Suganon

Pink, round, biconvex, film-coated tablet, "SNT" embossed on one side, and plain on the other side.
Each tablet contains evogliptin tartrate equivalent to 5 mg of evogliptin.
Excipients/Inactive Ingredients: Core tablet: Mannitol, Pre-gelatinized starch, Low substituted hydroxypropyl cellulose, Hydroxypropyl cellulose, Colloidal silicon dioxide, Magnesium stearate.
Coated tablet: OPADRY 03B650009 Red.

Pharmacotherapeutic group: Drugs used in type 2 diabetes, dipeptidyl peptidase 4 (DPP4) inhibitors. ATC code: A10BH07 evogliptin.
Pharmacology: Pharmacodynamics: Mechanism of action: Evogliptin is a member of a class of oral anti-hyperglycaemic agents called DPP-4 inhibitors. Evogliptin selectively inhibits the activity of DPP-4 by reversibly binding to DPP-4, an enzyme that inactivates incretin hormones such as GLP-1 (Glucagon-like peptide-1). Evogliptin dose-dependently inhibits the activity of DPP-4, thereby blocking GLP-1 from being inactivated by DPP-4, increasing the concentration of endogenous active GLP-1 and prolonging its action, and improves glucose-dependent insulin secretion in pancreatic beta cells by GLP-1, and suppresses increase in blood sugar. The IC50 of evogliptin against recombinant human DPP-4 was 0.980 nM, and the inhibitory constant (Ki) was 0.525 nM. Compared to DPP-8 and DPP-9, evogliptin showed high selectivity of about 7,898 times and about 6,058 times, respectively, to DPP-4 (in vitro).
Information on clinical trial: Monotherapy: A randomized, double-blinded, placebo-controlled, 24-week (extension up to 52 weeks) clinical trial to investigate the efficacy and safety of evoglitpin monotherapy was performed in 160 patients with type 2 diabetes mellitus who have inadequate glycemic control on diet and exercise. When administering evogliptin orally, once daily, the difference of changes in hemoglobin A1C (HbA1c) between evogliptin verses placebo from baseline to 24 weeks of treatment was statistically significant (p<0.0001) (Table 1).
In the extension period up to 52 weeks, for patients who agreed to participate in the extension period (placebo arm was switched to evogliptin 5 mg), the efficacy of evogliptin, in terms of HbA1c, was maintained up to 52 weeks (Evogliptin/Evogliptin group showed -0.36% of HbA1c from the baseline). (See Table 1.)

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Combination therapy: Evogliptin add on to metformin monotherapy: A randomized, double-blind, active-controlled clinical trial to investigate the efficacy and safety of evogliptin when added to ongoing metformin monotherapy (≥1,000 mg/day) was performed in 222 patients with type 2 diabetes mellitus who have inadequate glycemic control with metformin monotherapy. When adding on evogliptin, orally, once daily, the difference of changes in HbA1c from baseline to 24 weeks was similar to that of sitagliptin 100 mg; the non-inferiority of evogliptin to sitagliptin was demonstrated in patients with type 2 diabetes mellitus who have inadequate glycemic control with metformin monotherapy (Table 2).
In the extension period up to 52 weeks, for patients who agreed to participate in the extension period (sitagliptin 100 mg arm was switched to evogliptin 5 mg), the efficacy of evogliptin, in terms of HbA1c, was maintained up to 52 weeeks (Evogliptin/Evogliptin group showed -0.44% of HbA1c from the baseline). (See Table 2.)

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Evogliptin add on to metformin and dapagliflozin combination therapy: A 24-week (extension period up to 52 weeks), multicenter, double-blind, placebo-controlled, randomized, parallel, clinical trial to evaluate the efficacy and safety of evogliptin when added to stable doses of metformin and dapagliflozin combination therapy was performed in 283 patients with type 2 diabetes (7.0% ≤HbA1c ≤10.5%) who have inadequate glycemic control with metformin and dapagliflozin combination therapy.
After 24 weeks, the least squares mean (LSmean) for HbA1c (%) change from baseline was -0.69% in evogliptin 5 mg and -0.04% in placebo. The difference of changes in HbA1c from baseline between the groups was -0.65% (95% CI: -0.79, -0.51), which showed a higher reduction in evogliptin 5 mg when compared to placebo. The difference was statistically significant (p<0.0001) (Table 3). In extension period up to 52 weeks, the effect of evogliptin 5 mg maintained, in terms of HbA1c, when compared with placebo. (See Table 3.)

