Zemidapa

Gemigliptin/Dapagliflozin is round shaped, bright brown colored, film-coated tablet, debossed with a "LG" symbol and a wave pattern on one side.
Each tablet contains gemigliptin tartrate sesquihydrate, equivalent to 50 mg of gemigliptin, and 10 mg of dapagliflozin.
Excipients/Inactive Ingredients: Tablet core: Microcrystalline Cellulose (Type 102), Lactose Anhydrous, Croscarmellose Sodium, Sodium stearyl Fumarate, Opadry II 85F665000 Brown.
Film coating: Polyvinyl Alcohol, Titanium Dioxide, Polyethylene Glycol 3350, Talc, Yellow Iron Oxide, Red Iron Oxide.

Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering drugs. ATC code: A10BD30.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Gemigliptin/Dapagliflozin combines two anti-hyperglycemic medicinal products with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: gemigliptin tartrate sesquihydrate, a DPP-4 inhibitor, and dapagliflozin, a SGLT 2 inhibitor.
Clinical efficacy and safety: Glycemic control: Gemigliptin add-on to metformin and dapagliflozin combination therapy: In a 24-week, multicenter, randomized, placebo-controlled, parallel-group, double-blind study, gemigliptin 50 mg was compared to placebo once daily as add-on therapy in subjects with inadequate glycemic control type 2 diabetes mellitus (7.0% ≤ HbA1c ≤ 11.0%) in combination with metformin (≥1,000 mg/day) and dapagliflozin (10 mg/day).
At week 24, the adjusted mean change in HbA1c from baseline was -0.86% for the gemigliptin 50 mg group and -0.20% for the placebo group. Gemigliptin 50 mg resulted in statistically significant (p-value <0.0001) reductions in HbA1c compared to placebo at week 24 (adjusted mean change difference: -0.66% (95% CI: -0.80%, -0.52%).
Gemigliptin: Mechanism of Action: Gemigliptin is a member of a class of oral anti-hyperglycemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors, which enhances the level of active incretin hormones, including GLP-1 and GIP, thereby reducing blood glucose levels. Active GLP-1 and GIP promote insulin production and release from pancreatic beta cells. GLP-1 also lowers the secretion of glucagon from pancreatic alpha cells, thereby resulting in a decreased hepatic glucose production. However, these incretins are rapidly degraded by the DPP-4. Gemigliptin selectively inhibits DPP-4 activity, enhancing prolonged activation of incretin hormones. Gemigliptin demonstrates >3,400-fold and >9,500-fold selectivity versus DPP-9 and DPP-8, respectively.
Clinical Efficacy and Safety: The benefit of administering gemigliptin in patients with type 2 diabetes and the risk associated with this treatment has been evaluated in the clinical program conducted in total 1473 subjects randomized in 6 clinical trials.
Gemigliptin dose finding: The efficacy and safety of gemigliptin monotherapy was evaluated in a placebo-controlled Phase II study of 12 weeks duration. The mean change in HbA1c from baseline at Week 12 was -0.98%, -0.74% and -0.78% (when adjusted with placebo data, -0.92%, -0.68% and -0.72%) at dosage levels of 50 mg, 100 mg and 200 mg, respectively.
Monotherapy: The efficacy and safety of gemigliptin monotherapy was evaluated in a placebo-controlled Phase III study of 24 weeks duration. The analysis of covariance for HbA1c change from baseline at Week 24 (W24 - W0) demonstrated that placebo-subtracted mean HbA1c reduction from baseline was -0.705% [95% CI -1.041 to -0.368]. Therefore, the clinical efficacy of gemigliptin was demonstrated to be superior to that of the placebo group. The study was extended through Week 52. In the extended part of the study, an analysis of HbA1c change from baseline revealed consistent glycemic control effect of gemigliptin over a period of 52 weeks. Further decrease in HbA1c was observed with continued treatment of gemigliptin 50 mg in the latter 28 weeks and the degree of change from baseline at Week 52 (-0.87%) was still clinically and statistically significant (p <0.0001).
Gemigliptin as add-on to metformin therapy: The efficacy and safety of gemigliptin add-on combination therapy was evaluated in an active-controlled Phase III study of 24 weeks duration. The analysis of covariance for HbA1c change from baseline at Week 24 (W24 - W0) demonstrated- that the between-group difference (each regimen group of gemigliptin-sitagliptin group) in the least square mean change from baseline was 0.056% [90% CI -0.117 to 0.23] for 50 mg, qd group and 0.04% [90% CI -0.121 to 0.2] for 25 mg, bid group. Therefore, the clinical efficacy of gemigliptin was demonstrated to be at least comparable with that of the comparator, sitagliptin. The study was extended through Week 52. In the extended part of the study, the change in HbA1c from baseline was clinically and statistically significant (p <0.0001) throughout the duration of 52 weeks in all treatment groups. The decrease in HbA1c was most prominent at Week 6 followed by further gradual decrease thereafter. Decreased HbA1c level was well maintained in all three groups during the extended 28 weeks.
Gemigliptin as add-on to a combination of metformin and sulfonylurea therapy: The efficacy and safety of gemigliptin triple combination therapy with metformin and sulfonylurea was evaluated in a placebo-controlled Phase III study of 24 weeks duration. Analysis of covariance (ANCOVA) was conducted using the HbA1c value at baseline as a covariate and including the glimepiride reduction as a factor in relation to the change in HbA1c at Week 24. In the main population for analysis, the least square mean of the HbA1c change at Week 24 after study treatment was -0.877±0.166% (p <0.0001) in gemigliptin group and -0.012±0.179% (p=0.9476) in the placebo group, showing a significant reduction compared to the baseline in the gemigliptin group. As the 95% CI for the difference in change between the treatment groups was (-1.092, -0.638), i.e., its upper limit was less than 0, the superiority of the gemigliptin group was demonstrated.
Gemigliptin and metformin as initial therapy: The efficacy and safety of gemigliptin initial combination therapy with metformin was evaluated in an active-controlled Phase III study of 24 weeks duration. For the change of HbA1c from baseline at Week 24, analysis of covariance was performed. As a result, 95% CI for between group difference in least square means of HbA1c changes in combination therapy group and each monotherapy group were (-1.02, -0.63) in combination therapy group compared with gemigliptin group and (-0.82, -0.41) in combination therapy group compared with metformin group, respectively. This showed that the upper limits of both CI were less than zero (p <0.001), confirming superiority of the combination therapy group.
