Jardins tablets 10mg, No. 30

For the treatment of type 2 diabetes in adults 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 mellitus and a high cardiovascular risk * in combination with standard cardiovascular therapy to reduce:

• overall mortality by reducing cardiovascular mortality;

• cardiovascular mortality or hospitalization for heart failure.

The drug is taken orally with water, regardless of food intake at any time of the day.

Monotherapy or combination therapy

The recommended starting dose is 10 mg (1 tablet with a dosage of 10 mg) 1 time / day. If the daily dose of 10 mg does not provide adequate glycemic control, the dose can be increased to 25 mg (1 tablet with a dosage of 25 mg) 1 time / day. The maximum daily dose is 25 mg.

When the drug JARDINSЃ is used together with sulfonylurea derivatives or insulin, it may be necessary to reduce the dose of sulfonylurea / insulin derivatives due to the risk of hypoglycemia.

Actions when you skip taking one or more doses of the drug

If a dose is missed, the patient should take the drug as soon as he remembers. Do not take a double dose in one day.

The use of the drug in special groups of patients

The use of the drug in patients with renal insufficiency with GFR <45 ml / min / 1.73 m2 is contraindicated. Therapy with JARDINSЃ should not be started in patients with GFR <60 ml / min / 1.73 m2; in the case of a decrease in GFR during therapy with the drug <60 ml / min / 1.73 m2, the dose of empagliflozin must be adjusted to 10 mg / day or maintained at the level of 10 mg / day; if the decrease is <45 ml / min / 1.73 m2, drug therapy should be discontinued. No dose adjustment is required in patients with GFR> 60 ml / min / 1.73 m2. Empagliflozin should not be used in patients with end-stage renal disease or on hemodialysis.

No dose adjustment is required in patients with impaired liver function.

Light yellow film-coated tablets

1 tab. empagliflozin

Excipients: lactose monohydrate, microcrystalline cellulose, hyprolose (hydroxypropyl cellulose), croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.

• hypersensitivity to empagliflozin and / or any excipient in the drug;

• type 1 diabetes mellitus;

• diabetic ketoacidosis;

• rare hereditary disorders (lactase deficiency, lactose intolerance, glucose-galactose malabsorption);

• renal failure with GFR <45 ml / min / 1.73 m2;

• pregnancy;

• breastfeeding period;

• age over 85;

• use in combination with analogs of glucagon-like peptide 1 (GLP-1) (due to the lack of data on efficacy and safety);

• age up to 18 years (due to insufficient data on efficacy and safety).

Carefully

• patients at risk of developing hypovolemia (use of antihypertensive drugs with a history of arterial hypotension);

• with diseases of the gastrointestinal tract, leading to loss of fluid;

• age over 75;

• use in combination with sulfonylurea derivatives or insulin;

• infections of the genitourinary system;

• a diet low in carbohydrates;

• history of diabetic ketoacidosis;

• low secretory activity of? -cells of the pancreas.

pharmachologic effect

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

In addition, empagliflozin was found to be highly selective for other glucose transporters responsible for glucose homeostasis in various tissues.

Sodium-dependent glucose transporter type 2 is the main transporter protein responsible for the reabsorption of glucose from the glomeruli back into the bloodstream.

Empagliflozin improves glycemic control in patients with type 2 diabetes mellitus (DM 2) by decreasing renal glucose reabsorption. The amount of glucose secreted by the kidneys by this mechanism depends on the blood glucose concentration and GFR. Inhibition of the sodium-dependent type 2 glucose transporter in patients with type 2 diabetes and hyperglycemia leads to the excretion of excess glucose by the kidneys.

During 4-week clinical studies, it was found that in patients with type 2 diabetes, the excretion of glucose by the kidneys increased immediately after the first dose of empagliflozin; this effect lasted for 24 hours. An increase in the excretion of glucose by the kidneys remained until the end of treatment, and, when using empagliflozin at a dose of 25 mg 1 time / day, on average, about 78 g / day. In patients with diabetes mellitus 2, an increase in glucose excretion by the kidneys led to an immediate decrease in plasma glucose concentration.

Empagliflozin (at a dose of 10 mg and 25 mg) reduces the concentration of glucose in the blood plasma both when taken on an empty stomach and after meals.

The mechanism of action of empagliflozin does not depend on the functional state of the ?-cells of the pancreas and insulin metabolism, which contributes to a low risk of possible hypoglycemia. A positive effect of empagliflozin on surrogate markers of ?-cell function, including the HOMA-? index, was noted. (model for assessing homeostasis -?) and the ratio of proinsulin to insulin. In addition, the additional excretion of glucose by the kidneys causes a loss of calories, which is accompanied by a decrease in the volume of adipose tissue and a decrease in body weight.

