Suglat tablets 50mg, No. 30

Type 2 diabetes mellitus to improve glycemic control by:

• monotherapy in case of ineffectiveness of diet therapy and physical activity;

• in combination with other hypoglycemic drugs, including metformin, pioglitazone, sulfonylurea derivatives, DPP-4 inhibitors, insulin (± DPP-4 inhibitor), metformin with sitagliptin, ?-glucosidase inhibitors (?-GI), nateglinide, GLP-1 analogs ( including in combination with sulfonylurea derivatives), in the absence of adequate glycemic control.

Suglate is recommended to be taken 1 time / day, regardless of food intake. The tablets should be swallowed whole with water.

The initial dose for an adult patient is 50 mg 1 time / day. If necessary, it is possible to increase the dose to 100 mg (2 tablets of 50 mg).

When used simultaneously with insulin preparations or drugs that increase insulin secretion (such as sulfonylurea derivatives), to reduce the risk of hypoglycemia, the dose of insulin or drugs that stimulate its secretion (such as sulfonylurea derivatives) should be reduced.

Elderly patients (? 65 years) do not need dose adjustment.

No dose adjustment is required in patients with mild to moderate renal impairment. Suglate should not be used in patients with severe renal impairment, end-stage renal failure, or in patients on dialysis. the drug is not expected to be effective in these populations.

For patients with mild to moderate hepatic impairment, dose adjustment is not required.
There are no clinical data on the use of Suglat in patients with severe hepatic dysfunction.

The efficacy and safety of the drug Suglat in children under 18 years of age has not been studied.

Skipping a dose

If a dose is missed, Suglat should be taken immediately after the patient remembers it; however, you should not take a double dose on the same day.

Film-coated tablets of light purple color, round, biconvex.

1 tab. ipragliflozin L-proline 64.3 mg,

which corresponds to the content of ipragliflozin 50 mg

Excipients: microcrystalline cellulose, sodium carboxymethyl starch (type A), hyprolose, magnesium stearate.

• Hypersensitivity to the active substance or any auxiliary component of the drug;

• severe ketoacidosis, diabetic coma, or precoma;

• severe infectious diseases, perioperative period, serious operations and injuries;

• severe impairment of renal function (GFR <30 ml / min / 1.73 m2), end-stage renal failure or patients on dialysis, due to a possible decrease in the hypoglycemic effect;

• severe liver failure;

• pregnancy;

• breastfeeding period;

• children under the age of 18 (the efficacy and safety of use in this category of patients has not been established).

pharmachologic effect

Ipragliflozin is an oral selective sodium-dependent glucose transporter type 2 (SGLT2) inhibitor. SGLT2 is the main transport protein involved in the reuptake of glucose in the proximal renal tubules and its active transfer from the lumen of the tubule into the blood against the concentration gradient. Ipragliflozin has a 254-fold higher selective inhibitory activity against SGLT2 compared to SGLT1 (the half-maximum inhibition concentration (IC50) of ipragliflozin against SGLT2 and SGLT1 is 7.38 and 1880 nmol / L, respectively).

By pronounced inhibition of SGLT2, expressed in the proximal tubule of the renal nephron, ipragliflozin reduces the reabsorption of glucose in the renal tubules and decreases the renal glucose threshold (RGT), which leads to an increase in urinary glucose excretion (EGM) and insulin-independent decrease in elevated blood glucose concentration. The amount of glucose excreted by the kidneys depends on the concentration of glucose in the blood and the glomerular filtration rate (GFR). An increase in EGM with inhibition of SGLT2 also leads to moderate osmodiuresis and diuretic effect, which helps to reduce systolic and diastolic blood pressure. Studies in patients with type 2 diabetes mellitus have shown that an increase in EGM leads to a loss of calories and, as a result, a decrease in body weight.

Pharmacodynamics

When determining EGM in phase I studies, it was shown that when taking clinically significant doses of ipragliflozin in healthy volunteers, the average increase in EGM over 24 hours was similar and amounted to approximately 39 g and 49 g for a dose of 50 mg and from 39 g to 56 g and from 35 g to 48 g for a dose of 100 mg in single and multiple doses, respectively.

In patients with type 2 diabetes mellitus, the effect of ipragliflozin on daily EGM was more pronounced. After 14 days of administration in the ipragliflozin group, there was a noticeable increase in the average daily EGM relative to the baseline level (by 81 g for the 50 mg dose and by 90 g for the 100 mg dose) compared with the placebo group (5 g).