Glycemic variability of gemigliptin versus sitagliptin or glimepiride: The efficacy of gemigliptin on MAGE (mean amplitude of glycemic excursions) and safety of initial combination therapy of gemigliptin versus sitagliptin or glimepiride with metformin in patients with type 2 diabetes was evaluated in a multicenter, randomized, active-controlled, parallel group, open-label, exploratory study. The change in MAGE at Week 12 was -43.11mg/dL, -38.27mg/dL and -21.74mg/dL in the gemigliptin and metformin group, sitagliptin and metformin group and glimepiride and metformin group, respectively. In the test result between the groups, DPP-4 inhibitors, i.e., the gemigliptin and metformin group and sitagliptin and metformin group, reduced the MAGE compared to sulfonylurea, i.e., glimepiride and metformin group (gemigliptin: p=0.0306, sitagliptin: p=0.0292).
The data collected in clinical studies demonstrated that gemigliptin was well tolerated and displayed an overall safety profile that is at least comparable with that of the comparator.
Dapagliflozin: Mechanism of action: Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of SGLT2. Dapagliflozin blocks reabsorption of filtered glucose from the S1 segment of the renal tubule, effectively lowering blood glucose in a glucose dependent and insulin-independent manner. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. The increased urinary glucose excretion with SGLT2 inhibition produces an osmotic diuresis, and can result in a reduction in systolic blood pressure.
Pharmacodynamic effects: Dapagliflozin's glucuretic effect is observed after the first dose, is continuous over the 24-hour dosing interval, and is sustained for the duration of treatment. Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in subjects with type 2 diabetes mellitus following the administration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in subjects with type 2 diabetes mellitus for 12 weeks. Evidence of sustained glucose excretion was seen in subjects with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years. Urinary uric acid excretion was also increased transiently (for 3-7 days) and accompanied by a sustained reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from -48.3 to -18.3 micromoles/L (-0.87 to -0.33 mg/dL).
Clinical efficacy and safety: Dapagliflozin Effect on Cardiovascular Events (DECLARE): Dapagliflozin Effect on Cardiovascular Events (DECLARE) was an international, multicentre, randomised, double-blind, placebo-controlled clinical study conducted to determine the effect of dapagliflozin compared with placebo on cardiovascular outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either at least two additional cardiovascular risk factors (age ≥55 years in men or ≥60 years in women and one or more of dyslipidaemia, hypertension or current tobacco use) or established cardiovascular disease.
Of 17,160 randomised patients, 6,974 (40.6%) had established cardiovascular disease and 10,186 (59.4%) did not have established cardiovascular disease. 8,582 patients were randomised to dapagliflozin 10 mg and 8,578 to placebo, and were followed for a median of 4.2 years.
The mean age of the study population was 63.9 years, 37.4% were female. In total, 22.4% had had diabetes for ≤5 years, mean duration of diabetes was 11.9 years. Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m².
At baseline, 10.0% of patients had a history of heart failure. Mean eGFR was 85.2 mL/min/1.73 m², 7.4% of patients had eGFR <60 mL/min/1.73 m², and 30.3% of patients had micro- or macroalbuminuria (urine albumin to creatinine ratio [UACR] ≥30 to ≤300 mg/g or >300 mg/g, respectively).
Most patients (98%) used one or more diabetic medications at baseline, including metformin (82%), insulin (41%) and sulfonylurea (43%).
The primary endpoints were time to first event of the composite of cardiovascular death, myocardial infarction or ischaemic stroke (MACE) and time to first event of the composite of hospitalisation for heart failure or cardiovascular death. The secondary endpoints were a renal composite endpoint and all-cause mortality.
Pharmacokinetics: Gemigliptin/Dapagliflozin: A bioequivalence study in healthy subjects demonstrated that the Gemigliptin/Dapagliflozin combination tablets are bioequivalent to co-administration of gemigliptin and dapagliflozin as individual tablets.
The effects of food on pharmacokinetics of Gemigliptin/Dapagliflozin combination tablets were similar to the known food effects of gemigliptin or dapagliflozin as individual tablets.
Gemigliptin: Absorption: Following a single oral administration of gemigliptin to healthy subjects, gemigliptin was rapidly absorbed, with T_max occurring 1 to 5 hours post-dose. At the clinical dose of 50 mg, C_max and AUC were 62.7 ng/mL and 743.1 ng·hr/mL, respectively. The system exposure was increased in a dose-proportional manner in the range of 50 ~ 400 mg. When co-administration of a high-fat meal with gemigliptin, food slightly delayed the absorption of gemigliptin, decreased the C_max by 39% but did not affect the AUC. These changes were not considered to be clinically meaningful.
Distribution: In vitro human plasma protein binding is 29% for gemigliptin and 35% ~ 48 % for the metabolites including the major active metabolite.
Biotransformation: The responsible enzyme for the metabolism of gemigliptin is CYP3A4. In plasma, gemigliptin and the major metabolite (LC15-0636) accounted for 65% ~ 100% and 9% ~ 18% of the sample radioactivity. LC15-0636, a hydroxylated metabolite of gemigliptin, is pharmacologically active and two times more potent than gemigliptin. In vitro studies indicated that gemigliptin is not an inhibitor of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4 and is not an inducer of CYP1A2, 2C8, 2C9, 2C19, or 3A4.
Elimination: Following oral administration of [¹⁴C] gemigliptin to healthy subjects, the administered radioactivity was recovered in feces (27%) or urine (63%). The elimination half-life after oral administration is approximately 17 hr and 24 hr for gemigliptin and LC15-0636, respectively.