Glucosuria, observed during the use of empagliflozin, is accompanied by a slight increase in urine output, which can contribute to a moderate decrease in blood pressure.

In clinical studies where empagliflozin was used as monotherapy; combination therapy with metformin; combination therapy with metformin in patients with newly diagnosed type 2 diabetes; combination therapy with metformin and sulfonylurea derivatives; combination therapy with pioglitazone ± metformin; combination therapy with linagliptin in patients with newly diagnosed type 2 diabetes; combination therapy with linagliptin added to metformin therapy; combination therapy with linagliptin versus placebo in patients with inadequate glycemic control while receiving linagliptin and metformin; combination therapy with metformin versus glimepiride (data from a 2-year study); combination therapy with insulin (multiple insulin injections regimen) ± metformin;combination therapy with basal insulin; combination therapy with a dipeptidyl peptidase-4 (DPP-4) inhibitor, metformin ± another hypoglycemic oral drug has been shown to have a statistically significant decrease in glycosylated hemoglobin (HbA1c), a decrease in fasting plasma glucose concentration, as well as a decrease in blood pressure and body weight.

In the course of a clinical study, the effect of JARDINSЃ on the incidence of cardiovascular events in patients with diabetes mellitus 2 and high cardiovascular risk (defined as the presence of at least one of the following diseases and / or conditions) was studied: arteries, coronary artery disease with damage to one coronary vessel, coronary artery disease with damage to several coronary vessels), ischemic or hemorrhagic stroke in history, peripheral arterial disease with or without symptoms), receiving standard therapy, which included hypoglycemic drugs and drugs for the treatment of cardiovascular diseases. Cases of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke were evaluated as the primary endpoint.Additional predetermined endpoints were cardiovascular death, overall mortality, development of nephropathy or progressive worsening of nephropathy, hospitalization for heart failure.

Empagliflozin improved overall survival by reducing cardiovascular deaths and reducing the risk of hospitalization for heart failure. Also, in the course of a clinical study, it was shown that JARDINSЃ reduced the risk of nephropathy or progressive deterioration of nephropathy.

In patients with baseline macroalbuminuria, it was found that JARDINSЃ was significantly more likely than placebo to lead to persistent normo- or microalbuminuria (hazard ratio 1.82 [95% CI 1.40; 2.37]).

Pharmacokinetics

The pharmacokinetics of empagliflozin has been comprehensively studied in healthy volunteers and in patients with diabetes mellitus 2.

Suction

After oral administration, empagliflozin is rapidly absorbed, Cmax of empagliflozin in blood plasma is reached after 1.5 hours. Then the concentration of empagliflozin in plasma decreases in two phases: with a fast distribution phase and a relatively slow final phase.

After taking the drug at a dose of 25 mg 1 time / day, the average AUC during the period of equilibrium plasma concentration was 4740 nmol h / L, and the Cmax value 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 in patients with diabetes mellitus 2 was generally similar.

Distribution

The apparent Vd during the period of equilibrium plasma concentration was approximately 73.8 L. After oral administration of labeled empagliflozin [14C] by healthy volunteers, plasma protein binding was 86%.

Metabolism

The main metabolic pathway of empagliflozin in humans is glucuronization with the participation of uridine-5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. The most commonly detected metabolites of empagliflozin are three glucuronic conjugates (2-O, 3-O and 6-O glucuronide). The systemic effect of each metabolite is small (less than 10% of the total effect of empagliflozin).

Withdrawal

T1 / 2 is approximately 12.4 hours. When using empagliflozin 1 time / day, Css in blood plasma was reached after the fifth dose. After oral administration of labeled empagliflozin [14C], approximately 96% of the dose was excreted in healthy volunteers (through the intestines - 41%, by the kidneys - 54%). Through the intestine, most of the labeled drug was excreted unchanged. Only half of the labeled preparation was excreted by the kidneys unchanged.

Pharmacokinetics in special patient groups

Impaired renal function. In patients with mild renal impairment (60 ? GFR <90 ml / min / 1.73 m2), moderate (30 ? GFR <60 ml / min / 1.73 m2), and severe (GFR <30 ml / min / 1.73 m2) and in patients with end-stage renal failure, the AUC values ??of empagliflozin increased by approximately 18%, 20%, 66% and 48%, respectively, compared with patients with normal renal function. In patients with moderate renal failure and in patients with end-stage renal failure, the Cmax of empagliflozin in plasma was similar to the corresponding values ??in patients with normal renal function. In patients with mild and severe renal insufficiency, the Cmax of empagliflozin in plasma was approximately 20% higher than in patients with normal renal function.Population pharmacokinetic analysis data showed that the total clearance of empagliflozin decreased with decreasing GFR, leading to an increase in drug exposure.