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Pharmacokinetics: Absorption: After a single oral administration of evogliptin 5 mg in fasting state, the maximum blood concentration reached in about 4 hours. In repeated oral administration, steady state reached in 48 hours after the first administration. Comparing the bioavailability of evogliptin 10 mg between fast state and fed state (high-fat meal), it was found that there is no food effect in terms of bioavailability of evogliptin.
Distribution: Evogliptin is widely distributed to tissues after administration. When reacting evogliptin in heparin-treated plasma of mice, rats, dogs, and humans, the plasma protein binding rates of evogliptin were about 63%, about 25%, about 43%, and about 46%, respectively; binding rates were not related to the concentration of evogliptin in the reacted range (100-1,000 ng/mL). In pregnant female rats and rabbits or lactating rats, the concentration of evogliptin in fetal plasma or milk increased maternal exposure dependently.
Metabolism: Metabolic stability of evogliptin was confirmed in in vitro tests using liver microsomes or hepatocytes. Evogliptin circulates in plasma mainly as parent, and the major metabolites are M16, M8, M7, and M13. The main metabolic pathways were hydroxylation (M7, M8), sulfation (M13) by CYP3A4 and glucuronidation by UGT2B7 (M7-M16). The major metabolites M16, M8, M7, and M13 were all identified as active forms, but showed at least 110 times lower DPP-4 inhibitory activity compared to the evogliptin parent. Therefore, considering the blood exposure level and inhibitory activity of major metabolites, it is very unlikely that the metabolites will reach effective blood levels.
Excretion: After a single oral administration of evogliptin 5 mg in fasting state, the mean half-life (t_½) of elimination was about 32.5 hours. After a single oral administration of [14C]-evogliptin 5 mg in fasting state, 74.9% to 93.9% were excreted through urine and feces, respectively. The average excretion rates in urine and feces were 46.1% and 42.8%, respectively, and the main excretory body was the evogliptin parent.
Characteristics in patients: Hepatic impairment: After a single oral administration of evogliptin 5 mg, the exposure of evogliptin, evaluated by C_max and AUC_last, was observed similarly between patients with mild liver dysfunction (Child-Pugh A) and healthy adults with normal liver function when matching with sex, age and weight. In patients with moderate hepatic dysfunction (Child-Pugh B), C_max and AUC_last were about 1.37 times and about 1.44 times, respectively, compared to healthy adults with normal liver function. However, these pharmacokinetic differences are not considered to have a clinically significant effect.
Renal impairment: After a single oral administration of evogliptin 5 mg, patients with mild renal impairment (60≤MDRD eGFR(mL/min/1.73m²)<90) had blood exposure similar to those of healthy adults with normal renal function (90≤MDRD eGFR(mL/min/1.73m²)). In patients with moderate renal impairment (30≤MDRD eGFR(mL/min/1.73m²)<60) and patients with severe renal impairment (15≤MDRD eGFR(mL/min/1.73m²)<30)), the AUC was about 1.8 times and about 1.98 times, and C_max about 1.32 times and about 1.52 times, respectively, compared to healthy adults with normal renal function. However, these pharmacokinetic differences are not considered to have a clinically significant effect.
After a single oral administration of evogliptin 5 mg before and after hemodialysis in patients with end-stage renal disease undergoing hemodialysis (MDRD eGFR(mL/min/1.73m²)<15), the AUC was about 1.30 times (administration before dialysis) and about 1.39 times (administration after dialysis), and C_max about 0.88 times (administration before dialysis) and about 1.20 times (administration after dialysis), respectively, compared to healthy adults with normal renal function (90≤MDRD eGFR(mL/min/1.73m²)). The AUC was about 0.95 times and Cmax was about 0.73 times, when administered before hemodialysis compared to when administered after hemodialysis. These pharmacokinetic differences are not considered to have a clinically significant effect.
Toxicology: Preclinical safety data: A safety pharmacology program compliant with GLP and ICH guidelines was conducted with evogliptin tartrate, encompassing central nervous system, respiratory, and cardiovascular systems.
A study of central nervous system effects after oral administration of evogliptin tartrate in rodents included body temperature and general behaviors including neurobehavior. Evogliptin tartrate did not produce any significant effects on general behavior and temperature at doses up to 300 mg/kg.
A study of respiratory function in rats was conducted at oral doses up to 300 mg/kg evogliptin tartrate. There were no statistically significant effects on respiratory parameters such as respiratory rate and tidal volume relative to vehicle controls, except a significant decrease in minute volume at 300 mg/kg 120 minutes after administration.
Studies in the cardiovascular system included evaluation of the human ether-à-go-go related gene (hERG) tail currents and electrocardiographic function in dogs. In the hERG patch clamp assay, the IC₅₀ value of evogliptin tartrate was 143.4 μM (>9,000 folds vs. C_max at the dose of 5 mg in humans from DA1229_DM_I). In dogs, evogliptin tartrate increased heart rate and changed several ECG parameters (shortened QT, QTcV and RR interval, elongated QRS interval) at 300 mg/kg, but did not affect blood pressure and temperature. These overall effects were restricted to high dose/concentration associated with evogliptin systemic exposure greatly exceeding those observed in humans.