Renal Impairment: The influence of renal impairment on the pharmacokinetics of gemigliptin has been evaluated. In patients with mild (CrCl: 50 ~ 80 mL/min), moderate (CrCl: 30 ~ 50 mL/min), severe (CrCl: <30 mL/min) and end stage renal disease (on hemodialysis), AUC_inf increased 1.20-, 2.04-, 1.50- and 1.69-fold for gemigliptin and 0.91-, 2.17-, 3.07- and 2.66-fold for LC15-0636, when compared with the normal kidney function group. Overall active moiety, the sum of gemigliptin and LC15-0636, was increased less than or approximately 2-fold in patients with moderate and severe renal impairment.
Hepatic Impairment: The influence of hepatic impairment on the pharmacokinetics of gemigliptin has been evaluated. In mild and moderate hepatic impairment, exposure to gemigliptin (AUC) after single dosing was 50% and 80% higher than in healthy subjects. Formation of LC15-0636, a metabolite of gemigliptin, was only slightly affected by mild hepatic impairment (5% to 10% lower), while in moderate hepatic impairment, formation of LC15-0636 was about 30% lower compared to healthy subjects. Urinary excretion parameters were not markedly influenced by hepatic impairment, so the decrease in total clearance of gemigliptin observed in hepatic impairment is due a decreased metabolization rate of gemigliptin. Half-lives of gemigliptin and of LC15-0636 were slightly increased in hepatic impairment.
In mild and moderate hepatic impairment, inhibition of DPP-4 was slightly decreased compared to healthy subjects (5% to 10%), however, neither the effect on AUEC nor on E_max of DPP-4 inhibition was statistically significant.
Gender: No dose adjustment is necessary based on gender. The differences in C_max and AUC_inf were not clinically significant.
Race: Caucasian subjects demonstrated 28% decrease in C_max and 5% decrease in AUC_inf when compared with Korean subjects.
Dapagliflozin: Absorption: Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (C_max) were usually attained within 2 hours after administration in the fasted state. Geometric mean steady-state dapagliflozin C_max and AUC_τ values following once daily 10 mg doses of dapagliflozin were 158 ng/mL and 628 ng h/mL, respectively. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%.
Distribution: Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment). The mean steady-state volume of distribution of dapagliflozin was 118 liters.
Biotransformation: Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the glucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP-mediated metabolism was a minor clearance pathway in humans.
Elimination: The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance of dapagliflozin administered intravenously was 207 mL/min. Dapagliflozin and related metabolites are primarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin.
Linearity: Dapagliflozin exposure increased proportional to the increment in dapagliflozin dose over the range of 0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated daily dosing for up to 24 weeks.
Renal impairment: At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had mean systemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively, than those of subjects with type 2 diabetes mellitus and normal renal function. The steady-state 24-hour urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. The impact of haemodialysis on dapagliflozin exposure is not known.
Hepatic impairment: In subjects with mild or moderate hepatic impairment (Child-Pugh class A and B), mean C_max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful. In subjects with severe hepatic impairment (Child-Pugh class C) mean C_max and AUC of dapagliflozin were 40% and 67% higher than matched healthy controls, respectively.
Elderly: There is no clinically meaningful increase in exposure based on age alone in subjects up to 70 years old. However, an increased exposure due to age-related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients >70 years old.
Gender: The mean dapagliflozin AUC_ss in females was estimated to be about 22% higher than in males.
Race: There were no clinically relevant differences in systemic exposures between White, Black or Asian races.
Body weight: Dapagliflozin exposure was found to decrease with increased weight. Consequently, low-weight patients may have somewhat increased exposure and patients with high-weight somewhat decreased exposure. However, the differences in exposure were not considered clinically meaningful.
Toxicology: Preclinical safety data: No animal studies have been conducted with Gemigliptin/Dapagliflozin.
The following data are findings in studies performed with gemigliptin or dapagliflozin individually.
Gemigliptin: A two-year carcinogenicity study was conducted in male and female rats given oral doses of gemigliptin of 50, 150, and 450 mg/kg/day. No evidence of carcinogenicity with gemigliptin was found in either male or female rats. This dose results in exposures approximately 129~170 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 50 mg/day based on AUC comparisons. A 6-month carcinogenicity study has been performed in TgrasH2 transgenic mice at doses of 200, 400, and 800 mg/kg/day in males and 200, 600, 1200 mg/kg/day in females. There was no evidence of carcinogenicity with gemigliptin at a dose of 1200 mg/kg/day, approximately 87 times the human exposure at the maximum recommended daily dose.
Genotoxicity assessments in the Ames test, chromosomal aberrations test and in vivo micronucleus tests in mice and rats were negative.
The fertility of gemigliptin was not affected at dose of 800 mg/kg/day in rat. Gemigliptin was not teratogenic up to 200 mg/kg/day in rats and 300 mg/kg/day in rabbits, which are respectively 83 and 153 times human exposure at the MRHD of 50 mg/day.
Gemigliptin at dose of 800 mg/kg/day in rat, approximately 264 times human exposure at the MRHD of 50 mg/day, increased the incidence of fetus cleft palate malformation, dilated renal pelvis, misshapen thymus and sternoschisis, with increasing dose.
In animal studies, gemigliptin was excreted at a ratio of 1: 4~10 in plasma and milk in rats. Therefore, Gemigliptin/Dapagliflozin should not be administered in nursing woman.
Dapagliflozin: Preclinical studies of dapagliflozin revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, or carcinogenicity.

