Evodin^® (Tablets) Instructions for Use

Marketing Authorization Holder

Geropharm, LLC (Russia)

ATC Code

A10BH07 (Evogliptin)

Active Substance

Evogliptin (Rec.INN registered by WHO)

Dosage Form

Evodin®

Film-coated tablets, 5 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from white to slightly yellow in color, engraved with “EVO” on one side, round in shape; the core on the cross-section is white or almost white.

Excipients: mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate.

Film coating composition: Opadry^® 03B28796 white (hypromellose, titanium dioxide, macrogol/polyethylene glycol).

7 pcs. – contour cell blisters (4) – cardboard packs.
14 pcs. – contour cell blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Hypoglycemic drug – dipeptidyl peptidase-4 inhibitor

Pharmacotherapeutic Group

Hypoglycemic agent – dipeptidyl peptidase-4 inhibitor

Pharmacological Action

Evogliptin is an oral hypoglycemic agent, a selective inhibitor of the serine protease enzyme dipeptidyl peptidase-4 (DPP-4), which is involved in the inactivation of incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both incretins are involved in maintaining glucose homeostasis. GLP-1 and GIP are secreted in the intestine; low basal concentrations of incretins throughout the day increase in response to food intake. Under physiological conditions, incretin activity is limited by the DPP-4 enzyme (GLP-1 and GIP are rapidly hydrolyzed by DPP-4 to form inactive forms). At low blood glucose concentrations, incretins do not affect insulin release and glucagon secretion. At normal or elevated blood glucose concentrations, GLP-1 and GIP promote increased insulin synthesis and its secretion by pancreatic beta-cells through intracellular signaling mechanisms associated with cyclic AMP. Furthermore, GLP-1 reduces glucagon secretion by pancreatic alpha-cells. The decrease in glucagon concentration against the background of increased insulin concentration leads to a reduction in glucose production in the liver, which in turn leads to a decrease in glycemia. Evogliptin reversibly binds to the DPP-4 enzyme, preventing the hydrolysis of incretins and causing a sustained increase in the concentration of active forms of GLP-1 and GIP. In patients with type 2 diabetes mellitus with hyperglycemia, the change in insulin and glucagon secretion leads to a significant decrease in the concentration of glycated hemoglobin and plasma glucose.

Evogliptin is associated with a lower risk of hypoglycemia compared to other oral hypoglycemic drugs from other groups. Unlike sulfonylurea derivatives and thiazolidinediones (glitazones), for which weight gain is a frequent adverse reaction during therapy, the use of evogliptin does not affect the patient’s body weight.

Pharmacokinetics

The bioavailability of evogliptin after a single oral dose is more than 50%. Concomitant administration of evogliptin with food does not affect absorption. In healthy patients after a single oral dose of evogliptin in doses from 1.25 mg to 60 mg, the time to reach C_max ranges from 3 to 5.5 hours. After a single dose of 5 mg of evogliptin in healthy volunteers, its C_max in blood plasma was 5.6±1.3 µg/L. With increasing dose, an increase in C_max in plasma and AUC is observed. With multiple oral administrations of evogliptin at doses of 5 mg, 10 mg, and 20 mg once daily, steady state is reached by the third day. At steady state, the C_max of evogliptin was observed 4.0-5 hours after drug administration.

It is distributed approximately equally between whole blood and plasma; about 46% of evogliptin binds to plasma proteins. Preclinical studies have established that Evogliptin is rapidly distributed to all body tissues (except heart tissue and mesentery), penetrates the fetal circulatory system and the milk of lactating rats.

The main part of evogliptin circulates in the blood unchanged (more than 80%). During biotransformation in humans, 5 metabolites are formed that do not possess DPP-4 inhibitory activity, detected mainly in plasma and urine. Evogliptin is metabolized primarily by CYP3A4. In in vitro studies, Evogliptin did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes and did not induce CYP1A2, 2B6, and 3A4 enzymes. After a single dose of evogliptin ranging from 1.25 to 60 mg, the mean T_1/2 ranges from 32.5 to 39.8 hours. With multiple doses – from 32.9 to 38.8 hours. In healthy adults, approximately 46.1% of the administered dose is excreted by the kidneys and approximately 42.8% is excreted via the intestine (including metabolites).

Indications

Type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control as monotherapy or in combination therapy with metformin.

ICD codes

Dosage Regimen

Administer orally.

The recommended dose is 5 mg once daily.

Take the tablet with or without food.

Use as monotherapy or in combination therapy with metformin.

The maximum daily dose is 5 mg; do not exceed this dose.

For patients with moderate or severe renal impairment, use with caution and monitor renal function.

For patients with hepatic impairment, use with caution; no specific dose adjustment is established.

