Jardins, 10 mg 30 pcs.

Empagliflozin is a reversible, highly active, selective and competitive inhibitor of the sodium-dependent glucose transporter type 2 with a concentration value of 1.3 nmol required to inhibit 50% of enzyme activity (IC50). The selectivity of empagliflozin is 5000 times greater than that of the type 1 sodium-dependent glucose transporter responsible for glucose absorption in the intestine. In addition, empagliflozin was 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 (type 2 DM) by reducing glucose reabsorption in the kidneys. The amount of glucose excreted by the kidneys through this mechanism depends on blood glucose concentration and glomerular filtration rate (GFR). Inhibition of type 2 sodium-dependent glucose transporter in patients with DM2 and hyperglycemia leads to excretion of excess glucose by the kidneys.

In clinical studies, 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. The increase in renal glucose excretion persisted until the end of the 4-week treatment period, averaging about 78 g/day when empagliflozin was used in 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 decreases plasma glucose concentrations both when taken on an empty stomach and after meals.

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

The effect of empagliflozin does not depend on the functional state of pancreatic beta cells and insulin metabolism. A positive effect of empagliflozin on surrogate markers of beta-cell function, including NOMA-ß index (homeostasis-B model) and proinsulin to 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 observed during use of empagliflozin is accompanied by a slight increase in diuresis, which may contribute to a moderate decrease in blood pressure.

In clinical trials where empagliflozin was used as monotherapy; combination therapy with metformin; combination therapy with metformin and sulfonylurea derivatives; combination therapy with metformin versus glimepiride; combination therapy with pioglitazone +/- metformin; as combination therapy with dipeptidyl peptidase-4 (DPP-4) inhibitor, metformin +/- another hypoglycemic oral medication; as combination therapy with insulin, a statistically significant decrease in glycosylated hemoglobin HbAlc and decrease in fasting plasma glucose concentration has been demonstrated.

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.

.

Active ingredient

Empagliflozin

Composition

Active substance:

empagliflozin – 10 mg.

Associates:

Lactose monohydrate – 162.5 mg,

Microcrystalline cellulose – 62.5 mg,

Hyprolose (hydroxypropyl cellulose) – 7.5 mg,

croscarmellose sodium – 5 mg,

colloidal silicon dioxide – 1.25 mg,

magnesium stearate – 1.25 mg.

Shell contents:

Opadray yellow (02B38190) – 7 mg (hypromellose 2910 – 3.5 mg, titanium dioxide – 1.733 mg, talc – 1.4 mg, macrogol 400 – 0.35 mg, iron oxide yellow dye – 0.018 mg).

.

How to take, the dosage

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

The recommended starting dose is 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 once daily.

The maximum daily dose is 25 mg.

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

Interaction

Pharmacodynamic interaction

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 increase 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.

Pharmacokinetic interaction

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

Empagliflozin is a substrate for P-glycoprotein and breast cancer resistance protein (BCRP), but it does not inhibit these proteins in 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 P-glycoprotein 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 (OAT2). However, drug interactions between empagliflozin and drugs that are substrates for the transporter proteins described above are considered unlikely.

Evaluation of drug interactions in vivo. When co-administration of empagliflozin with other commonly used drugs no clinically significant pharmacokinetic interaction was observed. The results of pharmacokinetic studies suggest that there is no need to change the dose of the drug Jardins® when it is used simultaneously with frequently used drugs.

The pharmacokinetics of empagliflozin does not change in healthy volunteers when used together 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 in healthy volunteers.

.

Special Instructions

The drug JARDINS is not recommended for use in patients with diabetes mellitus type 1 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 coadministering JARDINS with sulfonylurea derivatives or with insulin, it may be necessary to decrease the dose of sulfonylurea derivatives/insulin because of the risk of hypoglycemia.

