Джардинс

General characteristics. Structure:

Active ingredient: 10 mg or 25 mg of an empagliflozin.

Excipients: lactoses monohydrate, cellulose microcrystallic, hypro rod, croscarmellose sodium, silicon dioxide colloid, magnesium stearate.

Structure film cover: Опадрай yellow (02B38190), including gipromelloza 2910, titanium dioxide, talc, macrogoal 400, dye ferrous oxide yellow.

The drug reducing sugar level in blood.

Pharmacological properties:

Pharmacodynamics. Empagliflozin is a reversible, highly active, selection and competitive inhibitor of a natriyzavisimy carrier of glucose 2 types with the size of the concentration necessary for inhibition of 50% of activity of enzyme (IC50), equal 1,3 nmol. Selectivity of an empagliflozin by 5000 times exceeds selectivity of a natriyzavisimy carrier of glucose of 1 type responsible for absorption of glucose in intestines.

Besides, it was established what эмпаглифлозин has high selectivity concerning other carriers of glucose responsible for a glucose homeostasis in various fabrics.

The Natriyzavisimy carrier of glucose 2 types is the main protein carrier responsible for a glucose reabsorption from renal balls back in a blood stream.

Empagliflozin improves glycemic control at patients with a diabetes mellitus 2 types (SD 2) by reduction of a reabsorption of glucose in kidneys. The amount of the glucose emitted by kidneys by means of this mechanism depends on concentration of glucose in blood and the glomerular filtration rate (GFR). The inhibition of a natriyzavisimy carrier of glucose leads 2 types at patients with SD 2 and a hyperglycemia to removal of excess of glucose kidneys.

During clinical trials it was established that at patients with SD 2 glucose removal by kidneys increased at once after use of the first dose of an empagliflozin; this effect proceeded for 24 hours. Increase in removal of glucose kidneys remained until the end of the 4-week period of treatment, making at use of an empagliflozin in a dose 25 mg once a day, on average, about 78 g/day. At patients with SD 2 increase in removal of glucose kidneys led to immediate decrease in concentration of glucose in a blood plasma.

Empagliflozin reduces concentration of glucose in a blood plasma both in case of reception on an empty stomach, and after food.

The Insulinonezavisimy mechanism of action of an empagliflozin promotes low risk of possible development of a hypoglycemia.

The effect of an empagliflozin does not depend on a functional condition of beta cells of a pancreas and metabolism of insulin. Positive influence of an empagliflozin on substitute markers of function of beta cells, including the NOMA-β index (model for assessment gomeostaza-V) and the pro-insulin relation to insulin was noted. Besides, additional removal of glucose kidneys causes loss of calories that is followed by reduction of volume of fatty tissue and decrease in body weight.

The glucosuria which is observed during use of an empagliflozin. is followed by small increase in a diuresis which can promote a moderate lowering of arterial pressure.

In clinical trials where it was applied эмпаглифлозин in the form of monotherapy; a combination therapy with Metforminum; a combination therapy with Metforminum and derivatives of sulphonylurea; a combination therapy with Metforminum in comparison with glimepiridy; a combination therapy with pioglitazony +/-Metforminum; in the form of a combination therapy with inhibitor dipeptidilpeptidazy-4 (DPP-4), Metforminum +/-other hypoglycemic peroral medicine; in the form of a combination therapy with insulin statistically significant decrease in glikozilirovanny HbA1c hemoglobin and reduction of concentration of glucose of plasma on an empty stomach was proved.

Pharmacokinetics. The pharmacokinetics of an empagliflozin was comprehensively studied at healthy volunteers and at patients with SD 2.

Absorption. Empagliflozin after intake was quickly soaked up, the maximum concentration of an empagliflozin in a blood plasma (Cmax) was reached in 1.5 hours. Then concentration of an empagliflozin in plasma decreased in two phases.

After reception of an empagliflozin the average size of the area under a curve "concentration time" (AUC) in the period of steady concentration in a blood plasma made the 4740th nmol ×час/л, and the size Cmax - the 687th nmol/l.

Healthy volunteers and at patients with SD 2 had a pharmacokinetics of an empagliflozin, in general, similar.

Meal does not exert clinically significant impact on pharmacokinetics of an empagliflozin.