SUGANON is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Posology: Use in adults: The recommended dose of SUGANON is 5 mg once daily as monotherapy or combination therapy, and the maximum daily dose of SUGANON is 5 mg. SUGANON can be taken with or without food. Dosage and administration adjustment is not need in patients with mild to moderate hepatic impairment.
Use in pregnancy and nursing mothers: Use in pregnant women: No comparative study result is available in pregnant women. Results of animal studies showed that evogliptin was detected in the blood stream of fetus across the placenta up to 61.7% in pregnant rats and 14.1% in pregnant rabbits 2 hours after administration. Therefore, use in pregnant women is not recommended.
Use in nursing mothers: It is not evaluated whether SUGANON is excreted in human milk. Since animal studies confirmed that evogliptin is secreted in the milk, SUGANON should not be used in nursing mothers.
Use in Pediatrics: Safety and efficacy in pediatrics have not been established.
Use in the elderly: There were 119 elderly patients (22.6%) aged 65 years or older out of a total of 527 patients in the phase II and III clinical studies of SUGANON. The administration in elderly patients has not been fully investigated. Since the elderly generally have decreased physiological functions such as hepatic and renal functions, caution needs to be exercised during administration while monitoring the patient's condition.
Method of administration: For oral use.

In clinical trials of SUGANON, single dose of up to 60 mg daily was administered in healthy adults. In case of an overdose, perform symptomatic therapy (e.g., remove unabsorbed substance from the gastrointestinal tract, conduct clinical monitoring including electrocardiogram), and perform supportive therapy depending on the patient's condition.

Patients who show serious hypersensitivity such as anaphylaxis or angioedema to SUGANON or other dipeptidyl peptidase 4 (DPP4) inhibitors.
Patients with type I diabetes or diabetic ketoacidosis.

Heart failure: Caution should be exercised for patients with functional class I heart failure based on the New York Heart Association (NYHA) criteria as experience of administration is limited in such patients. Use of SUGANON is not recommended to patients with functional class II-IV based on the NYHA criteria due to the absence of clinical experience in such patients.
Renal impairment: It is confirmed that approximately 46.1% of the radioactivity administered by labeling evogliptin was excreted in urine and approximately 42.8% in feces in adults. This figure includes both the unchanged form and its metabolites. Since there is a concern that increased blood concentration of the unchanged form may persist in patients with moderate to severe renal impairment and end-stage renal impairment patients undergoing hemodialysis compared to patients with normal renal function, SUGANON should be cautiously administered while monitoring the patient's condition. Evogliptin can be administered regardless of time point of dialysis in end-stage renal impairment patients requiring hemodialysis.
Severe hepatic impairment: No study was conducted in patients with hepatic impairment. Therefore, caution should be exercised in such patients.
Acute pancreatitis: There is no report of acute pancreatitis in patients administered with SUGANON. However, acute pancreatitis has been reported in patients treated with DPP-4 inhibitors. Thus, characteristic symptoms of acute pancreatitis such as consistent and severe abdominal pain should be informed to patients. If pancreatitis is suspected after administration of SUGANON, the administration of SUGANON should be discontinued and SUGANON should not be re-administered. Caution should be exercised in patients with a medical history of pancreatitis.
General Precautions: Concomitant administration with drugs known to cause hypoglycemia: Insulin secretagogues such as insulin or sulfonylurea may cause hypoglycemia. Thus, lowering the dose of insulin or insulin secretagogues may be required to minimize the risk of hypoglycemia in case of concomitant administration with SUGANON.
Severe and disabling joint pain: Severe and disabling joint pain has been reported in patients administering other DPP-4 inhibitors in post-marketing studies. The time to onset of symptoms following initiation of drug therapy varied from 1 day to years. Patients experienced relief of symptoms upon discontinuation of the medication. Some patients had a recurrence of severe joint pain when restarted on either their original DPP-4 inhibitor medication or another DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue SUGANON if appropriate.
Bullous pemphigoid: Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with other DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving SUGANON. If bullous pemphigoid is suspected, SUGANON should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
Effects on ability to drive and use machines: No effect of DPP4 inhibitor on the ability to drive or operate machinery or mental functions has been known. The possibility of showing impaired ability to drive or operate machinery or impaired mental functions is expected to be low considering its pharmacological mechanism.