An increase in EGM led to a decrease in fasting plasma glucose (FPG) and after a meal, as well as fasting serum insulin concentration.

Clinical efficacy

Clinical studies have shown a statistically significant decrease in the level of glycated hemoglobin (HbA1c), FPG and body weight when using ipragliflozin alone, as well as in combination with metformin, pioglitazone, sulfonylurea derivatives (SM), an inhibitor of dipeptidyl peptidase-4-4 (Dipeptidyl peptidase-4), insulin (± DPP-4 inhibitor), metformin with sitagliptin, ?-glucosidase inhibitor (?-GI), nateglinide, an analog of glucagon-like peptide 1 (GLP-1) (± CM). In patients who did not achieve treatment goals when using ipragliflozin at a dose of 50 mg, with an increase in the dose to 100 mg, a further decrease in the level of HbA1c, FPG and body weight was noted.

Pharmacokinetics

Suction

After oral administration, ipragliflozin is rapidly absorbed. Both in healthy people and in patients with type 2 diabetes mellitus, the plasma concentration of ipragliflozin after single and multiple doses increases in a dose-dependent manner. After taking ipragliflozin on an empty stomach Cmax of the drug in blood plasma is reached within 1.1-2.3 hours. The absolute bioavailability with a single dose of 100 mg is 90.2%.

When taking the drug in a dose of 50 mg before taking a meal rich in fats, there was an increase in Cmax of ipraglyflozin by 1.23 times and a decrease in the time to reach it (Tmax) by 0.6 h; the AUC value did not change. When using the drug after a meal with a high fat content, the Cmax of ipragliflozin decreased by 0.82 times, and the Tmax increased by 0.9 h; the AUC value did not change. With repeated use of ipragliflozin, food intake did not have a clinically significant effect on its efficacy or safety. Therefore, ipragliflozin can be taken regardless of food intake.

Distribution

In the equilibrium state, the average Vd after intravenous administration at a dose of 25 mg is 127 liters, which indicates an extensive distribution of ipragliflozin in the tissues. Ipragliflozin is 94.6-96.5% bound to plasma proteins (mainly albumin). The binding of ipragliflozin to blood plasma proteins is comparable in healthy people and those with type 2 diabetes mellitus.

Impaired renal and hepatic function does not significantly affect the degree of binding of ipragliflozin to proteins.

In vivo, the proportion of the drug bound to blood plasma proteins in patients with type 2 diabetes mellitus and impaired renal function (with normal renal function or with mild to severe renal impairment) ranged from 96.2% to 97.2% versus 96.7 % -97.0% in healthy volunteers. A blood / plasma drug concentration ratio of 0.625 for AUCinf indicated a low distribution of radioactivity in erythrocytes.

Metabolism

Ipragliflozin undergoes significant metabolism in the human body, mainly in the liver. In blood plasma, urine and feces, 7 metabolites were identified: 5 glucuronides, S-oxide and ipragliflozin sulfate. The main pathway of ipragliflozin metabolism is glucuronidation with the participation of UDP-glucuronyltransferases (mainly UGT2B7, to a lesser extent UGT2B4, UGT1A8 and UGT1A9) with the formation of the main metabolite 2'-O-P-glucuronide ipraglyflozine.

In in vitro studies, no significant inhibition by ipragliflozin of cytochrome isoenzymes (CYP) and uridine diphosphate glucuronosyltransferase (UGT), as well as significant induction of CYP1A2 and CYP3A4, was observed.

Withdrawal

Ipragliflozin and its metabolites are excreted by the kidneys and through the intestines. After a single or multiple oral administration of ipragliflozin in doses of 50 and 100 mg, the average terminal T1 / 2 varies from 11.7 to 19.9 hours. The total clearance is 10.9 l / h, while the renal clearance is about 0.1 l / h. After intravenous administration of ipragliflozin, only 1.32% of the administered dose is excreted by the kidneys unchanged. In all studies, the proportion of excretion of unchanged ipragliflozin by the kidneys was low (<2% of the dose taken).

In the study of the mass balance after ingestion of 100 mg of 14C-ipragliflozin, most of the radioactivity (84.4%) was excreted by the kidneys and through the intestines after 48 hours; after 144 h, the ratio of excreted radioactivity was 67.9% by the kidneys and 32.7% through the intestines.