Distribution. Distribution volume in the period of steady concentration in a blood plasma made, about, 73,8 liters. After oral administration by healthy volunteers of a marked empagliflozin [14C] linkng with proteins of plasma made 86%.

Metabolism. The main way of metabolism of an empagliflozin at the person - a glyukuronidation with participation of uridine-5-diphospho-glyukuronoziltransferaz UGT2B7, UGT1A3, UGT1A8 and UGT1A9. The most often revealed metabolites of an empagliflozin are three glucuronic conjugates (2-O, 3-O and 6-O glucuronide). System influence of each metabolite is small (less than 10% of the general influence of an empagliflozin).

Removal. The elimination half-life made, about, 12.4 hours. In case of use of an empagliflozin once a day steady concentration in a blood plasma was reached after the fifth dose. After oral administration of a marked empagliflozin [14C] at healthy volunteers about 96% of a dose were removed (through intestines of 41% and kidneys of 54%). Through intestines the most part of marked drug was removed in not changed look. Kidneys in not changed look removed only a half of marked drug.

Pharmacokinetics at special populations of patients. Renal failure. At patients with a renal failure of easy, average and heavy severity (30 <SKF <90 ml/min. / 1,73 sq.m) and at patients with an end-stage of a renal failure of AUC value of an empagliflozin increased, respectively, approximately by 18%, 20%, 66% and 48% in comparison with patients with normal function of kidneys. At patients to a renal failure of moderate severity and at patients with an end-stage of a renal failure the maximum concentration of an empagliflozin in plasma was similar to the corresponding values at patients with normal function of kidneys. At patients with a renal failure of easy and heavy severity the maximum concentration of an empagliflozin in plasma was about 20% higher, than at patients with normal function of kidneys. Data of the population pharmacokinetic analysis showed that the general clearance of an empagliflozin decreased in process of decrease in SKF that led to increase in influence of drug.

Abnormal liver functions. At patients with abnormal liver functions of easy, average and heavy severity (according to classification of Chayld-Pyyu) AUC values of an empagliflozin increased, respectively, approximately by 23%, 47% and 75%, and Cmax values, respectively, approximately for 4%, 23% and 48% (in comparison with patients with normal function of a liver).

The body weight index, floor, race and age did not exert clinically significant impact on pharmacokinetics of an empagliflozin.

Children. Researches of pharmacokinetics of an empagliflozin at children were not conducted.

Indications to use:

Diabetes mellitus 2 types:

— as monotherapy at patients with inadequate glycemic control only against the background of a diet and physical exercises, purpose of Metforminum, it is considered which inexpedient in a type of intolerance;

— as a combination therapy with other hypoglycemic means, including insulin when the applied therapy together with a diet and physical exercises does not provide necessary glycemic control.

Route of administration and doses:

Monotherapy or combination therapy. The recommended initial dose makes 10 mg (1 tablet a dosage of 10 mg) once a day, inside.

If the daily dose of 10 mg does not provide adequate glycemic control, the dose can be increased to 25 mg (1 tablet by a dosage of 25 mg once a day). The maximum daily dose makes 25 mg.

Drug of Dzhardins can be accepted irrespective of meal at any time.

Actions at the admission of reception of one or several doses of medicine. At the admission of a dose, the patient should accept drug as soon as he remembers it. It is not necessary to accept a double dose in one day.

Special groups of patients. At a renal failure with SKF from 45 to 90 ml/min. / 1,73 the sq.m of dose adjustment is not required.

To patients with a renal failure with SKF less than 45 ml/min. / 1,73 the sq.m is not recommended to use drug in connection with inefficiency.

With abnormal liver functions of dose adjustment it is not required to patients.

Features of use:

Use at pregnancy and feeding by a breast. Use of an empagliflozin during pregnancy is contraindicated in view of insufficiency of data on efficiency and safety.

The data obtained in preclinical trials at animals confirm penetration of an empagliflozin into breast milk. The risk of impact on newborns and children when breastfeeding is not excluded. Use of an empagliflozin during breastfeeding is contraindicated. In need of use of an empagliflozin during breastfeeding, feeding by a breast should be stopped.

Use at abnormal liver functions. With abnormal liver functions of dose adjustment it is not required to patients.

