapy with linagliptin added to metformin therapy; combination therapy with linagliptin compared to placebo in patients with inadequate glycemic control on linagliptin and metformin; combination therapy with metformin versus glimepiride (data from a 2-year study); combination therapy with insulin (multiple insulin injection regimen) ± metformin; combination therapy with basal insulin; combination therapy with dipeptidyl peptidase-4 (DPP-4) inhibitor, metformin ± another hypoglycemic oral medication was shown to statistically significantly reduce glycosylated hemoglobin (HbA_1c), decrease fasting plasma glucose concentration, and decrease BP and body weight.

The clinical trial investigated the effect of JARDINS^® on the incidence of cardiovascular events in patients with DM2 and high cardiovascular risk (defined as having at least one of the following diseases and/or conditions CHD (history of myocardial infarction, coronary artery bypass grafting, CHD with a single coronary vessel lesion, CHD with multiple coronary vessels lesions), history of ischemic or hemorrhagic stroke, peripheral artery disease with or without symptoms) receiving standard therapy that included hypoglycemic drugs and medications for cardiovascular disease. Cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were assessed as the primary endpoint. Additional pre-specified end points were cardiovascular death, overall mortality, development of nephropathy or progressive worsening of nephropathy, and hospitalization for heart failure.

Empagliflozin improved overall survival by reducing cardiovascular death and reduced the risk of hospitalization for heart failure. JARDINS^® was also shown in a clinical trial to reduce the risk of nephropathy or progressive worsening of nephropathy.

In patients with baseline macroalbuminuria, JARDINS^® was found to result in sustained normo- or microalbuminuria significantly more often than placebo (hazard ratio 1.82 [95% CI 1.40; 2.37]).

Indications

Type 2 diabetes

Type 2 diabetes mellitus:

• as monotherapy in patients with inadequate glycemic control on diet and exercise alone, for whom the administration of metformin is not considered appropriate due to intolerance;

As combination therapy with other hypoglycemic agents, including insulin, when the therapy used together with diet and exercise does not provide the necessary glycemic control.

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Active ingredient

Empagliflozin

Composition

1 tablet contains:

The active ingredient:

empagliflozin 25 mg;

Associates:

Lactose monohydrate,

Microcrystalline cellulose,

Hyprolose (hydroxypropyl cellulose),

croscarmellose sodium,

colloidal silica,

Magnesium stearate.

Composition of the film coating:

Opadray Yellow (02B38190) (hypromellose 2910, titanium dioxide (E171), talc, macrogol 400, iron oxide yellow dye (E172)).

How to take, the dosage

The drug is taken orally with water, regardless of meals, at any time of day.

Monotherapy or combination therapy

The recommended starting dose is 10 mg (1 tablet of 10 mg) once daily. If the daily dose of 10 mg does not provide adequate glycemic control, the dose may be increased to 25 mg (1 tablet of 25 mg) once daily. The maximum daily dose is 25 mg.

When JARDINS ^® is coadministered with sulfonylurea derivatives or insulin, a reduction in the sulfonylurea/insulin derivative dose may be required due to the risk of hypoglycemia.

Actions to take when one or more doses of the drug are missed

If a dose is missed, the patient should take the drug as soon as they remember. Do not take a double dose over the course of one day.

The use of the drug in special patient groups

The drug is contraindicated in patients with renal insufficiency at a GFR of <45 ml/min/1.73 m² . Therapy with Jardins^® should not be started in patients with FFR <60 ml/min/1.73 m²; in case of FFR decrease during the drug therapy <60 ml/min/1.73 m² requires correction of empagliflozin dose to 10 mg/day or maintenance at 10 mg/day, in case of decrease <45 ml/min/1.73 m² the drug therapy should be stopped. Patients with a FFR >60 ml/min/1.73 m² do not require dose adjustment. Empagliflozin should not be used in patients with terminal renal failure or those on hemodialysis.

Patients with hepatic impairment do not require dose adjustment.

Interaction

In vitro evaluation of drug interactions

Empagliflozin does not inhibit, inactivate or induce CYP450 isoenzymes. The main route of metabolism of empagliflozin in humans is glucuronidation involving the uridine-5′-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8 and UGT1A9. Empagliflozin does not inhibit UGT1A1. Drug interactions between empagliflozin and drugs that are substrates of CYP450 and UGT1A1 isoenzymes are considered unlikely.