Gemigliptin/Dapagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Posology: Adults: The recommended dose is one tablet once daily in patients who need 50 mg of gemigliptin and 10 mg of dapagliflozin.
Special populations: Renal impairment: The efficacy and safety of Gemigliptin/Dapagliflozin is dependent on renal function, and renal function should be evaluated prior to initiation of Gemigliptin/Dapagliflozin and periodically thereafter.
For patients with eGFR ≥45 mL/min/1.73 m², no dose adjustment is required.
For patients with eGFR <45 mL/min/1.73 m², Gemigliptin/Dapagliflozin is not recommended.
Hepatic impairment: No dose adjustment is required for patient with mild or moderate hepatic impairment. The safety and efficacy of Gemigliptin/Dapagliflozin in patients with severe hepatic impairment have not yet been established.
Cardiac impairment: There is limited experience in patients with New York Heart Association (NYHA) Class I, II cardiac status in the case of gemigliptin. Therefore, Gemigliptin/Dapagliflozin should be used with caution in this population. Due to limited clinical experience in patients with NYHA Class III, IV cardiac status in the case of gemigliptin, the use of Gemigliptin/Dapagliflozin is not recommended in this population (see Precautions).
Elderly: Caution should be used in elderly patient because physiological functions including liver and kidney are usually decreased in this population.
Pediatric population: Safety and effectiveness in children and adolescents below 18 years of age have not been established. No data are available.
Method of administration: Gemigliptin/Dapagliflozin can be taken once daily with or without food.

