Suglat (Tablets) Instructions for Use

Marketing Authorization Holder

Astellas Pharma Europe B.V. (Netherlands)

Manufactured By

Astellas Pharma Inc. (Japan)

Packaging and Quality Control Release

DELPHARM MEPPEL, B.V. (Netherlands)

ATC Code

A10BK05 (Ipragliflozin)

Active Substance

Ipragliflozin (Rec.INN)

Dosage Form

Suglat

Film-coated tablets 50 mg: 10, 30, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light pink to light purple in color, round, biconvex, with the inscription “Suglat” in Japanese () and the number “50” on both sides of the tablet.

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

Shell composition: Opadry 03F40025 (hypromellose, macrogol 6000, titanium dioxide, talc, iron oxide red dye, iron oxide black dye).

10 pcs. – blisters (1) – cardboard packs with or without first opening control.
10 pcs. – blisters (3) – cardboard packs with or without first opening control.
10 pcs. – blisters (6) – cardboard packs with or without first opening control.
10 pcs. – blisters (10) – cardboard packs with or without first opening control.

Clinical-Pharmacological Group

Oral hypoglycemic drug – sodium-glucose cotransporter 2 inhibitor

Pharmacotherapeutic Group

Hypoglycemic agent for oral administration, sodium-dependent glucose transporter 2 inhibitor

Pharmacological Action

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

By pronounced inhibition of SGLT2, expressed in the proximal tubule of the kidney nephron, Ipragliflozin reduces glucose reabsorption in the renal tubules and lowers the renal threshold for glucose, which leads to increased urinary glucose excretion and insulin-independent reduction of elevated plasma glucose concentration. The amount of glucose excreted by the kidneys depends on the blood glucose concentration and GFR. Increased urinary glucose excretion with SGLT2 inhibition also leads to a moderate osmotic diuresis and diuretic effect, which contributes to the reduction of systolic and diastolic blood pressure. In studies of patients with type 2 diabetes, it was shown that increased urinary glucose excretion leads to calorie loss and, consequently, weight loss.

Pharmacokinetics

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

When the drug was taken at a dose of 50 mg before a high-fat meal, an increase in the C_max of ipragliflozin by 1.23 times and a reduction in the time to reach it (T_max) by 0.6 hours were noted; the AUC value did not change. When taken after a high-fat meal, the C_max of ipragliflozin decreased by 0.82 times, and the T_max increased by 0.9 hours; the AUC value did not change.

The binding of ipragliflozin to plasma proteins (mainly to albumin) is 94.6-96.5% and is comparable in healthy individuals and persons with type 2 diabetes. At equilibrium, the mean V_d after intravenous administration of a 25 mg dose is 127 L, indicating extensive distribution of ipragliflozin in tissues.

Ipragliflozin undergoes significant metabolism in the human body, mainly in the liver. Seven metabolites have been identified in plasma, urine, and feces: 5 glucuronides, an S-oxide, and a sulfate of ipragliflozin. The main metabolic pathway of ipragliflozin is glucuronidation involving UDP-glucuronosyltransferases (mainly UGT2B7, to a lesser extent UGT2B4, UGT1A8 and UGT1A9) with the formation mainly of the main metabolite 2′-O-P-glucuronide of ipragliflozin.

Ipragliflozin and its metabolites are excreted by the kidneys and through the intestines. After single or multiple oral doses of ipragliflozin 50 and 100 mg, the mean terminal T_1/2 ranges 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 by the kidneys unchanged. In all studies, the fraction of unchanged ipragliflozin excreted by the kidneys was low (<2% of the dose taken).

In a mass balance study after oral administration of 100 mg of ¹⁴C-ipragliflozin, most of the radioactivity (84.4%) was excreted by the kidneys and through the intestines by 48 hours; by 144 hours, the ratio of excreted radioactivity 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 C_max increases to a lesser extent.

Indications

Type 2 diabetes mellitus to improve glycemic control: as monotherapy in case of ineffectiveness of diet therapy and physical 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.

ICD codes

Dosage Regimen

Orally at an initial dose of 50 mg once a day. If necessary, the dose can be increased to 100 mg (2 tablets of 50 mg).

When used concomitantly with insulin preparations or drugs that enhance 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.

Adverse Reactions

Immune system disorders: frequency unknown – angioedema.

Infections and infestations: common – genital infection (vulvovaginal candidiasis, genital pruritus and other genital infections).