Use at renal failures. Efficiency of drug of Dzhardins depends on function of kidneys. Therefore it is recommended to control function of kidneys before its appointment and periodically during treatment (at least, once a year), and also before purpose of the accompanying therapy which can negatively influence function of kidneys.

At a renal failure with SKF from 45 to 90 ml/min. / 1,73 the sq.m of dose adjustment is not required.

To patients with a renal failure with SKF less than 45 ml/min. / 1,73 the sq.m is not recommended to use drug in connection with inefficiency.

Use for children. Contraindication: children's age up to 18 years (in connection with insufficiency of data on efficiency and safety

Use for elderly patients. Patients at the age of 75 years and more have an increased risk of dehydration. At such patients receiving эмпаглифлозин, more often (in comparison with the patients receiving placebo) the undesirable reactions which were caused by a hypovolemia were noted. Experience of use of an empagliflozin for patients is more senior than 85 years is limited therefore drug of Dzhardins to patients is not recommended to appoint more senior than 85 years.

Drug of Dzhardins is not recommended to be used to patients with a diabetes mellitus of 1 type and for treatment of diabetic ketoacidosis.

The maximum daily dose of drug of Dzhardins contains 113 mg of lactose therefore drug should not be used to patients with such rare inherited disorders as deficit of lactase, a lactose intolerance, glyukozo-galaktozny malabsorption.

Clinical trials showed that treatment empaglifloziny does not lead to increase in cardiovascular risk. Use of an empagliflozin in a dose of 25 mg does not lead to lengthening of an interval of QT.

At combined use of drug of Dzhardins with derivatives of sulphonylurea or with insulin the dose decline of derivatives of sulphonylurea / insulin because of risk of development of a hypoglycemia can be required.

Not studied combinations of hypoglycemic drugs. Empagliflozin was not studied in a combination with analogs of glyukagonopodobny peptide 1 (GPP-1).

Monitoring of function of kidneys. Efficiency of drug of Dzhardins depends on function of kidneys. Therefore it is recommended to control function of kidneys before its appointment and periodically during treatment (at least, once a year), and also before purpose of the accompanying therapy which can negatively influence function of kidneys. To patients with a renal failure (SKF less than 45 ml/min.), administration of drug is not recommended.

Patients of advanced age. Patients at the age of 75 years and more have an increased risk of dehydration. At such patients receiving эмпаглифлозин, more often (in comparison with the patients receiving placebo) the undesirable reactions which were caused by a hypovolemia were noted. Experience of use of an empagliflozin for patients is more senior than 85 years is limited therefore drug of Dzhardins to patients is not recommended to appoint more senior than 85 years.

Use for patients with risk of development of a hypovolemia. According to the action mechanism administration of drug of Dzhardins can lead to a moderate lowering of arterial pressure. Therefore it is necessary to use drug with care when the lowering of arterial pressure is undesirable, for example, at patients with cardiovascular diseases; (with cases of arterial hypotension in the anamnesis), and also at patients 75 years are more senior than the patients accepting hypotensive drugs.

If at the patient accepting drug of Dzhardins states which can lead to liquid loss (for example, at digestive tract diseases) develop, it is necessary to monitorirovat carefully a condition of the patient, arterial pressure, and also to control a hematocrit and electrolytic balance. Can be required temporary, up to recovery of a water balance, the termination of administration of drug.

Infections of urinary tract. Frequency of development of such side effects as infections of urinary tract, was comparable at use of an empagliflozin in a dose of 25 mg and placebo, and above at use of an empagliflozin in a dose of 10 mg. The complicated infections of urinary tract (such as pyelonephritis and urosepsis) were noted with a similar frequency at the patients accepting эмпаглифлозин and placebo. In case of development of the complicated infections of urinary tract the temporary termination of therapy empaglifloziny is necessary.

Laboratory analysis of urine. According to the action mechanism at the patients accepting drug of Dzhardins glucose in urine is defined.

Influence on ability to manage vehicles and mechanisms. Clinical trials on influence of an empagliflozin on ability to manage vehicles and mechanisms it was not carried out. Patients should be careful at control of vehicles and mechanisms as at use of drug of Dzhardins (especially in combinations with derivatives of sulphonylurea and/or insulin) the hypoglycemia can develop.

