Jardins coated pills 10mg N30
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Active ingredients
Empagliflozin
Release form
Pills
Composition
Empagliflozin 10 mg; Excipients: lactose monohydrate - 162.5 mg, microcrystalline cellulose - 62.5 mg, hyprolose (hydroxypropylcellulose) - 7.5 mg, croscarmellose sodium - 5 mg, silicon dioxide, colloidal - 1.25 mg, magnesium stearate - 1.25 mg., Composition: opadry yellow (02B38190) - 7 mg (hypromellose 2910 - 3.5 mg, titanium dioxide - 1.733 mg, talc - 1.4 mg, macrogol 400 - 0.35 mg, iron dye yellow oxide - 0.018 mg).
Pharmacological effect
Oral hypoglycemic drug. Empagliflozin is a reversible, highly active, selective and competitive inhibitor of sodium type 2 glucose transporter with a concentration required to inhibit 50% of the enzyme activity (IC50) of 1.3 nmol. The selectivity of empagliflozin is 5,000 times higher than the sodium-dependent glucose transporter type 1 responsible for the absorption of glucose in the intestine. In addition, it was found that empagliflozin has a high selectivity for other glucose transporters responsible for glucose homeostasis in various tissues. Sodium dependent type 2 glucose carrier is the main carrier protein responsible for the reabsorption of glucose from the renal glomeruli back into the bloodstream.; Empagliflozin improves glycemic control or in patients with type 2 diabetes mellitus by reducing the reabsorption of glucose in the kidney. The amount of glucose excreted by the kidneys through this mechanism depends on the concentration of glucose in the blood and GFR. Inhibition of type 2 sodium glucose transporter in patients with type 2 diabetes and hyperglycemia leads to excretion of excess glucose by the kidneys. During clinical studies, it was found that in patients with type 2 diabetes, kidney glucose excretion increased immediately after the first dose of empagliflozin; this effect lasted for 24 hours. The increase in glucose excretion by the kidneys persisted until the end of the 4-week treatment period, amounting to about 78 g / day when empagliflozin was used in a dose of 25 mg 1 time / day. In patients with type 2 diabetes, an increase in glucose excretion by the kidneys led to an immediate decrease in plasma glucose concentration.; Empagliflozin decreases plasma glucose concentration both in the case of fasting and after eating.; The mechanism of action of empagliflozin does not depend on the functional state β pancreatic cells and insulin metabolism.The positive effect of empagliflozin on surrogate markers of β-cell functional activity, including the HOMA-β index (a model for assessing homeostasis) and the ratio of proinsulin to insulin, was noted. In addition, the additional excretion of glucose by the kidneys causes a loss of calories, which is accompanied by a decrease in adipose tissue and weight loss.; Glycosuria, observed during the use of empagliflozin, is accompanied by a slight increase in diuresis, which can contribute to a moderate decrease in blood pressure. In clinical studies where used empagliflozin 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 mellitus; combination therapy with linagliptin, added to metformin therapy; combination therapy with metformin versus glimepiride (data from a 2-year study); combination therapy with insulin (the mode of multiple injections of insulin) +/- metformin; combination therapy with basal insulin; combination therapy with a dipeptidyl peptidase-4 inhibitor (DPP-4), metformin +/- another hypoglycemic oral drug was shown to be a statistically significant decrease in glycated hemoglobin (HbA1c), a decrease in fasting plasma glucose, as well as a decrease in blood pressure and body weight.
