Zemimet SR Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Monotherapy and additional combination therapy: Gemigliptin: Two placebo-controlled monotherapy studies, one of 12- and one of 24-week duration, included patients treated with gemigliptin 50 mg once daily. Table 1 summarizes the most common (≥3% of patients) adverse reactions reported in the group treated with gemigliptin 50 mg once daily. (See Table 1.)

Click on icon to see table/diagram/image

The 24-week monotherapy study was extended through 52-week. The adverse events that increased more than 1% during the latter 28 weeks when compared with the first 24 weeks, regardless of assessment of causality, were nasopharyngitis (4.44% vs 6.1%), upper respiratory tract infection (11% vs 6.1%) and increase in blood creatine phosphokinase (2.22% vs 4.88%). No new adverse events were reported in more than 2 patients (2.44%) in latter 28 weeks.
One active-controlled add-on combination therapy study with metformin included patients treated with gemigliptin 25 mg twice daily, gemigliptin 50 mg once daily and sitagliptin 100 mg once daily. Table 2 summarizes the most common (≥3% of patients) adverse reactions reported in this study. (See Table 2.)

Click on icon to see table/diagram/image

The 24-week add-on combination therapy was extended through 52-week with gemigliptin 50 mg once daily added on to stable dose of metformin. The adverse events that increased more than 1% during the latter 28 weeks when compared with the first 24 weeks, regardless of assessment of causality, were diarrhea (0.71% vs 2.7%), urinary tract infection (0.71% vs 1.8%), hypoglycemia (0.71% vs 2.7%), dizziness (0.71% vs 3.6%) and nausea (1.43% vs 2.7%). The adverse events reported in more than 2 patients (1.8%) during the latter 28 weeks were asthenia (1.8%) and myalgia (1.8%).
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with gemigliptin.
Gemigliptin 50 mg was given in patients inadequately controlled on their maximal tolerated dose of metformin and a glimepiride for 24 weeks. Table 3 summarizes the most common (≥3% of patients) adverse reactions reported in this study. (See Table 3.)

Click on icon to see table/diagram/image

In a 12-week study conducted in patients with mild and moderate renal impairment, gemigliptin 50 mg was given and Table 4 summarizes the most common (≥3% of patients) adverse reactions reported in this study. (See Table 4.)

Click on icon to see table/diagram/image

Metformin: In placebo-controlled clinical trials of extended-release metformin monotherapy, adverse reactions including diarrhea and nausea/vomiting were reported in greater than 5% of the metformin patients and that were more common in metformin than placebo treated patients (diarrhea 9.6% vs 2.6%, nausea/vomiting 6.5% vs 1.5%). Diarrhea led to discontinuation of study medication in 0.6% of patients treated with extended-release metformin.
Initial combination therapy: In a 24 weeks clinical trial that studied initial combination of metformin, gemigliptin 50 mg and metformin were individually administered and co-administered once daily. Table 5 summarizes the most common (≥3% of patients) adverse reactions reported in this study. (See Table 5.)