For elderly patients, use with caution due to potential age-related decline in renal or hepatic function.

Do not use in patients with end-stage renal disease requiring dialysis.

If a dose is missed, take it as soon as remembered unless it is almost time for the next dose; do not double the dose.

Adverse Reactions

Gastrointestinal system disorders gastritis.

Infectious and parasitic diseases nasopharyngitis.

Musculoskeletal and connective tissue disorders arthralgia.

Skin and subcutaneous tissue disorders contact dermatitis.

General disorders and administration site conditions toothache.

Contraindications

Type 1 diabetes mellitus, diabetic ketoacidosis, chronic heart failure NYHA class II-IV; pregnancy, breastfeeding period, age under 18 years.

With caution

In patients with chronic heart failure NYHA class I, in patients with moderate and severe renal impairment, in patients with hepatic impairment, in patients with a history of acute pancreatitis, in elderly patients.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Use with caution in patients with hepatic impairment.

Use in Renal Impairment

Use with caution in patients with moderate and severe renal impairment.

Pediatric Use

Use is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Since elderly people generally have reduced physiological functions, including liver and kidney function, caution should be exercised when using the drug and the patient’s condition should be monitored.

Special Precautions

When treating patients with chronic heart failure NYHA class I, caution should be exercised due to limited practical experience with evogliptin in such patients. The use of evogliptin is contraindicated in patients with CHF NYHA class II-IV due to the lack of clinical experience with the drug in such patients.

It has been confirmed that in healthy adults, approximately 46.1% of the administered dose was excreted by the kidneys and approximately 42.8% was excreted via the intestine (including metabolites). Since there is a risk of sustained elevation of unchanged evogliptin levels in the blood of patients with moderate and severe renal impairment, caution should be exercised when using evogliptin and renal function should be monitored. Since there is no clinical experience with evogliptin in patients with end-stage renal disease requiring dialysis, the use of evogliptin in such patients is not recommended.

No study has been conducted in patients with hepatic impairment. There are no data on dose adjustment of evogliptin. Therefore, caution should be exercised when treating such patients.

There have been no reports of acute pancreatitis in patients taking Evogliptin. However, acute pancreatitis has been observed in patients taking DPP-4 inhibitors. Therefore, patients should be informed about the characteristic symptoms of acute pancreatitis, such as persistent and severe abdominal pain. If pancreatitis is suspected after taking evogliptin, its use should be discontinued and not resumed. Caution should be exercised when treating patients with a history of pancreatitis.

Effect on ability to drive vehicles and operate machinery

During treatment with evogliptin, dizziness may occur, which can affect the performance of potentially hazardous activities requiring special attention and quick reactions (driving vehicles, working with moving machinery).

Drug Interactions

Preclinical studies have shown that Evogliptin is primarily metabolized by the CYP3A4 isoenzyme.

Concomitant administration of evogliptin 5 mg and metformin 1000 mg twice daily until steady-state concentration was reached did not reveal clinically significant changes in the pharmacokinetic parameters of evogliptin and metformin. The steady-state AUC values did not differ either after simultaneous administration of evogliptin and metformin (T) and evogliptin alone (R) – AUC ratio (T/R) = 1.02 (90% CI 0.99 – 1.06), or after simultaneous administration of evogliptin and metformin (T) and metformin alone (R) – AUC ratio (T/R) = 0.94 (90% CI 0.89 – 0.98). The steady-state values of the maximum drug concentrations also did not differ clinically either after simultaneous administration of evogliptin and metformin (T) and evogliptin alone (R) – C_max ratio (T/R) = 1.06 (90% CI 1.01 – 1.12), or after simultaneous administration of evogliptin and metformin (T) and metformin alone (R) – AUC ratio (T/R) = 0.84 (90% CI 0.79 – 0.89).

The degree of DPP-4 inhibition was comparable with concomitant use of evogliptin and metformin and with the use of evogliptin alone at a dose of 5 mg. At the same time, concomitant use of evogliptin and metformin showed a tendency to increase the concentration of active GLP-1 compared to the use of evogliptin alone or metformin alone.

Multiple administration of the potential CYP3A4 inhibitor clarithromycin at a daily dose of 1000 mg until steady-state concentration was reached and a single dose of evogliptin 5 mg showed an increase in the C_max of evogliptin by 2.17 times and an increase in the AUC of evogliptin by 2.02 times. Caution is advised, as the pharmacokinetic parameters of evogliptin may increase when co-administered with CYP3A4 inhibitors.

Multiple administration of the potential CYP3A4 inducer rifampicin at a daily dose of 600 mg until steady-state concentration was reached and a single dose of evogliptin 5 mg did not show significant changes in the C_max values of evogliptin, but showed a 63% decrease in AUC compared to evogliptin monotherapy.

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.