Liver dysfunction. In patients with mild, moderate and severe liver dysfunction (according to the Child-Pugh classification), the AUC values ??of empagliflozin increased by about 23%, 47% and 75%, respectively, and the Cmax values ??by about 4%, 23% and 48%, respectively. (compared to patients with normal liver function).

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

Children. Studies of the pharmacokinetics of empagliflozin in children have not been conducted.

Application during pregnancy and lactation

The use of empagliflozin during pregnancy is contraindicated due to insufficient data on efficacy and safety.

Data obtained in preclinical studies in animals indicate the excretion of empagliflozin in breast milk. The risk of exposure to newborns and children during breastfeeding is not excluded. The use of empagliflozin during breastfeeding is contraindicated. If it is necessary to use empagliflozin during breastfeeding, breastfeeding should be discontinued.

Application for violations of liver function

No dose adjustment is required in patients with impaired liver function.

Application for impaired renal function

It is contraindicated for use in patients with renal insufficiency with GFR <45 ml / min / 1.73 m2.

Application in children

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

Use in elderly patients

Patients aged 75 and over have an increased risk of dehydration. In such patients who received empagliflozin, adverse reactions caused by hypovolemia were more often (compared with patients receiving placebo).

The experience of using empagliflozin in patients over 85 years of age is limited, therefore, it is not recommended to prescribe JARDINSЃ to patients of this age group.

special instructions

The use of JARDINSЃ is contraindicated in patients with type 1 diabetes mellitus.

Diabetic ketoacidosis

With the use of empagliflozin, cases of diabetic ketoacidosis, a serious and life-threatening condition requiring urgent hospitalization, have been reported, incl. with a lethal outcome. In some of these cases, the manifestations were atypical and were expressed in a moderate increase in blood glucose concentration (no more than 14 mmol / L (250 mg / dL)).

The risk of developing diabetic ketoacidosis should be considered if non-specific symptoms such as nausea, vomiting, lack of appetite, abdominal pain, severe thirst, difficulty breathing, disorientation, unmotivated fatigue or drowsiness appear. If such symptoms develop, patients should be promptly evaluated for ketoacidosis regardless of blood glucose concentration. If ketoacidosis is suspected, the use of JARDINSЃ should be discontinued, the patient should be examined and treatment should be immediately prescribed.

Patients who may have a higher risk of developing diabetic ketoacidosis when taking JARDINSЃ include patients on a very low carbohydrate diet (in this case, this combination may further increase the production of ketones in the body), patients with acute diseases , patients with pancreatic disease suggesting an insulin deficiency (eg, type 1 diabetes mellitus, history of pancreatitis, or pancreatic surgery), with a decrease in insulin dose (including ineffective insulin pump), alcohol abuse patients, patients with severe dehydration, and patients with a history of ketoacidosis. In such patients, JARDINSЃ should be used with caution. Care should be taken when reducing the dose of insulin. In patients receiving JARDINSЃ,consideration should be given to monitoring ketoacidosis and temporarily discontinuing JARDINSЃ in clinical situations that predispose to the development of ketoacidosis (for example, prolonged fasting due to an acute illness or surgery).

JARDINSЃ in a 10 mg tablet contains 162.5 mg of lactose, with a dosage of 25 mg - it contains 113 mg of lactose, so the drug should not be used in patients with such rare hereditary disorders as lactase deficiency, lactose intolerance, 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.

Unstudied combinations of hypoglycemic drugs

Empagliflozin has not been studied in combination with GLP-1 analogues.

Monitoring kidney function

The effectiveness of JARDINSЃ depends on renal function, therefore, it is recommended to monitor renal function before prescribing it 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 insufficiency (GFR <45 ml / min / 1.73 m2) are contraindicated in taking the drug.

Elderly patients

Patients aged 75 years and older have an increased risk of dehydration, therefore JARDINSЃ should be prescribed with caution to this category of patients. In such patients, who received empagliflozin, more often (compared with patients who received placebo) there were HP caused by hypovolemia.

The experience of using empagliflozin in patients over 85 years of age is limited, therefore, it is not recommended to prescribe JARDINSЃ to patients of this age group.

Use in patients at risk of developing hypovolemia

According to the mechanism of action, the use of JARDINSЃ can lead to a moderate decrease in blood pressure. Therefore, the drug should be used 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 the age of 75 years.

If a patient taking JARDINSЃ develops conditions that can lead to fluid loss (for example, in diseases of the gastrointestinal tract), careful monitoring of the patient's condition, blood pressure should be carried out, as well as hematocrit and electrolyte balance should be monitored. It may be necessary to temporarily stop taking the drug until the water balance is restored.