No data are available with regard to overdose of Gemigliptin/Dapagliflozin.
Gemigliptin: During clinical trials in healthy subjects, multiple doses of up to 600 mg gemigliptin were administered for duration of 10 days. One case of increased heartbeat was observed at a single dose of 600 mg gemigliptin. There is no experience with daily doses above 600 mg in clinical studies. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status.
Dapagliflozin: Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose). These subjects had detectable glucose in the urine for a dose-related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration, hypotension or electrolyte imbalance, and with no clinically meaningful effect on QTc interval. The incidence of hypoglycemia was similar to placebo. In clinical studies where once-daily doses of up to 100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthy subjects and type 2 diabetes subjects, the incidence of hypoglycemia was slightly higher than placebo and was not dose-related. Rates of adverse events including dehydration or hypotension were similar to placebo, and there were no clinically meaningful dose-related changes in laboratory parameters, including serum electrolytes and biomarkers of renal function.
In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. The removal of dapagliflozin by haemodialysis has not been studied.

Gemigliptin/Dapagliflozin is contraindicated in patients with/on: hypersensitivity to the active substances or to any of the excipients listed in Description, or a history of serious hypersensitivity reactions, i.e., angioedema or anaphylaxis, to another dipeptidyl peptidase-4 (DPP-4) inhibitor or sodium glucose cotransporter (SGLT) 2 inhibitor (see Precautions); type 1 diabetes or diabetic ketoacidosis; rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption; hemodialysis.