Side effects:

The patients receiving эмпаглифлозин or placebo in clinical trials had a similar general frequency of the undesirable phenomena. The hypoglycemia noted at use of an empagliflozin in a combination with derivatives of sulphonylurea or insulin (see the description of separate undesirable reactions) was the most frequent undesirable reaction.

The undesirable reactions observed at the patients receiving эмпаглифлозин in placebo - controlled researches, are given below in the Table (undesirable reactions were classified by bodies and systems and according to preferred in Meddraterminami) with the indication of their absolute frequency. Categories of frequency are defined as follows: very frequent (≥1/10), frequent (from ≥1/100 to <1/10), infrequent (from ≥1/1 000 to <1/100), rare (from ≥1/10000 to <1/1000) or very rare (<1/10000); also undesirable reactions which frequency is unknown are allocated (it cannot be estimated on the basis of the available data).

Table. The side effects noted in placebo - controlled researches:

Classification by bodies and systems	Very frequent	Frequent
Infectious and parasitic diseases		Vaginal candidiasis, vulvovaginitis, balanitis and other genital infections Infections of urinary tract
Disturbances from a metabolism and food	Hypoglycemia (at combined use with derivatives of sulphonylurea or insulin)	Hypovolemia
Disturbances from kidneys and urinary tract		The speeded-up urination

Description of separate undesirable reactions. Hypoglycemia. Frequency of a hypoglycemia depended on the applied accompanying hypoglycemic therapy.

Easy hypoglycemia (glucose of blood of 3,0 - 3,8 mmol/l (54-70 mg/dl)). The patients accepting эмпаглифлозин or placebo in the form of monotherapy had a similar frequency of development of an easy hypoglycemia and also in case of addition of an empagliflozin to Metforminum and in case of addition of an empagliflozin to a pioglitazon (± Metforminum). In case of purpose of an empagliflozin in a combination with Metforminum and derivatives of sulphonylurea the frequency of development of a hypoglycemia was higher (10 mg: 10,3%; 25 mg: 7,4%), than at purpose of placebo in the same combination (5,3%).

Heavy hypoglycemia (glucose of blood is lower than 3 mmol/l (54 mg/dl)). The patients accepting эмпаглифлозин had a similar frequency of development of a heavy hypoglycemia and placebo in the form of monotherapy. In case of purpose of an empagliflozin in a combination with Metforminum and derivatives of sulphonylurea the frequency of development of a hypoglycemia was higher (10 mg: 5,8%; 25 mg: 4,1%) than at purpose of placebo in the same combination (3,1%).

The speeded-up .mocheispuskaniye. Frequency of the speeded-up urination (such symptoms as a pollakiuria, a polyuria, a nocturia were estimated) was higher in case of use of an empagliflozin (in a dose of 10 mg: 3,4%, in a dose of 25 mg: 3,2%), than in case of placebo use (1%). Frequency of development of a nocturia was comparable in group of the patients accepting эмпаглифлозин and in group of the patients accepting placebo (less than 1%). Intensity of these side effects was weak or moderate.

Infections of urinary tract. Frequency of development of infections of urinary tract was similar in case of use of an empagliflozin of 25 mg and placebo (7,6%), but 10 mg (9,3%) are higher in case of use of an empagliflozin. Also as well as in case of use of placebo of an infection of urinary tract against the background of reception of an empagliflozin were more often noted at patients with persistent and recurrent infections of urinary tract in the anamnesis. The patients accepting эмпаглифлозин had a similar intensity of infections of urinary tract and placebo. Infections of urinary tract were more often noted at women.

Genital infections. Frequency of development of such undesirable phenomena as vaginal candidiasis. a vulvovaginitis, a balanitis and other genital infections was higher in case of use of an empagliflozin (in a dose of 10 mg: 4,1%, in a dose of 25 mg: 3.7%), than at placebo use (0,9%). Genital infections were more often noted at women. Intensity of genital infections was weak or moderate.

Hypovolemia. Frequency of development of a hypovolemia (which was expressed by a lowering of arterial pressure, orthostatic arterial hypotension, dehydration, a faint) was similar in case of use of an empagliflozin (in a dose of 10 mg: 0,5%. in a dose of 25 mg: 0.3%) and placebo (0,3%). At patients was more senior than 75 years the frequency of development of a hypovolemia is comparable at the patients accepting эмпаглифлозин in a dose of 10 mg (2,3%) and placebo (2,1%), but is higher at the patients accepting эмпаглифлозин in a dose of 25 mg (4,4%).