Fertility: No study result of the effect on human fertility has been performed. In fertility and early embryonic development study in rats, the no-observed-adverse-effect-level (NOAEL) was 100 mg/kg/day for male fertility and 300 mg/kg/day for female fertility and early embryonic development. The exposure of NOAEL for male and female fertility is approximately 300 times and 950 times the maximum-recommended-human-dose (MRHD), respectively.
Teratogenicity: When administered up to evogliptin 1,000 and 250 mg/kg in the reproductive toxicity studies in rats and rabbits, respectively, no anomaly or mutation in fetus was shown. The NOAEL for reproductive toxicity in fetus was 300 mg/kg/day for rats and 250 mg/kg/day for rabbits, which is approximately 950 and 1,100 times the MRHD, respectively, based on AUC comparison.
Carcinogenesis: As a result of a two-year carcinogenicity study conducted in male and female rats with doses of evogliptin 5, 30, and 100 mg/kg/day, there was no incidence of tumor in both male and female rats. Based on AUC comparisons, the dose of 100 mg/kg/day in rats results in exposures approximately 250 times the maximum recommended human dose (MRHD) of 5 mg. A two-year carcinogenicity study was conducted in male and female mice with doses of evogliptin 10, 30, and 100 mg/kg/day. Any type of tumor in any organ was not shown in up to 100 mg/kg/day, an exposure of 90 times or higher than the MRHD.
Pregnancy: No comparative study result is available in pregnant women. Results of animal studies showed that evogliptin was detected in the blood stream of fetus across the placenta up to 61.7% in pregnant rats and 14.1% in pregnant rabbits 2 hours after administration. Therefore, use in pregnant women is not recommended.
Lactation: It is not evaluated whether SUGANON is excreted in human milk. Since animal studies confirmed that evogliptin is secreted in the milk, SUGANON should not be used in nursing mothers.

Monotherapy: In the 12-week placebo-controlled monotherapy study using 2.5 mg, 5 mg, or 10 mg of SUGANON or placebo once daily, the adverse events reported with a frequency of 3% or higher are listed in Table 4. (See Table 4.)

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In the 24-week placebo-controlled monotherapy study using 5 mg of SUGANON or placebo once daily, the adverse events reported with a frequency of 3% or higher are listed in Table 5. (See Table 5.)

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In patients administering SUGANON 5 mg once daily as monotherapy for 52 weeks, the adverse events that occurred during the extension period (last 28 weeks) regardless of causality with increased frequency by 1% or higher compared to those of the 24-week study were toothache (3.1% vs. 1.3%) and contact dermatitis (3.1% vs. 1.3%). Compared to the 24-week study, there was no newly reported adverse event that occurred in two or more subjects (3.1%).
Combination therapy: In the 24-week active-drug-controlled combination therapy study with stable doses of metformin and either SUGANON 5 mg or sitagliptin 100 mg once daily, the adverse events reported with a frequency of 3% or higher are listed in Table 6. (See Table 6.)

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In the 52-week study using SUGANON 5 mg once daily combined with metformin, the adverse events that occurred during the extension period (last 28 weeks) regardless of causality with increased frequency by 1% or higher compared to those of the 24-week study were gastritis (2.2% vs. 0.9%) and upper respiratory tract infection (4.3% vs. 2.7%). Compared to the 24-week study, sciatica (2.2%) was a newly reported adverse event that occurred in two or more subjects (2.2%).
In the clinical trial in which SUGANON 5 mg or a placebo was additionally administered once daily for 52 weeks in patients with type 2 diabetes who have inadequate glycemic control with the stable doses of metformin and dapagliflozin combination therapy, the adverse events reported with a frequency of 1% or higher are listed in Table 7. (See Table 7.)