Urinary tract infections

The incidence of such HPs as urinary tract infections was comparable with the use of empagliflozin at a dose of 25 mg and placebo, and higher with the use of empagliflozin at a dose of 10 mg. Complicated urinary tract infections, incl. pyelonephritis and urosepsis have been reported in patients taking empagliflozin in post-marketing studies. In the case of the development of complicated urinary tract infections, it is necessary to temporarily discontinue therapy with empagliflozin.

Laboratory analysis of urine

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

Influence on the ability to drive vehicles and use mechanisms

 линических исследований по вли¤нию эмпаглифлозина на способность управл¤ть транспортными средствами и механизмами не проводилось. ѕациентам следует соблюдать осторожность при управлении транспортными средствами и механизмами, т.к. при применении препарата ??ј–?»Ќ—Ѓ (особенно в комбинации с производными сульфонилмочевины и/или инсулином) может развитьс¤ гипогликеми¤.

ѕередозировка

—имптомы: во врем¤ проведени¤ контролируемых клинических исследований у здоровых добровольцев однократные дозы эмпаглифлозина, достигавшие 800 мг (в 32 раза превышавшие максимальную суточную дозу), и многократные дозы, достигавшие 100 мг (в 4 раза превышавшие максимальную суточную дозу) у пациентов с —? 2, переносились хорошо. Ќаблюдавшеес¤ увеличение объема мочи не зависело от величины дозы и не имело клинического значени¤.

Ћечение: в случае передозировки эмпаглифлозина поддерживающее лечение должно проводитьс¤ соответственно клиническому состо¤нию пациента. ¬ыведение эмпаглифлозина с помощью гемодиализа не изучалось.

Ћекарственное взаимодействие

‘армакодинамическое взаимодействие

?иуретики. Ёмпаглифлозин может усиливать диуретический эффект тиазидных и 'петлевых' диуретиков, что, в свою очередь, может увеличить риск развити¤ дегидратации и артериальной гипотензии.

»нсулин и препараты, усиливающие его секрецию, такие как производные сульфонилмочевины, могут увеличивать риск гипогликемии. ѕоэтому при одновременном применении эмпаглифлозина с инсулином и препаратами, усиливающими его секрецию, может потребоватьс¤ снижение их дозы, во избежание риска развити¤ гипогликемии.

‘армакокинетическое взаимодействие

ќценка лекарственного взаимодействи¤ in vitro. Ёмпаглифлозин не ингибирует, не инактивирует и не индуцирует изоферменты CYP450. ќсновным путем метаболизма эмпаглифлозина у человека ¤вл¤етс¤ глюкуронизаци¤ с участием уридин-5'-дифосфо-глюкуронозилтрансфераз UGT2B7, UGT1A3, UGT1A8 и UGT1A9. Ёмпаглифлозин не ингибирует UGT1A1, UGT1A3, UGT1A8, UGT1A9 или UGT2¬7. Ћекарственное взаимодействие эмпаглифлозина и лекарственных препаратов, ¤вл¤ющихс¤ субстратами изоферментов CYP450 и UGT, считаетс¤ маловеро¤тным.

Ёмпаглифлозин ¤вл¤етс¤ субстратом дл¤ –-гликопротеина (P-gp) и белка, определ¤ющего резистентность рака молочной железы (BCRP), но в терапевтических дозах не ингибирует эти белки. Ќа основании данных, полученных в исследовани¤х in vitro, считаетс¤, что способность эмпаглифлозина вступать во взаимодействие с препаратами, которые ¤вл¤ютс¤ субстратами дл¤ P-gp, маловеро¤тна. Ёмпаглифлозин ¤вл¤етс¤ субстратом дл¤ органических анионных переносчиков: ќј“3, ќј“–1¬1 и ќј“–1¬3, но не ¤вл¤етс¤ субстратом дл¤ органических анионных переносчиков 1 (ќAT1) и органических катионных переносчиков 2 (ќ—“2). ќднако лекарственное взаимодействие эмпаглифлозина с препаратами, ¤вл¤ющимис¤ субстратами дл¤ вышеописанных белков-переносчиков, считаетс¤ маловеро¤тным.

ќценка лекарственного взаимодействи¤ in vivo. ѕри совместном применении эмпаглифлозина с другими часто используемыми лекарственными препаратами клинически значимого фармакокинетического взаимодействи¤ не наблюдалось. –езультаты фармакокинетических исследований свидетельствуют об отсутствии необходимости измен¤ть дозу препарата ??ј–?»Ќ—Ѓ при одновременном его применении с часто используемыми лекарственными препаратами.

The pharmacokinetics of empagliflozin does not change in healthy volunteers in the case of its combined use with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin and in patients with diabetes mellitus in the case of combined use with torasemide and hydrorasemidazone. With the combined use of empagliflozin with gemfibrozil, rifampicin and probenecid, there was an increase in the AUC value of empagliflozin by 59%, 35% and 53%, respectively, but these changes were not considered clinically significant.

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