Empagliflozin is a substrate for glycoprotein P (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these proteins at therapeutic doses. Based on the data obtained in in-vitro studies, it is believed that the ability of empagliflozin to interact with drugs that are substrates for glycoprotein P (P-gp) is unlikely. Empagliflozin is a substrate for organic anion transporters: OAT3, OATP1B1 and OATP1B3, but is not a substrate for organic anion transporter 1 (OAT1) and organic cation transporter 2 (OCT2). However, drug interactions of empagliflozin with drugs that are substrates for the transporter proteins described above are considered unlikely.

In vivo evaluation of drug interactions

The pharmacokinetics of empagliflozin is not altered in healthy volunteers when co-administered with metformin. glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, thorasemide and hydrochlorothiazide. When co-administration of empagliflozin with gemfibrozil, rifampicin and probenecid there were increased AUC values of empagliflozin by 59%, 35% and 53%, respectively, but these changes were not considered to be clinically significant.

Empagliflozin has no clinically significant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, thorasemide and oral contraceptive drugs.

Diuretics

Empagliflozin may increase 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

Insulin and drugs that enhance its secretion, such as sulfonylurea derivatives, may increase the risk of hypoglycemia. Therefore, concomitant use of empagliflozin with insulin and the drugs that enhance its secretion may require reducing their dose to avoid the risk of hypoglycemia.

Special Instructions

Jardins is not recommended for use in patients with type 1 diabetes and for the treatment of diabetic ketoacidosis.

The maximum daily dose of Jardins contains 113 mg of lactose, therefore the drug should not be used in patients with such rare hereditary disorders as lactase deficiency, lactose intolerance and glucose-galactose malabsorption.

Clinical studies have shown that treatment with empagliflozin does not increase cardiovascular risk. The use of empagliflozin at a dose of 25 mg does not lead to prolongation of the QT interval.

When Jardins is used concomitantly with sulfonylurea derivatives or with insulin, it may be necessary to decrease the dose of sulfonylurea derivatives/insulin because of the risk of hypoglycemia.

Unstudied combinations of hypoglycemic drugs

Empagliflozin has not been studied in combination with analogues of glucagon-like peptide 1 (GFP-1).

Monitoring of renal function

The efficacy of Jardine depends on renal function. Therefore, it is recommended that renal function be monitored before and periodically during treatment (at least once a year) and before the administration of concomitant therapy that may adversely affect renal function. In patients with renal insufficiency (GFR less than 45 ml/min), taking the drug is not recommended.

Patients of advanced age

Patients aged 75 years and older have an increased risk of dehydration. In these patients who received empagliflozin, adverse reactions caused by hypovolemia were more common (compared to patients who received placebo). Experience of empagliflozin use in patients older than 85 years is limited, therefore it is not recommended to prescribe Jardins to patients older than 85 years.

Use in patients at risk of hypovolemia

Based on the action of Jardins, administration of the drug may lead to moderate decrease in blood pressure. This is why caution should be exercised when lowering of blood pressure is not desired, such as in patients with cardiovascular disease; patients taking hypotensive drugs (with a history of hypotension); and patients older than 75 years.

If patients on Jardins develop conditions which can cause fluid loss (e.g. gastrointestinal disorders), the patient’s condition, blood pressure, and hematocrit and electrolyte balance should be monitored closely. It may be necessary to temporarily discontinue the drug until the water balance is restored.

Urinary tract infections

The incidence of side effects such as urinary tract infections was comparable with empagliflozin at a dose of 25 mg and placebo, and higher with empagliflozin at a dose of 10 mg. Complicated urinary tract infections (such as pyelonephritis and urosepsis) occurred with similar frequency in patients receiving empagliflozin and placebo. In the case of complicated urinary tract infections, temporary discontinuation of empagliflozin therapy is necessary.

Lab urinalysis

According to the mechanism of action, glucose in the urine is determined in patients taking Jardins.

The effect on the ability to drive and operate vehicles

There have been no clinical studies on the effect of empagliflozin on the ability to drive and operate vehicles. Patients should use caution when driving and operating machinery because hypoglycemia may occur when using Jardins (especially in combination with sulfonylurea derivatives and/or insulin).

