Evogliptin

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.

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.