Hepatic impairment: Gemigliptin/Dapagliflozin should be used with caution as there is no experience in clinical studies in patients with severe hepatic impairment in the case of gemigliptin. There is limited experience in clinical studies in patients with hepatic impairment in the case of dapagliflozin. Dapagliflozin exposure is increased in patients with severe hepatic impairment (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cardiac impairment: There is limited clinical experience in patients with NYHA Class I, II cardiac status in the case of gemigliptin. Therefore, Gemigliptin/Dapagliflozin should be used with caution in this population. Gemigliptin/Dapagliflozin should be avoided in patients with NYHA Class III, IV cardiac status (see Dosage & Administration).
Acute pancreatitis: Pancreatitis has been reported in patients taking DPP-4 inhibitors including gemigliptin. Therefore, patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, Gemigliptin/Dapagliflozin should be discontinued and should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Use with medicinal products known to cause hypoglycemia: Patients receiving Gemigliptin/Dapagliflozin in combination with a sulfonylurea or with insulin may be at risk for hypoglycemia. Therefore, a reduction in the dose of the sulfonylurea or insulin maybe necessary.
Severe and disabling arthralgia: There have been post-marketing reports of severe and disabling arthralgia in patients taking other DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
Bullous pemphigoid: There have been post-marketing reports of bullous pemphigoid requiring hospitalization in patients taking other DPP-4 inhibitors. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Patient should be instructed to report development of blisters or erosions to their doctors while receiving Gemigliptin/Dapagliflozin. If bullous pemphigoid is suspected, Gemigliptin/Dapagliflozin should be discontinued and a dermatologist should be consulted for diagnosis and proper treatment.
Hypersensitive reactions: This medicinal product must not be used in patients who have had any serious hypersensitivity reaction to a DPP-4 inhibitor or a SGLT2 inhibitor (see Contraindications).
Severe hypersensitivity reactions have been reported in patients treated with gemigliptin post marketing, including Stevens-Johnson syndrome. If serious hypersensitivity reaction is suspected, this drug should be discontinued, other potential causes of the reaction should be identified, and administer other diabetes therapies.
Use in patients at risk for volume depletion and/or hypotension: Due to dapagliflozin's mechanism of action, this medicinal product increases diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see Pharmacology: Pharmacodynamics under Actions). It may be more pronounced in patients with very high blood glucose concentrations.
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension or elderly patients.
In case of intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption of treatment with this medicinal product is recommended for patients who develop volume depletion until the depletion is corrected (see Adverse Reactions).
Diabetic ketoacidosis: Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including dapagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/litres (250 mg/dL). It is not known if DKA is more likely to occur with higher doses of dapagliflozin.
The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.
In patients where DKA is suspected or diagnosed, treatment with this medicinal product should be discontinued immediately.
Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with dapagliflozin may be restarted when the ketone values are normal and the patient's condition has stabilised.
Before initiating treatment with this medicinal product, factors in the patient history that may predispose to ketoacidosis should be considered.
Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g. type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
The safety and efficacy of the Gemigliptin/Dapagliflozin in patients with type 1 diabetes have not been established and it should not be used for treatment of patients with type 1 diabetes. In type 1 diabetes mellitus studies with dapagliflozin, DKA was reported with common frequency.
Genital mycotic infections: Dapagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat appropriately.
Urinary laboratory assessments: Due to its mechanism of action, patients taking dapagliflozin will test positive for glucose in their urine.
Body weight loss: In placebo-controlled study of 24-week duration in subjects with inadequately controlled type 2 diabetes mellitus, dapagliflozin resulted in greater body weight reduction from baseline compared with placebo (-3.16 kg and -2.19 kg, respectively).
Lower limb amputations: An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term, clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. It is unknown whether this constitutes a class effect. It is important to counsel patients with diabetes on routine preventative foot care.
Necrotising fasciitis of the perineum (Fournier's gangrene): Post-marketing cases of necrotising fasciitis of the perineum (also known as Fournier's gangrene) have been reported in female and male patients taking SGLT2 inhibitors (see Adverse Reactions). This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.
Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier's gangrene is suspected, Gemigliptin/Dapagliflozin should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed with Gemigliptin/Dapagliflozin. However, patients should be alerted to the risk of hypoglycemia when Gemigliptin/Dapagliflozin is used in combination with other anti-diabetic medicinal products known to cause hypoglycemia (e.g. sulfonylureas).
Use in the Elderly: Elderly patients are more likely to have impaired renal function, and/or to be treated with anti-hypertensive medicinal products that may cause changes in renal function such as angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB). The same recommendations for renal function apply to elderly patients as to all patients.
Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics.
There are insufficient data to draw conclusions regarding exposure in patients ≥70 years old.