Contraindications

• high sensitivity to any component of the drug;
• Type 1 diabetes mellitus;
• diabetic ketoacidosis;
• hereditary rare disorders (lactase deficiency, lactose intolerance, glucose-lactose malabsorptionrare hereditary disorders (lactase deficiency, lactose intolerance, glucose-galactose malabsorption);
• renal insufficiency with FFR < 45 ml/min per 1.73 m² (due to ineffectiveness);
• pregnancy and breastfeeding period;
• age above 85 years of age;
• use in combination with analogues of glucagon-like peptide 1 (due to lack of efficacy and safety data);
• children under 18 years of age (due to lack of efficacy and safety data).

With caution

• Patients at risk of hypovolemia (use of hypotensive drugs with a history of arterial hypotension);
• Age over 75 years of age;
• use in combination with sulfonylurea derivatives or insulin;
• infections of the urogenital system.

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Side effects

The overall incidence of adverse events in patients treated with empagliflozin or placebo in clinical trials was similar. The most common adverse reaction was hypoglycemia, which was observed when using empagliflozin in combination with sulfonylurea derivatives or insulin (see description of individual adverse reactions).

The adverse reactions observed in patients receiving empagliflozin in placebo-controlled trials are presented in the Table below (adverse reactions were classified by organs and systems and according to MedDRA preferred terms) with an indication of their absolute frequency. Frequency categories are defined as follows: very frequent (≥1/10), frequent (≥1/100 to

Table. Side effects reported in placebo-controlled studies

Description of individual adverse reactions

Hypoglycemia

The frequency of hypoglycemia depended on the concomitant hypoglycemic therapy used.

Mild hypoglycemia (blood glucose 3.0 to 3.8 mmol/L (54-70 mg/dL))

The incidence of mild hypoglycemia was similar in patients receiving empagliflozin or placebo as monotherapy and when empagliflozin was added to metformin and when empagliflozin was added to pioglitazone (± metformin). When empagliflozin was prescribed in combination with metformin and sulfonylurea derivatives, the incidence of hypoglycemia was higher (10 mg: 10.3%; 25 mg: 7.4%) than when placebo was prescribed in the same combination (5.3%).

Severe hypoglycemia (blood glucose below 3 mmol/L (54 mg/dL)

The incidence of severe hypoglycemia was similar in patients receiving empagliflozin and placebo as monotherapy. The incidence of hypoglycemia was higher (10 mg: 5.8%; 25 mg: 4.1%) when empagliflozin was used in combination with metformin and sulfonylurea derivatives than when placebo was used in the same combination (3.1%).

Paceful urination

The frequency of frequent urination (symptoms such as pollakiuria, polyuria, nycturia were assessed) was higher with empagliflozin (10 mg dose: 3.4%, 25 mg dose: 3.2%) than with placebo (1%). The incidence of nicturia was comparable in the group of patients receiving empagliflozin and in the group of patients receiving placebo (less than 1%). The intensity of these side effects was mild to moderate.

Urinary tract infections

The incidence of urinary tract infections was similar between empagliflozin 25 mg and placebo (7.6%) but higher in the case of empagliflozin 10 mg (9.3%). As with placebo, urinary tract infections on empagliflozin were more frequent in patients with a history of chronic and recurrent urinary tract infections. The intensity of urinary tract infections was similar in patients taking empagliflozin and placebo. Urinary tract infections were more frequent in women.

The incidence of adverse events such as vaginal candidiasis. vulvovaginitis, balanitis and other genital infections was higher with empagliflozin (in 10 mg dose: 4.1%, in 25 mg dose: 3.7%) than with placebo (0.9%). Genital infections were more frequent in women. The intensity of genital infections was mild to moderate.

Hypovolemia

The incidence of hypovolemia (which was expressed by decreased blood pressure, orthostatic arterial hypotension, dehydration, syncope) was similar with empagliflozin (10 mg dose: 0.5%. 25 mg dose: 0.3%) and placebo (0.3%). In patients older than 75 years, the incidence of hypovolemia was comparable in patients taking empagliflozin at 10 mg (2.3%) and placebo (2.1%), but higher in patients taking empagliflozin at 25 mg (4.4%).

Overdose

Symptoms

In controlled clinical trials, single doses of empagliflozin reaching 800 mg (32 times the maximum daily dose) in healthy volunteers and multiple doses reaching 100 mg (4 times the maximum daily dose) in patients with T2DM were well tolerated. The observed increase in urine volume was independent of the dose amount and had no clinical significance. There is no experience with a dose greater than 800 mg.

Treatment

In case of overdose, removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring and symptomatic treatment are recommended.