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Precautions for use: Patients with a history of serious hypersensitivity reactions, i.e., angioedema or anaphylaxis, to the active substances or to any of the excipients of this medication or another dipeptidyl peptidase-4 (DPP4) inhibitor.
Renal impairment (e.g., serum creatinine levels ≥15 mg/dL for men, ≥14 mg/L for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
Patients with congestive heart failure requiring medication.
Radiologic studies including the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving products containing metformin. Therefore, in patients in whom any such study is planned, this drug should be discontinued at least 48 hours prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Patients with type 1 diabetes or acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, or history of ketoacidosis (Type 1 diabetes and diabetic ketoacidosis should be treated with insulin).
Pre-diabetic coma.
Known hypersensitivity to components of this drug or biguanides.
Therapy should be temporarily suspended in patients with severe infection or traumatism and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Therapy should be temporarily discontinued 48 hours prior to any surgical procedure (except minor procedures not associated with restricted intake of food and fluids), and withheld for at least 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Debilitated, malnourished or starved patients, and those with adrenal or pituitary insufficiency.
Patients with hepatic impairment (because patients with hepatic impairment has been associated with some cases of lactic acidosis, use of this drug should be avoided in patients with clinical or laboratory evidence of hepatic impairment), pulmonary infarction, severe respiratory insufficiency, and any conditions that induce hypoxemia, excessive alcohol, dehydration, gastrointestinal symptoms such as diarrhea and vomiting.
Pregnant or potentially pregnant women and nursing mothers.
Caution should be exercised when Gemigliptin/Metformin HCl is administered to: Metformin (Possibility of lactic acidosis and hypoglycemia): Irregular diet, lack of food intake; Intense muscle exercise; Patients taking drugs that interact with metformin.
Acute pancreatitis: Pancreatitis has been reported in the patients treated with gemigliptin. Therefore, patients should be informed of the characteristic symptoms of acute pancreatitis such as persistent, severe abdominal pain. If pancreatitis is suspected, administration of gemigliptin should be discontinued and this product should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
General Precautions: Lactic Acidosis: Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with Gemigliptin/Metformin HCl and is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate concentrations (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 ug/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is fairly low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, because alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. Patients should be educated to promptly report these symptoms to their physician should they occur. If present, metformin should be withdrawn until lactic acidosis is ruled out. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measure promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.
Monitoring of renal functions: Metformin is known to be substantially excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Gemigliptin/Metformin HCl.
Before initiation of Gemigliptin/Metformin HCl and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated (for example, patients with advance age), renal function should be assessed more frequently and Gemigliptin/Metformin HCl discontinued if evidence of renal impairment is present.
Impaired hepatic function: Impaired hepatic function has been associated with some cases of lactic acidosis. Gemigliptin/Metformin HCl should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels: In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from B12-intrinsic factor complex, is, however very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. 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.
Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two-to three-year intervals may be useful.
Alcohol intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Therefore, should not consume alcohol while receiving Gemigliptin/Metformin HCl.
Surgical procedures: Therapy should be temporarily discontinued at the time of or prior to any surgical procedure (except minor procedures not associated with restricted intake of food and fluids), and should not be restarted until the patients oral intake has resumed and renal function has been evaluated as normal.
Change in clinical status of patients with previously controlled type 2 diabetes: A patient with type 2 diabetes previously well controlled on Gemigliptin/Metformin HCl who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, metformin must be stopped immediately and other appropriate corrective measure initiated.
Hypoglycemia: Gemigliptin: Hypoglycemia has been observed when gemigliptin was used in combination with a sulfonylurea. Therefore, to reduce the risk of hypoglycemia caused by sulfonylurea, a lower dose of sulfonylurea may be considered.
Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Concomitant medications affecting renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.
Radiologic studies involving the use of intravascular iodinated contrast materials: Iodinated contrast materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving this drug. Therefore, in patients in whom any such study is planned, this drug should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Hypoxic states: Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on metformin therapy, Gemigliptin/Metformin HCl should be promptly discontinued.
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: Bullous pemphigoid requiring hospitalization was reported in the post-marketing surveillance in the patients who took other DPP-4 inhibitors. The patients recovered in general after the stop of the DPP-4 inhibitors administration and the use of local or general immunosuppressants. It should be notified to the patients if the patients experience blisters or erosions, it should be notified to their doctors. If bullous pemphigoid is suspected, please stop taking this medical product and consult dermatologists for diagnosis and proper treatment.
Hypersensitivity Reaction: There have been postmarketing reports of severe hypersensitivity reactions in patients treated with gemigliptin including Stevens-Johnson syndrome. If a severe hypersensitivity reaction is suspected, discontinue this product, assess for other potential causes for the event, and initiate alternative treatment for diabetes.
The skin of tablets may come out through feces, and patients should be informed in advance that this is a normal phenomenon. The inactive portion (excipients) of this product may be excreted in the form of soft hydrates looking like the tablets through feces. If this material is found repeatedly in feces, it should be reported to the health care professional. If it was reported repeatedly by a patient that the product was found in feces, the health care professional should evaluate whether the glycemic control is being properly made.
Others: No animal studies have been conducted with the combined products in Gemigliptin/Metformin HCl to evaluate carcinogenesis, mutagenesis or impairment of fertility. The following data are based on the findings in studies with gemigliptin and metformin 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, and 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 patient 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.
Metformin: Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.
Use in Children: Safety and effectiveness in children and adolescents have not been established.
Use in the Elderly: Gemigliptin/Metformin HCl: Aging can be associated with reduced renal function. Because metformin is contraindicated in patients with renal dysfunction, renal function should be carefully monitored in the elderly and should be used with caution as age increases.
Gemigliptin: Of the total number of subjects (N=1,605) in Phase II and III clinical studies of gemigliptin, 306 patients (191%) were 65 years and over. The efficacy and safety of gemigliptin were not different between young and elderly patients. However, caution should be used in elderly patient because physiological functions including liver and kidney are usually decreased in this population.
Metformin: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of lactic acidosis to the drug is greater in patients with impaired renal function, Gemigliptin/Metformin HCl should only be used in patients with normal renal function. Because aging is associated with reduced renal function, the initial and maintenance dosing of metformin should be conservative. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function.