Pregnancy: No studies have been conducted with the combined active substances of Gemigliptin/Dapagliflozin. Studies in animals with gemigliptin have shown that gemigliptin was transferred to placenta and up to 48.1% and 1.6% were detected in amniotic fluids when administered to pregnant rats and rabbits, respectively, at 2 hours post dose. Studies with dapagliflozin in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy (see Pharmacology: Toxicology: Preclinical safety data under Actions). Therefore, Gemigliptin/Dapagliflozin should not be used during pregnancy. If pregnancy is detected, treatment with Gemigliptin/Dapagliflozin should be discontinued.
Breast-feeding: No studies have been conducted with the combined active substances of Gemigliptin/Dapagliflozin. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in breast-feeding offspring (see Pharmacology: Toxicology: Preclinical safety data under Actions). A risk to the newborns/infants cannot be excluded. Gemigliptin/Dapagliflozin should not be used while breast-feeding.
Fertility: No studies have been conducted with the combined active substances of Gemigliptin/Dapagliflozin. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested. Animal studies with gemigliptin do not indicate harmful effects to fertility in male and female rat.

Summary of the safety profile: In a 24-week study in type 2 diabetes mellitus patients who had inadequate blood glucose control in combination with metformin and dapagliflozin, gemigliptin 50 mg or placebo was administered once daily as an add-on combination. The table summarizes the most common (≥1.0% of patients) adverse events reported in this study. (See table.)

Click on icon to see table/diagram/image

The 24-week add-on combination therapy was extended through 52-week with gemigliptin 50 mg added on to stable dose of metformin and dapagliflozin. The new adverse events that occurred in 2 or more patients (1.30%) during the latter 28 weeks when compared with the first 24 weeks, regardless of assessment of causality, were hyperglycemia (0% vs 1.30%) and headache (0% vs. 1.30%).
Description of selected adverse reactions: Hypoglycemia: In a 24-week study in which gemigliptin 50 mg or placebo was administered once daily in patients with combination of metformin and dapagliflozin, hypoglycemia was reported in 1 patient (0.63%) in the gemigliptin 50 mg group. The hypoglycemia experienced by the patient in the clinical trial was at level 1 (hypoglycemic alert value) in severity and fully recovered, which was not related to gemigliptin 50 mg administration. During the latter 28 weeks in the extended 52-week study of gemigliptin 50 mg, 2 patients (1.30%) reported hypoglycemia. Two patients (1 patient (1 case) with level 1 and 1 patient (1 case) with level 2 (clinically significant hypoglycemia)) recovered during the clinical trial, which was not related to gemigliptin 50 mg administration.