Linearity / non-linearity

In the dose range from 1 to 600 mg, AUC increases in proportion to the dose, while Cmax increases to a lesser extent relative to the dose increase, but this effect is minimal and has no clinical significance. With repeated use of ipragliflozin, no signs of autoinduction or autoinhibition were observed.

Pharmacokinetics in special clinical situations

Use in patients with impaired renal function. After a single dose of ipragliflozin in doses of 50 mg and 100 mg in patients with type 2 diabetes mellitus, the AUC value gradually increased as renal function decreased. In patients with mild renal impairment (eGFR from 60 to <90 ml / min / 1.73 m2), the AUC value did not increase or increased slightly (by 1.25 times). In patients with moderate (eGFR from 30 to <60 ml / min / 1.73 m2) and severe (eGFR from 15 to <30 ml / min / 1.73 m2) renal impairment, the AUC value increased 1.21-1.40 times and 1.46 times, respectively. No significant change in Cmax was observed. The effect of dialysis on the pharmacokinetics of ipragliflozin has not been studied.

Use in patients with impaired liver function. After a single oral administration of ipragliflozin in a dose of 100 mg on an empty stomach in patients with moderate hepatic dysfunction (class B according to the Child-Pugh classification, 7-9 points), the Cmax and AUC values ??increased by 1.27 and 1.25 times, respectively, in comparison with healthy volunteers. Pharmacokinetics in patients with severe hepatic dysfunction has not been studied. For patients with mild to moderate hepatic impairment, dose adjustment is not required.

Elderly patients (age? 65 years). There was no clinically significant increase in ipragliflozin exposure in elderly patients.

Application in children. Pharmacokinetics in children under 18 years of age has not been studied.

Floor. Despite the fact that the Cmax of ipragliflozin in women is higher than in men, this difference is insignificant; therefore, gender is not considered as a factor that has a clinically significant effect on the pharmacokinetics of ipragliflozin.

Race and Ethnicity. No clinically significant differences in systemic exposure were found between Caucasians and Japanese.

Application during pregnancy and lactation

Pregnancy

There are no data on the use of ipragliflozin in pregnant women. The data of preclinical studies in rats indicate the penetration of the drug into the fetus.

The use of ipragliflozin during pregnancy is contraindicated. If pregnancy is detected, treatment with ipragliflozin should be discontinued.

Breastfeeding period

Data from preclinical studies in rats have shown that ipragliflozin passes into breast milk and inhibits the growth of offspring. Risk to newborns / babies cannot be excluded. The use of ipragliflozin during breastfeeding is contraindicated.

Fertility

The effect of ipragliflozin on fertility in humans has not been studied. No effects of ipragliflozin on fertility were found in male and female rats.

Application for violations of liver function

Contraindication: severe hepatic impairment.

Application for impaired renal function

Contraindications: severe renal impairment (GFR <30 ml / min / 1.73 m2), end-stage renal disease or patients on dialysis, due to a possible decrease in the hypoglycemic effect;

Application in children

Contraindication: children under the age of 18 years (efficacy and safety of use in this category of patients has not been established).

Use in elderly patients

Treatment with ipragliflozin in this category of patients should be carried out under close supervision.

special instructions

Impaired renal function

Ipragliflozin should not be used in patients with severe renal impairment, end-stage renal failure or in patients on dialysis, since the drug is likely to be ineffective in this category of patients. During treatment with ipragliflozin, renal function may deteriorate. When using ipragliflozin, there may be an increase in the concentration of creatinine and urea in the blood, as well as a decrease in the estimated glomerular filtration rate (eGFR). Before starting treatment with ipragliflozin, it is necessary to assess renal function, as well as periodically monitor it during treatment.

Use in patients at risk of developing adverse reactions associated with a decrease in BCC

The mechanism of action of ipragliflozin leads to the fact that an increase in EGM can induce osmotic diuresis and a diuretic effect, which can lead to a decrease in BCC and a decrease in blood pressure. Adequate hydration and monitoring of the BCC are recommended (eg, physical examination, blood pressure measurement, laboratory tests, including indicators of renal function, electrolyte composition).

