VALERA Film-coated tablet Ref.[50715] Active ingredients: Evogliptin

1) 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 Evogliptin 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.

2) Renal impairment

It is confirmed that approximately 46.1% of the administered radioactivity was excreted in urine and approximately 42.8% in feces in healthy 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 compared to patients with normal renal function, Evogliptin should be cautiously administered while monitoring the patient’s condition. As there is no clinical experience of Evogliptin in patients with end-stage renal impairment requiring dialysis, administration of Evogliptin is not recommended in such patients.

3) Hepatic impairment

Dosage and administration adjustment is not needed in patients with mild to moderate hepatic impairment. No study was conducted in patients with severe hepatic impairment. Therefore, caution should be exercised in such patients.

4) Acute pancreatitis

Use of DPP4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominal pain. If pancreatitis is suspected, Evogliptin should be discontinued; if acute pancreatitis is confirmed, Evogliptin should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

In postmarketing experience of Evogliptin, there have been spontaneously reported adverse reaction of acute pancreatitis.

1) 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.

2) 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%.

Drug-Drug Interaction Study with Pioglitazone:

This study, in which Evogliptin 5 mg and Pioglitazone 30 mg were repeatedly administered individually or in combination with healthy volunteers to evaluate the drugs' pharmacokinetics, pharmacodynamics, tolerability and safety.

For Evogliptin, the geometric mean ratio (GMR of E/(E + P)), and 90% confidence interval (CI) for C_max,ss and AUC_τ,ss after co-administration of Evogliptin and Pioglitazone (E+P), compared to the administration of Evogliptin alone, were 1.01 (0.97-1.05) and 1.01 (0.98- 1.04), respectively.

For Pioglitazone, the geometric mean ratio (GMR of P/(E + P)) and 90% confidence interval (CI) for C_max,ss and AUC_τ,ss after co-administration of Evogliptin and Pioglitazone (E+P), compared to the administration of Pioglitazone alone, were 1.07 (0.99-1.17) and 1.08 (0.99–1.17), respectively.

Drug-Drug Interaction Study with Glimepiride:

This study in which Evogliptin 5 mg and Glimepiride 4 mg were repeatedly administered individually or in combination in healthy volunteers to evaluate pharmacokinetics, pharmacodynamics, tolerability, and safety of these drugs.

For Evogliptin, the geometric mean ratio (GMR of (E+G)/E) and the 90% confidence interval (CI) for C_max,ss and AUC_τ,ss after co-administration of Evogliptin and Glimepiride (E+G) compared to administration of Evogliptin alone (E) were 1.02 (0.98-1.06) and 0.97 (0.95–1.00)), respectively. For Glimepiride, the geometric mean ratio (GMR of (E+G)/G)) and the 90% confidence interval (CI) for C_max,ss and AUC_τ,ss after co-administration of Evogliptin and Glimepiride (E+G) compared to administration of Glimepiride alone (G) were 1.08 (1.01-1.17) and 1.08 (1.02–1.14)), respectively.

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 evogliptin is excreted in human milk. Since animal studies confirmed that evogliptin is secreted in the milk, evogliptin should not be used in nursing mothers.

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be alerted to the risk of hypoglycaemia especially when Evogliptin is co-administered with sulphonylurea and/or insulin.

1) Monotherapy

In the 12-week placebo-controlled monotherapy study using 2.5 mg, 5 mg, or 10 mg of evogliptin or placebo once daily, the adverse events reported with a frequency of 3% or higher are listed in Table 1.

Table 1. Adverse events reported in 3% or more patients in the 12-week placebo-controlled monotherapy study (regardless of investigator’s causality assessment):

In the 24-week placebo-controlled monotherapy study using 5 mg of evogliptin or placebo once daily, the adverse events reported with a frequency of 3% or higher are listed in Table 2.

Table 2. Adverse events reported in 3% or more patients in the 24-week placebo-controlled monotherapy study (regardless of investigator’s causality assessment):

In patients administering evogliptin 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%).

2) Combination therapy

In the 24-week active-drug-controlled combination therapy study with stable doses of metformin and either evogliptin 5 mg or Sitagliptin 100 mg once daily, the adverse events reported with a frequency of 3% or higher are listed in Table 3.

Table 3. Adverse events reported in 3% or more patients in the 24-week active-controlled combination therapy study (regardless of investigator’s causality assessment):

In the 52-week study using evogliptin 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%).

3) Hypoglycemia

In the 24-week monotherapy and combination therapy study with evogliptin 5 mg, hypoglycemia was each reported in one patient (monotherapy 1.3%, combination therapy 0.9%). All reported hypoglycemia cases were mild in severity and resolved without any action taken.

4) Vital signs

No clinically significant change in vital signs was observed in patients treated with Evogliptin.

Phase III clinical trial done by Alkem: A total of 38 (20.7%) patients reported 43 treatment emergent adverse events (TEAEs) during the study. No serious TEAEs were reported. No action was required (with IP or patient) for these 43 TEAEs. None of the TEAEs were severe or life threatening or fatal. No action was taken against study medication for all the 38/184 (20.7%) patients with 43 TEAEs. The study medication was neither interrupted nor discontinued for any patient. No patient was withdrawn from the study due to TEAEs. Majority of the TEAEs were mild in nature, dyslipidemia was most common, 6 events were reported in Evogliptin treatment group while 4 events were reported in Sitagliptin treatment group.

General Precautions

1) 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 evogliptin. Severe and disabling joint pain

2) 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 evogliptin if appropriate.