In vitro assessment of interactions: Gemigliptin: The responsible enzyme for the metabolism of gemigliptin is CYP3A4. In vitro studies indicated that gemigliptin and its active metabolite are not inhibitors of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4 and are not inducers of CYP1A2, 2C8, 2C9, 2C19, or 3A4. Therefore, gemigliptin is unlikely to cause interactions with other drugs that utilize these metabolic pathways but maybe affected by CYP3A inhibitors or inducers. Gemigliptin mildly inhibited P-gp mediated transport at a high concentration.
Effects of gemigliptin on other medicinal products: In clinical studies, gemigliptin did not meaningfully alter the pharmacokinetics of metformin, pioglitazone and glimepiride.
Metformin: Repeated co-administration of 50 mg gemigliptin with 2000 mg metformin decreased the C_max of metformin by 13% but did not affect the area under the curve (AUC) of metformin at steady state.
Pioglitazone: Repeated co-administration of 200 mg gemigliptin with 30 mg pioglitazone, decreased the AUC and C_max of pioglitazone by 15% and 17%, respectively. However, those of the active metabolites of pioglitazone were not changed at steady state.
Glimepiride: Co-administration of multiple doses of 50 mg gemigliptin with a single dose of 4 mg glimepiride did not meaningfully alter the pharmacokinetics of glimepiride at steady state. The effect of co-administration of gemigliptin on the AUC and C_max of glimepiride was less than 3%.
Effects of other medical products on gemigliptin: In clinical studies, metformin and pioglitazone did not meaningfully alter the pharmacokinetics of gemigliptin. Ketoconazole alters the pharmacokinetics of gemigliptin and its active metabolite but extended interaction was not considered clinically significant, and no dose adjustment is required. Therefore, strong and moderate CYP3A4 inhibitors would not cause clinically meaningful drug interactions. Rifampicin (rifampin), on the other hand, significantly decreased exposure of gemigliptin. Therefore, co-administration with other strong CYP3A4 inducers, including rifampicin (rifampin), dexamethasone, phenytoin, carbamazepine, rifabutin and phenobarbital, is not recommended.
Metformin: Repeated co-administration of 50 mg gemigliptin with 2000 mg metformin did not meaningfully alter the pharmacokinetics of gemigliptin and its active metabolite at steady state. The AUC and C_max of gemigliptin were decreased by 9% and 8%, respectively, and AUC and C_max of LC15-0636 were decreased by 5%.
Pioglitazone: Repeated co-administration of 200 mg gemigliptin with 30 mg of pioglitazone did not meaningfully alter the pharmacokinetics of gemigliptin and its active metabolite at steady state. The AUC of gemigliptin was increased by 6% while C_max was decreased by 3%. The AUC and C_max of active metabolite were increased by 3% and 9%, respectively.
Ketoconazole: Co-administration of multiple doses of 400 mg ketoconazole, a strong inhibitor of CYP3A4, with a single dose of 50 mg gemigliptin increased the AUC of active moiety, the sum of gemigliptin and its active metabolite, by 1.9-fold at steady state.
Rifampicin: Co-administration of multiple doses of 600 mg rifampicin, a strong inducer of CYP3A4, with a single dose of 50 mg gemigliptin decreased the AUC and C_max of gemigliptin by 80% and 59%, respectively. The C_max of active metabolite of gemigliptin was not significantly affected while the AUC was decreased by 36% at steady state (see Contraindications and Precautions).
Dapagliflozin: Pharmacodynamics interactions: Diuretics: Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension.
Insulin and insulin secretagogues: Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with dapagliflozin in patients with type 2 diabetes mellitus.
Pharmacokinetic interactions: The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9).
In in vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolized by these enzymes.
Effect of other medicinal products on dapagliflozin: Interaction studies conducted in healthy subjects, using mainly a single-dose design, suggest that the pharmacokinetics of dapagliflozin are not altered by metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin.
Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine, phenytoin, phenobarbital) is not expected.
Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended.
Effect of dapagliflozin on other medicinal products: In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the anticoagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.
Interference with 1,5-anhydroglucitol (1,5-AG) assay: Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use of alternative methods to monitor glycemic control is advised.

Incompatibilities: Not applicable
Special precautions for disposal and other handling: Any unused product or waste material should be disposed of in accordance with local requirements.

Store at temperatures not exceeding 30°C.
Shelf life: 36 months.
Special precautions for storage: Store in the originally purchased container. Placing in container other than the ones provided by the manufacturer may lead to drug misuse or affect the quality of the drug product.

Antidiabetic Agents

A10BD30 - gemigliptin and dapagliflozin ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.

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