Pharmacokinetics
The pharmacokinetics of empagliflozin were comprehensively studied in healthy volunteers and in patients with type 2 diabetes.; Absorption; After oral administration, empagliflozin is rapidly absorbed, Cmax of empagliflozin in the blood plasma is reached after 1.5 h. Then, the concentration of empagliflozin in plasma decreases two-phase. After taking the drug in a dose of 25 mg 1 time / day, the average AUC value during the period of stable plasma concentration was 4740 nmol h / l, and the Cmax value was 687 nmol / l. Eating does not have a clinically significant effect on the pharmacokinetics of empagliflozin.; The pharmacokinetics of empagliflozin in healthy volunteers and in patients with type 2 diabetes were, on the whole, similar.; Distribution; Vd during the period of stable plasma concentration is approximately 73.8 l. After ingestion of labeled empagliflozin [14C] by healthy volunteers, plasma protein binding was 86.2%.When empagliflozin was used 1 time / day Css in plasma was reached after the fifth dose. Metabolism; The main metabolic pathway of empagliflozin in humans is glucuronidation with the participation of uridine-5'-diphospho-glucuronosyltransferase UGT2B7, UGT1A3, UGT1A3 and UGT1A and UGT. The most frequently 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) .; Excretion; T1 / 2 is approximately 12.4 hours. After ingestion of labeled empagliflozin [14C] in healthy volunteers, approximately 96% of the dose was eliminated (through the intestines - 41%, by the kidneys - 54%). Through the intestines most of the labeled drug was excreted unchanged. Only half of the labeled drug was excreted unchanged by the kidneys.; Pharmacokinetics in special groups of patients; In patients with mild renal failure (60<скф<90 мл/мин/1.73="" м2),="" средней="">скф<90><скф<60 мл/мин/1.73="" м2)="" и="" тяжелой="" степени="" (скф<30="" мл/мин/1.73="" м2)="" и="" у="" пациентов="" с="" терминальной="" стадией="" почечной="" недостаточности="" значения="" auc="" эмпаглифлозина="" увеличивались="" приблизительно="" на="" 18%,="" 20%,="" 66%="" и="" 48%="" соответственно,="" по="" сравнению="" с="" пациентами="" с="" нормальной="" функцией="" почек.="" у="" пациентов="" с="" почечной="" недостаточностью="" средней="" степени="" тяжести="" и="" у="" пациентов="" с="" терминальной="" стадией="" почечной="" недостаточности="" cmax="" эмпаглифлозина="" в="" плазме="" была="" сходна="" с="" соответствующими="" значениями="" у="" пациентов="" с="" нормальной="" функцией="" почек.="" у="" пациентов="" с="" почечной="" недостаточностью="" легкой="" и="" тяжелой="" степени="" cmax="" эмпаглифлозина="" в="" плазме="" была="" примерно="" на="" 20%="" выше,="" чем="" у="" пациентов="" с="" нормальной="" функцией="" почек.="" данные="" популяционного="" фармакокинетического="" анализа="" показали,="" что="" общий="" клиренс="" эмпаглифлозина="" уменьшался="" по="" мере="" снижения="" скф,="" что="" приводило="" к="" увеличению="" воздействия="" препарата.;у="" пациентов="" с="" нарушениями="" функции="" печени="" легкой,="" средней="" и="" тяжелой="" степени="" (согласно="" классификации="" чайлд-пью)="" значения="" auc="" эмпаглифлозина="" увеличивались="" приблизительно="" на="" 23%,="" 47%="" и="" 75%="" соответственно,="" а="" значения="" cmax="" приблизительно="" на="" 4%,="" 23%="" и="" 48%="" соответственно="" (по="" сравнению="" с="" пациентами="" с="" нормальной="" функцией="" печени).;имт,="" пол,="" раса="" и="" возраст="" не="" оказывали="" клинически="" значимого="" влияния="" на="" фармакокинетику="" эмпаглифлозина.;исследования="" фармакокинетики="" эмпаглифлозина="" у="" детей="" не="">скф<60>
Indications
Diabetes mellitus type 2: - as monotherapy in patients with inadequate glycemic control only on the background of diet and exercise, the appointment of metformin which is considered inappropriate because of intolerance; - as part of combination therapy with other hypoglycemic agents, including insulin, when applied therapy in conjunction with diet and exercise does not provide the necessary glycemic control.
Contraindications
- diabetes mellitus type 1; - diabetic ketoacidosis; - rare inherited disorders (lactase deficiency, lactose intolerance, glucose-galactose malabsorption); - renal failure with persistent GFR <45 ml / min / 1.73 m2; - use in combination with analogues of glucagon-like peptide-1 (due to the lack of data on efficacy and safety); - pregnancy; - lactation period (breastfeeding); - age over 85 years; - children and adolescents up to 18 years (due to the lack of data on efficacy and safety); - Hypersensitivity to any component of the drug. With caution: patients at risk of developing hypovolemia (use of antihypertensive drugs with cases of arterial hypotension in the anamnesis); in diseases of the gastrointestinal tract, leading to fluid loss; infections of the genitourinary system; use in combination with sulfonylurea derivatives or insulin; low carbohydrate diet; a history of diabetic ketoacidosis; low secretory activity of pancreatic β-cells; patients over the age of 75 years.
Use during pregnancy and lactation
The use of empagliflozin during pregnancy is contraindicated due to insufficient data on efficacy and safety. The use of empagliflozin during breastfeeding is contraindicated. The data obtained in preclinical studies in animals indicate the release of empagliflozin with breast milk. The risk of exposure to newborns and breastfed babies is not excluded. If necessary, the use of empagliflozin during lactation, breast-feeding should be discontinued.
Dosage and administration
The drug is taken orally, at any time of the day, regardless of the meal. The recommended initial dose is 10 mg 1 time / day. If the daily dose of 10 mg does not provide adequate glycemic control, the dose may be increased to 25 mg 1 time / day; The maximum daily dose is 25 mg. When you skip the dose, the patient should take the drug as soon as he remembers. You should not take a double dose in one day.; It is not recommended to use the drug in patients with renal insufficiency with GFR <45 ml / min / 1.73 m2.; Dose adjustment is not required in patients with impaired liver function.