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Hypoglycemia: In the 24-week monotherapy and metformin combination therapy study with evogliptin 5 mg, hypoglycemia was each reported in one patient (monotherapy 1.3%, metformin combination therapy 0.9%). All reported hypoglycemia cases were mild in severity and resolved without any action taken. In the clinical trial in which SUGANON 5 mg or a placebo was additionally administered once daily for 52 weeks in patients with type 2 diabetes who have inadequate glycemic control with the stable doses of metformin and dapagliflozin combination therapy, hypoglycemia was each reported in one patient (evogliptin 5 mg 0.71%, placebo 0.71%). All were asymptomatic hypoglycemia, resolved during the study without any action taken and the causality was related.
Vital signs: No clinically significant change in vital signs was observed in patients treated with SUGANON.
Bullous pemphigoid: There have been post marketing reports of bullous pemphigoid requiring hospitalization in patients taking other DPP-4 inhibitors.
Post-marketing surveillance result: Post-marketing surveillance result for re-examination in Korea: In the post-marketing surveillance in 3,445 patients for 6 years for re-examination in Korea, the incidence of adverse events, regardless of causality, was 8.59% (296/3,445 patients, 355 cases in total). Of these events, both serious adverse drug reactions and unexpected adverse drug reactions, which the causal relationship with SUGANON could not be excluded, are listed in the following table, in the order of frequency. (See Table 8.)

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In vitro assessment: Evogliptin is mainly metabolized by CYP3A4. In in vitro studies, evogliptin was not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes or an inducer of CYP1A2, 2B6, and 3A4 enzymes. Thus, evogliptin is unlikely to cause interactions with other drugs acting as a substrate of such enzymes. Although evogliptin was proved to be a p-glycoprotein (P-gp) substrate and weak BCRP substrate based on in vitro studies, it did not inhibit transport mediated by these transporters. In addition, evogliptin was not a substrate of OAT1, OAT3, OCT2, OATP1B1, and OATP1B3, and did not inhibit them. Therefore, evogliptin is unlikely to cause interactions with drugs that act as a substrate of such transporters in the clinical dose.
In vivo assessment: Interaction of evogliptin with other drugs: Metformin: Multiple administration of evogliptin 5 mg and twice daily Metformin 1,000 mg (a substrate of OCT1 and OCT2) until steady state was reached did not show clinically meaningful change in the pharmacokinetics of evogliptin or Metformin.
Clarithromycin: Multiple administration of a potent CYP3A4 inhibitor, clarithromycin 1,000 mg/day, until steady state was reached and single administration of evogliptin 5 mg showed increased C_max of evogliptin by 2.1 times and its AUC by 2.0 times. Caution needs to be exercised as pharmacokinetic exposure of evogliptin may increase with concomitant administration of CYP3A4 inhibitors.
Rifampicin: Multiple administration of a potent CYP3A4 inducer, rifampicin 600 mg/day, until steady state was reached and single administration of evogliptin 5 mg showed no significant change in C_max of evogliptin but showed a decrease in AUC by 63%.
Pioglitazone: Multiple administration of evogliptin 5 mg and pioglitazone 30 mg (a substrate of CYP2C8 and CYP3A4) did not show clinically meaningful change in the pharmacokinetics of evogliptin or pioglitazone.
Glimepiride: Multiple administration of evogliptin 5 mg and glimepiride 4 mg (a substrate of CYP2C9) did not show clinically meaningful change in the pharmacokinetics of evogliptin or glimepiride.
Dapagliflozin: Multiple administration of evogliptin 5 mg and dapagliflozin 10 mg (a substrate of UGT1A9) did not show clinically meaningful change in the pharmacokinetics of evogliptin or dapagliflozin.
Empagliflozin: Multiple administration of evogliptin 5 mg and empagliflozin 25 mg (a substrate of UGT2B7, UGT1A3, UGT1A8 and UGT1A9) did not show clinically meaningful change in the pharmacokinetics of evogliptin or empagliflozin.

Incompatibilities: No applicable data has been studied.
Special precautions for disposal of a used medicinal product: Any used or waste product should be discarded in accordance with appropriate local requirements.

As keeping this drug in other containers may result in an accident caused by misuse or in decreased quality of the drug, store in the original container.
This medicinal product does not need to be stored at any special conditions.
Shelf life: 3 years.

Antidiabetic Agents

A10BH07 - evogliptin ; Belongs to the class of dipeptidyl peptidase 4 (DPP-4) inhibitors. Used in the treatment of diabetes.

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