Not studied combinations of hypoglycemic drugs

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

Monitoring of renal function

The efficacy of JARDINS depends on renal function. Therefore, it is recommended that renal function be monitored before its administration 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 (FFR less than 45 ml/min). taking the drug is not recommended.

Elderly patients

Patients aged 75 years and more 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.

Application in patients at risk of hypovolemia

According to the mechanism of action, administration of JARDINS may lead to a moderate decrease in blood pressure. Therefore the drug should be used with caution in cases when the decrease of blood pressure is undesirable, e.g. in patients with cardiovascular diseases; patients taking hypotensive drugs (with a history of arterial hypotension) and in patients older than 75 years.

If a patient taking JARDINS. develops conditions that can lead to fluid loss (e.g., gastrointestinal disorders), the patient’s condition, blood pressure, and hematocrit and electrolyte balance should be monitored closely. It may be required temporary discontinuation of the drug until the water balance is restored.

Infections of the urinary tract

. 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.

Laboratory urinalysis

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

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 vehicles and operating machinery because hypoglycemia may occur when using JARDINS (especially in combination with sulfonylurea derivatives and/or insulin).

Contraindications

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

With cautiousness: patients at risk of hypovolemia (use of hypotensive drugs with a history of arterial hypotension); in gastrointestinal diseases leading to fluid loss; urinary tract infections; use in combination with sulfonylurea derivatives or insulin; low-carbohydrate diet; history of diabetic ketoacidosis; low pancreatic β-cell secretory activity; patients aged over 75 years.

.

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.

The adverse reactions observed in patients receiving empagliflozin in placebo-controlled trials are presented below according to organ and system classification and MedDRA preferred terms with their absolute frequency. Frequency categories are defined as follows: very common (≥1/10), common (≥1/100 to < 1/10), infrequent (≥1/1,000 to < 1/100), rare (≥1/10,000 to < 1/1000) or very rare (< 1/10,000); adverse reactions whose frequency is unknown (cannot be estimated from available data) are also identified.

Infectious and parasitic diseases:often, vaginal candidiasis, vulvovaginitis, balanitis and other genital infections, urinary tract infections.

Metabolism and nutrition:very often – hypoglycemia (when combined with sulfonylurea derivatives or insulin).

Cardiovascular system disorders: infrequently – hypovolemia.

In the urinary system:often – frequent frequent urination; infrequent – dysuria.

Skin and subcutaneous tissue:often – skin itching.

Description of individual adverse reactions

Hypoglycemia

The incidence of hypoglycemia depended on the concomitant hypoglycemic therapy used and was similar in patients receiving empagliflozin or placebo as monotherapy, as well as when empagliflozin was added to metformin and when empagliflozin was added to pioglitazone (±metformin).

The incidence of hypoglycemia was higher when empagliflozin was used in combination with metformin and sulfonylurea derivatives and when empagliflozin was used in combination with insulin (+/- metformin and +/- sulfonylurea derivative) than when placebo was used in the same combination.

Severe hypoglycemia (condition requiring medical intervention).

Frequent urination

The incidence of frequent urination (symptoms such as pollakiuria, polyuria, nycturia were evaluated) was higher with empagliflozin (10 mg dose: 3.5%, in 25 mg dose: 3.3%) than when placebo was used (1.4%). The incidence of nicturia was comparable in the group of patients taking empagliflozin and in the group of patients taking 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 in the 25-mg dose of empagliflozin and placebo (7.0% and 7.2%, respectively), but higher with empagliflozin at a dose of 10 mg (8.8%). 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.

Genital infections

The incidence of adverse events such as vaginal candidiasis, vulvovaginitis, balanitis, and other genital infections was higher with empagliflozin (10 mg dose: 4.0%, 25 mg dose: 3.9%) than with placebo (1.0%). 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 BP, orthostatic arterial hypotension, dehydration, syncope) was similar with empagliflozin (10 mg dose: 0.6%, 25 mg dose: 0.4%) and placebo (0.3%). In patients over 75 years of age, 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 (4.3%).