Side effects
The overall incidence of adverse events in patients receiving empagliflozin or placebo was similar in clinical studies. The most frequent adverse reaction was hypoglycemia, which was observed when using empagliflozin in combination with sulfonylurea or insulin derivatives; indicating their absolute frequency. Frequency categories are defined as follows: very often (≥1 / 10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1,000 to <1/100), rarely (from ≥1 / 10,000 to <1/1000) or very rarely (<1/10 000); undesirable reactions are also highlighted, the frequency of which is unknown (cannot be estimated on the basis of available data) .; Infectious and parasitic diseases: often - vaginal candidiasis, vulvovaginitis, balanitis and other genital infections, urinary tract infections; very often - hypoglycemia (when used together with sulfonylurea derivatives orinsulin); From the side of the cardiovascular system: infrequently - hypovolemia. From the urinary system: often - frequent urination; infrequently - dysuria.; From the skin and subcutaneous tissues: often - pruritus; Description of individual adverse reactions; Hypoglycemia; The frequency of hypoglycemia depended on the concomitant hypoglycemic therapy used and was similar in patients taking empagliflozin or placebo as monotherapy, when empagliflozin is added to metformin and when empagliflozin is added to pioglitazone (± metformin). When empagliflozin was used in combination with metformin and sulfonylurea derivatives, and when empagliflozin was used in combination with insulin (+/- metformin and +/- sulfonylurea), the incidence of hypoglycemia was higher than with placebo in the same combination.; hypoglycemia (a condition requiring medical intervention). The incidence of severe hypoglycemia was low (<1%) and was similar in patients taking empagliflozin and placebo as monotherapy, as well as in case of adding empagliflozin to metformin and in the case of adding empagliflozin to pioglitazone (± metformin). In the case of empagliflozin in combination with metformin and sulfonylurea derivatives, in combination with insulin (+/- metformin and +/- sulfonylurea), the incidence of hypoglycemia was higher than with placebo in the same combination. Frequent urination; Frequent urination (symptoms such as pollakiuria, polyuria, nocturia) were evaluated in case of empagliflozin (at a dose of 10 mg: 3.5%, at a dose of 25 mg: 3.3%) than in the case of placebo (1.4%). The incidence of nocturia 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 or moderate.; Urinary tract infection; The incidence of urinary tract infections was similar in the case of empagliflozin 25 mg and placebo (7.0% and 7.2%, respectively), but higher in the case of empagliflozin 10 mg (8.8%). As with placebo, urinary tract infections with empagliflozin were more common 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 common in women. Genital infections; The incidence of adverse events such as vaginal candidiasis, vulvovaginitis, balanitis, and other genital infections was higher with empagliflozin (at a dose of 10 mg: 4.0%, at 25 mg: 3.9%) than with placebo (1.0%). Genital infections are more common in women. The intensity of genital infections was mild or moderate.; Hypovolemia; The incidence of hypovolemia (expressed as a decrease in blood pressure, orthostatic hypotension, dehydration, syncope) was similar in the case of empagliflozin (at a dose of 10 mg: 0.6%, at a dose of 25 mg: 0.4% ) and placebo (0.3%). In patients over the age of 75, the incidence of hypovolemia was comparable in patients taking empagliflozin at a dose of 10 mg (2.3%) and placebo (2.1%), but higher in patients taking empagliflozin at a dose of 25 mg (4.3%).
Overdose
Symptoms: during controlled clinical trials, single doses of empagliflozin, reaching 800 mg (32 times the maximum daily dose) in healthy volunteers, and multiple doses up to 100 mg (4 times the maximum daily dose) in patients with diabetes mellitus 2 type, tolerated well. The observed increase in urine volume did not depend on the magnitude of the dose and had no clinical significance. Experience with the use of the drug in doses exceeding 800 mg, no.; Treatment: conducting maintenance therapy in accordance with the clinical condition of the patient. The removal of empagliflozin using hemodialysis has not been studied.