Metabolism and nutrition disorders: common – hypoglycemia, thirst; uncommon – feeling of hunger; frequency unknown – ketoacidosis.

Nervous system disorders: common – dizziness.

Eye disorders: uncommon – diabetic retinopathy.

Gastrointestinal disorders: common – constipation; uncommon – nausea, vomiting.

Skin and subcutaneous tissue disorders: common – eczema, rash; uncommon – pruritus, urticaria.

Musculoskeletal and connective tissue disorders: common – back pain; uncommon – myalgia.

Renal and urinary disorders: common – pollakiuria (or polyuria), urinary tract infection.

Metabolism and nutrition disorders: common – weight loss.

General disorders and administration site conditions: uncommon – asthenia.

Contraindications

Hypersensitivity to ipragliflozin; severe ketoacidosis, diabetic coma or precoma; severe infectious diseases, perioperative period, major surgeries and trauma; severe renal impairment (GFR <30 mL/min/1.73 m²), end-stage renal disease or patients on dialysis, due to possible reduction of the hypoglycemic effect; severe hepatic impairment; pregnancy; breastfeeding period; children under 18 years of age.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindication: severe hepatic impairment.

Use in Renal Impairment

Contraindications: severe renal impairment (GFR <30 mL/min/1.73 m²), end-stage renal disease or patients on dialysis, due to possible reduction of the hypoglycemic effect.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

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

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

If symptoms of ketoacidosis appear, such as nausea and vomiting, loss of appetite, abdominal pain, excessive thirst, increased fatigue, breathing problems, impaired consciousness or other symptoms, it is necessary to consider performing laboratory tests (including determination of ketone bodies in 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.

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

During treatment with ipragliflozin, fungal infections of the genital organs may develop. Therefore, patients should be thoroughly examined for signs and symptoms of genital infections. If signs and symptoms of fungal infections of the genital organs appear, appropriate therapy should be carried out.

In long-term clinical studies of another SGLT2 inhibitor, an increase in cases of lower limb amputation (primarily toes) was noted. It is not known whether this effect is specific to the entire pharmacological class. It is important to counsel all patients with diabetes on standard preventive foot care.

To reduce the risk of hypoglycemia when using ipragliflozin in combination with insulin or drugs that stimulate insulin secretion (e.g., sulfonylurea drugs), it is necessary to consider reducing the dose of insulin or drugs that stimulate insulin secretion.

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

Due to the mechanism of action, patients taking Ipragliflozin will have positive results for glucose in the urine.

Effect on ability to drive vehicles and operate machinery

There are no data on the negative effect of ipragliflozin on the ability to drive vehicles and operate machinery. It is expected that Ipragliflozin will not affect the ability to drive vehicles and operate machinery, 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 (e.g., sulfonylurea derivatives), as well as an increased risk of adverse reactions associated with a decrease in circulating blood volume, for example, dizziness and arterial hypotension.

Drug Interactions

Adding multiple doses of ipragliflozin to multiple doses of metformin led to an increase in 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 arterial hypotension. The use of insulin and drugs that stimulate insulin secretion (e.g., sulfonylurea derivatives) may cause hypoglycemia. In this regard, to reduce the risk of hypoglycemia with the simultaneous use of ipragliflozin 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 mainly by conjugation with glucuronic acid via the enzyme UGT2B7 and to a lesser extent by the enzymes UGT2B4, UGT1A8 and UGT1A9. In vitro studies have shown that Ipragliflozin is a substrate of the efflux transporter P-glycoprotein (P-gp), but not of the breast cancer resistance protein (BCRP) or multidrug resistance protein 2 (MRP2). Ipragliflozin is not a substrate of influx transporters such as OATP1B1, OATP1B3, OCT1 and OCT2.
Clinical interaction studies with UGT inhibitors or inducers have not been conducted. It was assumed that co-administration with UGT inhibitors would lead to an increase in ipragliflozin exposure, but this is not considered a safety issue, since daily doses up to 300 mg were well tolerated by patients. UGT inducers may reduce the effects of ipragliflozin. Thus, if Ipragliflozin is used concomitantly with UGT inducers, it is necessary to monitor clinical efficacy and, if necessary, consider increasing the dose of ipragliflozin from 50 mg to 100 mg.

Taking ipragliflozin 300 mg once daily enhanced the effect of metformin (AUC) by 1.18 times, which is not clinically significant.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.