Ketoacidosis

If symptoms of ketoacidosis develop, such as nausea and vomiting, loss of appetite, abdominal pain, excessive thirst, increased fatigue, impaired breathing, impaired consciousness, or other symptoms, laboratory tests (including determination of ketone bodies in blood and urine) should be considered ... When diabetic ketoacidosis is diagnosed, treatment with ipragliflozin should be discontinued and adequate supportive therapy initiated to normalize the patient's condition.

Elderly patients (?65 years old)

In elderly patients, a decrease in physiological functions is more often observed, as well as a higher risk of dehydration, therefore, treatment with ipragliflozin in this category of patients should be carried out under close supervision.

Genital infections

During treatment with ipragliflozin, fungal infections of the genital organs may develop. Therefore, patients should be carefully evaluated for signs and symptoms of genital infections. When signs and symptoms of fungal infections of the genital organs appear, appropriate therapy is necessary.

Lower limb amputation

In long-term clinical studies of another SGLT2 inhibitor, an increase in the incidence of amputation of the lower extremities (primarily toes) has been noted. It is unknown if this effect is specific to the entire pharmacological class. It is important to advise all patients with diabetes mellitus on routine preventive foot care.

Hypoglycemia

The use of hypoglycemic drugs can cause hypoglycemia. In clinical studies, the incidence of hypoglycemia in patients taking ipragliflozin both as monotherapy and as part of combination therapy with other hypoglycemic drugs (with the exception of insulin, see the 'Side effects' section) was the same as when taking placebo. To reduce the risk of hypoglycemia when using ipragliflozin in combination with insulin or drugs that stimulate insulin secretion (for example, sulfonylureas), it is necessary to consider reducing the dose of insulin or drugs that stimulate insulin secretion

Urinary tract infection

During treatment with ipragliflozin, urinary tract infections, including pyelonephritis, may develop. Patients should be carefully evaluated to identify possible signs and symptoms of urinary tract infections and, if necessary, appropriate treatment should be provided.

Chronic heart failure

The experience of using ipragliflozin in chronic heart failure (CHF) I-II functional class (NYHA classification) is limited; there is no experience with CHF III-IV functional class according to NYHA.

Laboratory examination of urine

Due to the mechanism of action, patients taking ipragliflozin will test positive for the presence of glucose in the urine.

Application in children

The efficacy and safety of using ipragliflozin in children under 18 years of age has not been studied.

Influence on the ability to drive vehicles and mechanisms

There are no data on the negative effect of ipragliflozin on the ability to drive vehicles and mechanisms. It is expected that ipragliflozin will not affect the ability to drive vehicles and mechanisms, or this effect will be minimal.

Patients should be warned about the risk of hypoglycemia, especially when using ipragliflozin in combination with insulin or drugs that stimulate insulin secretion (for example, sulfonylurea derivatives), as well as an increased risk of developing adverse reactions associated with a decrease in BCC, for example, dizziness and arterial hypotension.

Overdose

Clinical studies in healthy volunteers have demonstrated the safety and good tolerance of single doses of ipragliflozin up to 600 mg, as well as multiple doses of up to 300 mg 1 time / day.

Treatment: in case of overdose, symptomatic therapy should be carried out in accordance with the clinical condition of the patient. Standard supportive measures are advisable, incl. removal of non-absorbed substances from the gastrointestinal tract and the implementation of clinical observation.

The elimination of ipragliflozin by dialysis has not been studied.

Drug interactions

Pharmacodynamic interaction

Effect of other drugs on ipragliflozin

—овместное применение с лекарственными средствами, снижающими уровень глюкозы, не вли¤ло на эффект ипраглифлозина в отношении Ёvћ у здоровых людей. ќднократные дозы пиоглитазона или ситаглиптина не вли¤ли на Ёvћ, индуцированную многократным приемом ипраглифлозина; многократный прием пиоглитазона, глимепирида или ситаглиптина не вли¤л на Ёvћ, индуцированную однократным приемом ипраглифлозина. ?обавление многократного приема ипраглифлозина к многократному приему метформина приводило к увеличению Ёvћ.

¬ли¤ние ипраглифлозина на другие лекарственные средства

¬ли¤ние ипраглифлозина на изменени¤ электролитного состава и объема мочи, вызванные применением 'петлевого' диуретика фуросемида, было незначительным непродолжительным.