Interaction with other drugs
Pharmacodynamic interaction; Empagliflozin may enhance the diuretic effect of thiazide and "loop" diuretics, which, in turn, may increase the risk of dehydration and hypotension.; Insulin and secretion enhancing drugs, such as sulfonylurea derivatives, may increase the risk of hypoglycemia. Therefore, with simultaneous use of empagliflozin with insulin and drugs that increase its secretion, it may be necessary to reduce their dose, in order to avoid the risk of hypoglycemia.; Pharmacokinetic interaction; Evaluation of drug interactions in vitro.Empagliflozin does not inhibit, does not inactivate and does not induce CYP450 isoenzymes. The main pathway of human metabolism of empagliflozin is glucuronidation involving uridine-5'-diphospho-glucuronosyltransferase UGT2B7, UGT1A3, UGT1A8 and UGT1A9. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9 or UGT2B7. Drug interaction of empagliflozin and drugs, which are substrates of CYP450 and UGT1A1 isoenzymes, is considered unlikely.; Empagliflozin is a substrate for P-glycoprotein and protein that determines breast cancer resistance (BCRP), but does not inhibit these proteins in therapeutic doses. Based on data obtained in in vitro studies, it is believed that the ability to interact with drugs that are substrates for P-glycoprotein, is unlikely. Empagliflozin is a substrate for organic anionic carriers: OAT3, OATP1B1 and OATP1B3, but is not a substrate for organic anionic carriers 1 (OAT1) and organic cationic carriers 2 (OCT2). However, the drug interaction of empagliflozin with drugs, which are substrates for the above carrier proteins, is considered unlikely.; Evaluation of drug interactions in vivo. When empagliflozin was used together with other commonly used drugs, no clinically significant pharmacokinetic interaction was observed. The results of pharmacokinetic studies indicate no need to change the dose of the drug Jardins; while its use with frequently used drugs.; The pharmacokinetics of empagliflozin does not change in healthy volunteers when it is used together with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, rasipril, simagastin, ragipril, simfastin, linagliptin, warfarin, verapamil, ramipril, simagastin, linagliptin, warfarin, verapamil, ramipril, pioglitazone, zyagliptin, linagliptin, wargarin The combined use of empagliflozin with gemfibrozil, rifampicin and probenecid showed an increase in the AUC values of empagliflozin by 59%, 35% and 53%, respectively, however, these changes were not considered clinically significant.; sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, Torsemide and oral contraceptive drugs in healthy volunteers.
special instructions
Drug Jardins; It is not recommended for patients with type 1 diabetes and for the treatment of diabetic ketoacidosis. With the use of sodium-dependent inhibitors of type 2 glucose, including empagliflozin, rare cases of diabetic ketoacidosis have been reported. In some of these cases, the manifestations were atypical and 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 nonspecific symptoms such as nausea, vomiting, lack of appetite, abdominal pain, marked thirst, difficulty breathing, disorientation, unmotivated fatigue or drowsiness. If such symptoms develop, patients should be promptly examined for ketoacidosis, regardless of the blood glucose concentration. Use of the drug Jardins; should be stopped or suspended until a diagnosis is made. A higher risk of developing diabetic ketoacidosis is possible in patients on a diet with a very low carbohydrate content, patients with severe dehydration, patients with a history of ketoacidosis or in patients low secretory activity of pancreatic β-cells. In these patients, the drug Jardins; should be used with caution. Care must be taken when reducing the dose of insulin.; In the preparation of Jardins; in a tablet with a dosage of 10 mg contains 162.5 mg of lactose, with a dosage of 25 mg contains 113 mg of lactose, so the drug should not be used in patients with rare inherited disorders such as lactase deficiency, lactose intolerance, glucose-galactose malabsorption; Clinical studies have shown that treatment with empagliflozin does not lead to an increase in cardiovascular risk. The use of empagliflozin in a dose of 25 mg does not lead to prolongation of the QT interval. With the joint use of the drug Jardins; sulfonylurea derivatives or insulin derivatives may require a reduction in the dose of sulfonylurea / insulin derivatives due to the risk of hypoglycemia; Empagliflozin has not been studied in combination with glucagon-like peptide-1 analogues (GLP-1); The effectiveness of Jardins; depends on kidney function, therefore, it is recommended to monitor kidney function before prescribing it and periodically during treatment (at least 1 time per year), as well as before prescribing concomitant therapy, which can adversely affect kidney function.The use of the drug in patients with renal insufficiency (GFR <45 ml / min) is not recommended. Patients aged 75 years and older have an increased risk of dehydration, therefore the drug Jardins; should be administered with caution to patients in this category. In these patients receiving empagliflozin, more often (compared to patients receiving placebo), adverse reactions caused by hypovolemia were observed. Experience with empagliflozin in patients older than 85 years is limited, therefore, prescribe drug Jardins; patients in this age group are not recommended. According to the mechanism of action, the use of the drug Jardins; 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; , should carefully monitor the patient's condition, blood pressure, and monitor hematocrit and electrolyte balance. It may be necessary to temporarily, until the water balance is restored, discontinue the use of the drug; Complicated urinary tract infections (such as pyelonephritis and urosepsis) were observed with a similar frequency in patients taking empagliflozin and placebo. In the case of the development of complicated urinary tract infections, a temporary cessation of empagliflozin therapy is necessary. According to the mechanism of action, patients taking the drug Jardins; urine glucose is determined. vehicles and mechanisms were not carried out. Patients should be careful when driving vehicles and mechanisms, becausewhen using the drug Jardins; (especially in combination with sulfonylurea derivatives and / or insulin) hypoglycemia may develop.