Interaction with other medicines:

Assessment of medicinal interactions of in vitro. Empagliflozin does not inhibit, does not inactivate and does not induce CYP450 isoenzymes. The main way of metabolism of an empagliflozin at the person is the glyukuronidation with participation of uridine-5-diphospho-glyukuronoziltransferaz UGT2B7, UGT1A3, UGT1A8 and UGT1A9. Empagliflozin does not inhibit UGT1A1. Medicinal interactions of an empagliflozin and the medicines which are substrates of isoenzymes of CYP450 and UGT1A1 are considered as improbable.

Empagliflozin is substrate for a glycoprotein P (P-gp) and the protein defining resistance of a breast cancer (BCRP), but in therapeutic doses does not inhibit these proteins. On the basis of the data obtained in the researches invitro it is considered that ability of an empagliflozin to enter interactions with drugs which are substrates for a glycoprotein P (P-gp). it is improbable. Empagliflozin is substrate for organic anion carriers: OAT3, OATP1B1 and OATP1B3, but is not substrate for organic anion carriers of 1 (OAT1) and organic cationic carriers 2 (OCT2). However medicinal interactions of an empagliflozin reckon with the drugs which are substrates for the above described proteins carriers as improbable.

Assessment of medicinal interactions of in vivo. The pharmacokinetics of an empagliflozin does not change at healthy volunteers in case of its combined use with Metforminum. glimepiridy, pioglitazony, sitagliptiny, linagliptiny, warfarin, verapamil, ramiprily, simvastatiny, torasemidy and hydrochlorothiazide. At combined use of an empagliflozin with gemfibrozily, rifampicin and probenetsidy noted increase in AUC value of an empagliflozin by 59%, 35% and 53%, respectively, however these changes were not considered as clinically significant.

Empagliflozin does not exert clinically significant impact on pharmacokinetics of Metforminum, a glimepirid, a pioglitazon, a sitagliptin, a linagliptin, warfarin, digoxin, a ramipril, a simvastatin, a hydrochlorothiazide, a torasemid and peroral contraceptive drugs.

Diuretics. Empagliflozin can strengthen diuretic effect of thiazide and "loopback" diuretics that in turn can increase risk of development of dehydration and arterial hypotension.

The insulin and drugs strengthening its secretion. The insulin and drugs strengthening its secretion such as sulphonylurea derivatives, can increase risk of a hypoglycemia. Therefore at simultaneous use of an empagliflozin with the insulin and drugs strengthening its secretion decrease in their dose, in order to avoid risk of development of a hypoglycemia can be required.

Contraindications:

— hypersensitivity to any component of drug;

— diabetes mellitus of 1 type;

— diabetic ketoacidosis;

— rare inherited disorders (deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption);

— a renal failure at SKF <45 ml/min. on 1,73 ^sq.m (in connection with inefficiency);

— pregnancy and period of breastfeeding;

— the age is more senior than 85 years;

— use in a combination with analogs of glyukagonopodobny peptide 1 (due to the lack of data on efficiency and safety);

— children's age up to 18 years (in connection with insufficiency of data on efficiency and safety).

With care

— patients with risk of development of a hypovolemia (use of hypotensive drugs with cases of arterial hypotension in the anamnesis);

— at the gastrointestinal diseases leading to liquid loss;

— the age is more senior than 75 years;

— use in a combination with derivatives of sulphonylurea or insulin;

— infections of urinogenital system.

Overdose:

Symptoms. During performing controlled clinical trials the single doses of an empagliflozin reaching 800 mg at healthy volunteers and the repeated doses reaching 100 mg (by 4 times exceeding the maximum daily dose) at patients with SD 2 were transferred (to 32 times exceeding the maximum daily dose) well. The observed increase in volume of urine did not depend on the size of a dose and had no clinical value. Experience of use of the dose exceeding 800 mg no.

Treatment. In case of overdose removal of not absorbed drug from digestive tract, implementation of clinical control and carrying out a symptomatic treatment is recommended.

Storage conditions:

To store at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 3 years.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in blisters PVC, on 1 or 3 blisters in a cardboard pack Is scarlet/.