Click on icon to see table/diagram/image

Hypoglycemia: Gemigliptin: In two placebo-controlled clinical studies, one of 12- and one of 24-week duration, of gemigliptin 50 mg once daily as monotherapy, 2 patients (1.59%) reported hypoglycemia. One patient (0.71%) reported hypoglycemia in 24-week active-controlled add-on combination study. In the 24-week study of initial therapy, gemigliptin 50 mg once daily with metformin to a maximum dose of 2000 mg, hypoglycemia was reported in 3 patients (2.13%). In the extended 52-week studies of gemigliptin 50 mg once daily, 3 patients (2.7%) reported hypoglycemia. 10 patients (9.35%) reported hypoglycemia when gemigliptin 50 mg was given once daily as an add-on therapy in patients with inadequate glycemic control with metformin and sulfonylurea dual therapy. In a 12-week study conducted in patients with mild and moderate renal impairment, 9 patients (13.6%) reported hypoglycemia in the group treated with gemigliptin 50 mg and six patients (9.1%) in the placebo group. In the 52-week extension study where those previously receiving placebo were switched to linagliptin, 10 patients (20.0%) in the group treated with gemigliptin 50 mg reported hypoglycemia, whereas 15 patients (28.9%) reported hypoglycemia in the active comparator group. The hypoglycemia experienced by patients in clinical trials was considered mostly mild in severity and patients fully recovered.
Subjects with inadequate glycemic control on insulin monotherapy or dual therapy with insulin plus metformin were studied with add-on therapy of Gemigliptin administered once daily for 24 weeks.
The incidence rates of hypoglycaemia were 29 subjects (15.1%) in the gemigliptin group and 15 subjects (15.6%) in the placebo group. The symptomatic hypoglycaemias reported were of mild or moderate severity as the incidence rates of hypoglycaemia accompanied by symptoms (symptomatic hypoglycaemia) were 11 subjects (5.7%) in the gemigliptin group and 5 subjects (5.2%) in the placebo group. Most of the subjects recovered from these events during the study, and most of the events were deemed unrelated to the investigational drug. The incidence rates of hypoglycaemia not accompanied by symptoms (asymptomatic hypoglycaemia) were 21 subjects (10.9%) in gemigliptin group and 10 subjects (10.4%) in the placebo group.
Hypersensitivity reaction: Gemigliptin: In a 24-week active-controlled add-on combination study, two patients (1.71%) receiving 25 mg gemigliptin twice daily on a stable dose of metformin in the first 24-week and 50 mg once daily in the remaining 28 weeks reported hypersensitivity reactions, which was not related to gemigliptin exposure.
Pancreatitis: Gemigliptin: In clinical studies of sitagliptin, a member of dipeptidyl peptidase 4 (DPP-4) inhibitors, the incidence of acute pancreatitis was 0.1 per 100 patient-years (4 patients with an event in 4708 patient-years for sitagliptin treated group). In two placebo-controlled studies, one of 12-week and one of 24-week duration, of gemigliptin 50 mg once daily as monotherapy, 1 patient (1.59%) reported acute pancreatitis, which was not related to gemigliptin exposure.
Vitamin B12: Metformin: Metformin may lower Vitamin B12 levels. Measurement of hematologic parameters on an annual basis is advised in patients on Gemigliptin/Metformin HCl and any apparent abnormalities should be appropriately investigated and managed.
Bullous pemphigoid: Gemigliptin: In the post-marketing surveillance in the patients treated with other DPP-4 inhibitors, bullous pemphigoid requiring hospitalization has been reported.
Results of post-marketing surveillance in Korea (gemigliptin tartrate (single agent, for oral administration)): In the results of post-marketing surveillance conducted in 3,036 subjects for 6 years as the re-examination of gemigliptin tartrate (single agent, for oral administration) in Korea, the incidence of adverse events was reported to be 8.17% (248/3,036 subjects, 328 cases in total) regardless of causality. Among them, the serious adverse events regardless of causality are listed in table 6. No serious adverse drug reactions for which the causality could not be excluded were reported. (See Table 6.)

Click on icon to see table/diagram/image

In addition, the unexpected adverse events regardless of causality and the unexpected adverse drug reactions for which the causality could not be excluded are listed in the table as follows. (See Table 7.)

Click on icon to see table/diagram/image

Results of post-marketing surveillance in Korea (gemigliptin tartrate and metformin hydrochloride (combination agents, for oral administration): In the results of post-marketing surveillance conducted in 624 subjects as the re-examination of gemigliptin tartrate and metformin hydrochloride (combination agents, for oral administration) in Korea, the incidence of adverse events was reported to be 5.45% (34/624 subjects, 43 cases in total) regardless of causality. Among them, neither serious adverse events regardless of causality nor serious adverse drug reactions for which the causality could not be excluded were reported.
In addition, the unexpected adverse events regardless of causality and the unexpected adverse drug reactions for which the causality could not be excluded are listed in the table 8. (See Table 8.)

Click on icon to see table/diagram/image

Domestic and foreign post-marketing spontaneous reports: The followings are the adverse events which were additionally identified during postmarketing use of the product. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Pruritus, Rash and Urticaria.