Suglat, 50 mg 30 pcs

ipragliflozin

Indications

Type 2 diabetes mellitus to improve glycemic control: as monotherapy in case of ineffectiveness of diet therapy and exercise; in combination with other hypoglycemic drugs, including metformin, pioglitazone, sulfonylurea derivatives, DPP-4 inhibitors, insulin (± DPP-4 inhibitor), metformin with sitagliptin, α-glucosidase inhibitors (α-GI), nateglinide, GLP-1 analogues (including in combination with sulfonylurea derivatives), in the absence of adequate glycemic control control.

Pharmacological effect

Pharmacotherapeutic group: Hypoglycemic agent for oral administration – inhibitor of sodium-dependent glucose transporter type 2

Pharmacological action

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

By potently inhibiting SGLT2 expressed in the proximal tubule of the renal nephron, ipragliflozin reduces renal tubular glucose reabsorption and decreases the renal glucose threshold, resulting in increased urinary glucose excretion and an insulin-independent reduction in elevated plasma glucose concentrations. The amount of glucose excreted by the kidneys depends on the concentration of glucose in the blood and GFR. Increased urinary glucose excretion with SGLT2 inhibition also leads to moderate osmodiuresis and a diuretic effect, which helps reduce systolic and diastolic blood pressure. Studies in patients with type 2 diabetes have shown that increased urinary glucose excretion leads to calorie loss and, as a result, weight loss.

Pharmacokinetics

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

When taking the drug at a dose of 50 mg before eating a fat-rich meal, there was an increase in Cmax of ipragliflozin by 1.23 times and a reduction in the time to reach it (Tmax) by 0.6 hours; the AUC value did not change. When administered after a high-fat meal, the Cmax of ipragliflozin decreased by 0.82 times, and the Tmax increased by 0.9 hours; AUC value did not change.

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

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

Ipragliflozin and its metabolites are excreted by the kidneys and 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, with renal clearance being about 0.1 l/h. After intravenous administration of ipragliflozin, only 1.32% of the administered dose is excreted unchanged by the kidneys. In all studies, the proportion of urinary excretion of unchanged ipragliflozin was low (< 2% of the administered dose).In a mass balance study after oral administration of 100 mg 14C-ipragliflozin, most of the radioactivity (84.4%) was excreted by the kidneys and intestines after 48 hours; after 144 hours, the ratio of radioactivity excreted was 67.9% by the kidneys and 32.7% through the intestines.In the dose range from 1 to 600 mg, AUC increases proportionally to the dose, while Cmax increases less.

Special instructions

Ipragliflozin should not be used in patients with severe renal impairment, end-stage renal disease, or in patients on dialysis because it is likely that the drug will be ineffective in this category of patients. Renal function may deteriorate during treatment with ipragliflozin. When using ipragliflozin, there may be an increase in creatinine and urea concentrations in the blood, as well as a decrease in the estimated glomerular filtration rate (eGFR). Renal function should be assessed before starting treatment with ipragliflozin and monitored periodically during treatment.

During the treatment period, adequate hydration and monitoring of blood volume (including physical examination, blood pressure measurement, laboratory tests, including indicators of renal function, electrolyte composition) are recommended.

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

Elderly patients are more likely to experience a decrease in physiological functions, as well as a higher risk of dehydration, so treatment with ipragliflozin in this category of patients should be carried out under close supervision.

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

In long-term clinical trials of another SGLT2 inhibitor, an increase in lower extremity (primarily toe) amputations was noted. It is unknown whether this effect is specific to the entire pharmacological class. It is important to counsel all patients with diabetes on standard preventative foot care.

To reduce the risk of hypoglycemia when using ipragliflozin in combination with insulin or drugs that stimulate insulin secretion (for example, sulfonylureas), consider reducing the dose of insulin or drugs that stimulate insulin secretion

Urinary tract infections, including pyelonephritis, may develop during treatment with ipragliflozin. Patients should be carefully assessed for possible signs and symptoms of urinary tract infections and, if necessary, treated accordingly.

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

Impact on the ability to drive vehicles and machinery

There is no data on the negative effect of ipragliflozin on the ability to drive vehicles and operate machinery. It is expected that ipragliflozin will have no or minimal effect on the ability to drive vehicles and machines.

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, sulfonylureas), as well as the increased risk of adverse reactions associated with a decrease in blood volume, such as dizziness and hypotension.

Active ingredient

Ipragliflozin

Composition

Active substance: ipragliflozin

Pregnancy

Contraindicated for use during pregnancy and breastfeeding.

Contraindications

Hypersensitivity to ipragliflozin; severe ketoacidosis, diabetic coma or precoma; severe infectious diseases, perioperative period, major operations and injuries; severe renal impairment (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 18 years of age.

Side Effects

From the immune system: frequency unknown – angioedema.

Infections and infestations: often – infection of the genital organs (vulvovaginal candidiasis, genital itching and other infections of the genital organs).

Metabolism: often – hypoglycemia, thirst; infrequently – feeling of hunger; frequency unknown – ketoacidosis.

From the nervous system: often – dizziness.

On the part of the organ of vision: infrequently – diabetic retinopathy.

From the digestive system: often – constipation; infrequently – nausea, vomiting.

From the skin and subcutaneous tissues: often – eczema, rash; uncommon – itching, urticaria.

From the musculoskeletal system: often – back pain; infrequently – myalgia.

From the kidneys and urinary system: often – pollakiuria (or polyuria), urinary tract infection.

Metabolism: often – weight loss.

General reactions: infrequently – asthenia.

Interaction

Adding multiple doses of ipragliflozin to multiple doses of metformin resulted in increased urinary glucose excretion.

The effect of ipragliflozin on changes in electrolyte composition and urine volume caused by the use of the loop diuretic furosemide was insignificant and short-lived.

Ipragliflozin may enhance the effects of diuretics, as well as increase the risks associated with their use, for example, the risk of dehydration and hypotension. The use of insulin and drugs that stimulate insulin secretion (for example, sulfonylurea derivatives) can cause hypoglycemia. In this regard, to reduce the risk of hypoglycemia when using ipragliflozin simultaneously with insulin and drugs that enhance its secretion, it may be necessary to reduce the dose of insulin and drugs that stimulate its secretion.

Ipragliflozin is metabolized predominantly by conjugation with glucuronic acid by the enzyme UGT2B7 and to a lesser extent by the enzymes UGT2B4, UGT1A8 and UGT1A9. In in vitro studies, ipragliflozin has been shown to be a substrate of the efflux transporter P-glycoprotein (P-gp), but not breast cancer resistance protein (BCRP) or multidrug resistance protein 2 (MRP2). Ipragliflozin is not a substrate of intracellular transporters such as OATP1B1, OATP1B3, OCT1 and OCT2.
Clinical interaction studies with UGT inhibitors or inducers have not been conducted. Concomitant use of UGT inhibitors was expected to increase ipragliflozin exposure, but this is not considered a safety concern as daily doses of up to 300 mg were well tolerated. UGT inducers may reduce the effects of ipragliflozin. Therefore, if ipragliflozin is co-administered with UGT inducers, monitor clinical efficacy and consider increasing the ipragliflozin dose from 50 mg to 100 mg if necessary.

Taking ipragliflozin 300 mg 1 time/day increased the effect of metformin (AUC) by 1.18 times, which is not clinically significant.

Manufacturer

Astellas Pharma Tech Co. Ltd., Japan