»праглифлозин может усиливать эффекты диуретиков, а также увеличивать риски, св¤занные с их применением, например, риск дегидратации и артериальной гипотензии. ѕрименение инсулина и препаратов, стимулирующих секрецию инсулина (например, производных сульфонилмочевины) может быть причиной развити¤ гипогликемии. ¬ св¤зи с этим дл¤ снижени¤ риска развити¤ гипогликемии при одновременном применении ипраглифлозина с инсулином и препаратами, усиливающими его секрецию, может потребоватьс¤ снижение дозы инсулина и препаратов, стимулирующих его секрецию.

‘армакокинетическое взаимодействие

¬ли¤ние других лекарственных средств на ипраглифлозин

»праглифлозин метаболизируетс¤ преимущественно путем конъюгации с глюкуроновой кислотой с помощью фермента UGT2B7 и в меньшей степени с участием ферментов UGT2B4, UGT1A8 и UGT1ј9. ¬ исследовани¤х in vitro было показано, что ипраглифлозин ¤вл¤етс¤ субстратом эффлюксного переносчика –-гликопротеина (P-gp), но не белка резистентности к раку молочной железы (BCRP) или белка множественной лекарственной устойчивости 2 (MRP2). »праглифлозин не ¤вл¤етс¤ субстратом переносчиков веществ внутрь клетки, таких как ќј“–1¬1, ќј“–1¬«, ќ—“1 и ќ—“2.
 линические исследовани¤ взаимодействи¤ с ингибиторами или индукторами UGT не проводились. ѕредполагалось, что совместное применение ингибиторов UGT приведет к увеличению экспозиции ипраглифлозина, однако это не рассматриваетс¤ как проблема безопасности, поскольку суточные дозы до 300 мг хорошо переносились пациентами. »ндукторы UGT могут уменьшать эффекты ипраглифлозина. “аким образом, если ипраглифлозин примен¤етс¤ совместно с индукторами UGT, необходимо контролировать клиническую эффективность, и при необходимости рассмотреть вопрос о повышении дозы ипраглифлозина с 50 мг до 100 мг.

 линические исследовани¤ межлекарственного взаимодействи¤ с ингибиторами P-gp не проводились. ќднако учитыва¤ высокую биодоступность ипраглифлозина (90/2%), маловеро¤тно, что ингибирование P-gp будет клинически значимо вли¤ть на абсорбцию препарата.

ѕри одновременном применении ипраглифлозина с другими гипогликемическими препаратами, такими как метформин, ситаглиптин, пиоглитазон, глимепирид, миглитол или митиглинид, клинически значимые изменени¤ фармакокинетики ипраглифлозина отсутствовали.

ѕрепараты, повышающие pH желудка, не вли¤ют на биодоступность ипраглифлозина, так как его растворимость не зависит от pH.

¬ли¤ние ипраглифлозина на другие лекарственные средства

¬ исследовани¤х in vitro ипраглифлозин не про¤вл¤л какой-либо значимой ингибирующей активности в отношении изоферментов цитохрома –450 (CYP) 1ј2, 2ј6, 2¬6, 2—8, 2—9, 2—19, 2D6, 2?1, 3ј4, и 4ј11, а также значимых индуцирующих эффектов в отношении CYP1ј2 и CYP3A4. »праглифлозин не показывал какой-либо значимой ингибирующей активности в отношении ферментов UGT, включа¤ UGT1A1, UGT1A4, UGT1A6, UGT1A9 и UGT2B7. »нгибирующего вли¤ни¤ ипраглифлозина на активность эффлюксных переносчиков P-gp, BCRP, MRP2 или на транспорт, опосредованный белком множественной резистентности и выведени¤ токсинов 1 (ћј“?1) и 2-  (ћј“?2- ), не наблюдалось. »нгибирующих эффектов ипраглифлозина в отношении переносчиков веществ внутрь клетки, таких как ќј“–1¬1, ќј“–1¬3, ќ—“1 и ќ—“2, не вы¤влено.

Drug interaction studies in healthy volunteers did not reveal the effect of repeated use of ipragliflozin on the pharmacokinetics of single doses of glimepiride (CYP2C9 substrate), pioglitazone (CYP2C8 substrate), sitagliptin and mitiglinide. Taking ipragliflozin 300 mg 1 time / day increased the effect of metformin (AUC) 1.18 times, which is not clinically significant.

Thus, it is believed that ipragliflozin will not interact with other drugs that are substrates for the aforementioned CYP, UGT enzymes and carriers.