Instructions Duglimax tablets 500 mg + 2 mg blister No. 60
Composition
active ingredients: metformin hydrochloride, glimepiride;
1 tablet contains metformin hydrochloride (prolonged-release) 500 mg and glimepiride 2 mg;
excipients (tablets 500 mg/2 mg): sodium carboxymethylcellulose, hypromellose, microcrystalline cellulose, magnesium stearate, lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, Pigment Blend RV-51323 green.
Dosage form
Pills.
Main physicochemical properties:
Duglimax® (500 mg/2 mg): two-layer, capsule-shaped, biconvex tablets, green on one side and white on the other, smooth on both sides; marbling is allowed.
Pharmacotherapeutic group
Antidiabetic drugs. Combination of oral hypoglycemic drugs. ATC code A10B D02.
Pharmacological properties
Pharmacodynamics
Glimepiride is a substance with hypoglycemic activity when administered orally and belongs to the group of sulfonylurea derivatives. It can be used in non-insulin-dependent diabetes mellitus.
The effect of glimepiride is realized by stimulation of insulin release from pancreatic β-cells. Like other sulfonylureas, it increases the sensitivity of pancreatic β-cells to physiological glucose stimulation. In addition, glimepiride, like other sulfonylureas, is likely to have a pronounced extrapancreatic effect.
Insulin release.
Sulfonylureas regulate insulin secretion by closing ATP-sensitive potassium channels on the β-cell membrane. This closure leads to depolarization of the cell membrane, which opens calcium channels and allows large amounts of calcium to enter the cell.
This stimulates the release of insulin by exocytosis.
Glimepiride binds with high affinity to a protein on the β-cell membrane associated with the ATP-sensitive potassium channel, but not at the site to which sulfonylureas usually bind.
Extrapancreatic activity.
The extrapancreatic action consists, in particular, in increasing the sensitivity of peripheral tissues to insulin and reducing insulin uptake by the liver.
The transfer of glucose from the blood to peripheral muscle and adipose tissue occurs through special transport proteins localized on the cell membrane. It is the transport of glucose to these tissues that is the rate-limiting step in glucose uptake. Glimepiride very rapidly increases the number of active glucose transporters on the plasma membrane of muscle and adipose cells, thereby stimulating glucose uptake.
Glimepiride increases the activity of phospholipase C specific for glycosyl-phosphatidylinositol, and this may be associated with the increased lipogenesis and glycogenesis observed in isolated fat and muscle cells under the influence of this agent.
Glimepiride inhibits the formation of glucose in the liver by increasing the intracellular concentration of fructose-2,6-diphosphate, which, in turn, inhibits gluconeogenesis.
Metformin.
Metformin is a biguanide with hypoglycemic action, which is manifested by a decrease in both basal and postprandial plasma glucose levels. It does not stimulate insulin secretion and therefore does not lead to the development of hypoglycemia.
Metformin may act through three mechanisms:
by reducing glucose production by the liver by inhibiting gluconeogenesis and glycogenolysis; in muscles by increasing insulin sensitivity, improving peripheral glucose uptake and utilization; and by delaying glucose absorption in the intestine.
Metformin stimulates intracellular glycogen synthesis by affecting glycogen synthase.
Metformin increases the transport capacity of specific membrane glucose transporters (GLUT-1 and GLUT-4).
In humans, metformin has an effect on lipid metabolism, independent of blood glucose levels. This has been shown at therapeutic doses in controlled, medium- or long-term clinical trials: metformin reduces total cholesterol, LDL (low-density lipoprotein) and triglycerides.
Pharmacokinetics
Absorption.
After oral administration of metformin, the time to reach maximum plasma concentration (tmax) is 2.5 hours. Absolute bioavailability of metformin at a dose of
After oral administration of 500 mg to healthy volunteers, the unabsorbed fraction recovered in the feces was approximately 20-30%.
Absorption of metformin after oral administration is saturable and incomplete. The pharmacokinetics of metformin absorption are assumed to be linear. Under normal conditions of metformin doses and dosing regimens, steady-state plasma concentrations are reached within 24-48 hours and are usually no more than 1 μg/ml. In controlled clinical studies, Cmax of metformin in plasma did not exceed 4 μg/ml, even at the highest doses.
Food intake reduces the extent and slightly prolongs the time of absorption of metformin. After administration of a dose of 850 mg with food, a 40% decrease in plasma Cmax, a 25% decrease in AUC, and a 35-minute prolongation of tmax were observed. The clinical significance of these changes is unknown.
Binding to blood proteins is insignificant. Metformin is distributed in erythrocytes. Cmax in blood is lower than Cmax in plasma and is reached in approximately the same time. Red blood cells are probably a secondary depot of distribution. The mean Vd ranges from 63-276 l.
Biotransformation and elimination.
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the terminal elimination half-life is approximately 6.5 hours. If renal function is impaired, renal clearance decreases in proportion to creatinine clearance, resulting in a prolonged elimination half-life, leading to increased metformin plasma levels.
Indication
As an adjunct to diet and exercise for patients with non-insulin-dependent type 2 diabetes:
if monotherapy with sulfonylureas or metformin does not provide adequate glycemic control; when replacing combination therapy with sulfonylureas and metformin.
Contraindication
Insulin-dependent type 1 diabetes mellitus (e.g. diabetes with a history of ketonaemia), diabetic ketonaemia, diabetic coma and precoma. Hypersensitivity to any of the excipients of this medicinal product or to sulphonylureas, sulphonamides or biguanides. Hepatic failure, severe hepatic impairment or patients on haemodialysis. In case of severe hepatic and renal impairment, the patient should be switched to insulin to achieve adequate blood sugar control. Renal failure, renal disease or renal impairment (as evidenced, for example, by an increase in plasma creatinine ≥ 1.5 mg/dl in men and ≥ 1.4 mg/dl in women or impaired creatinine clearance), which may also be caused by conditions such as cardiovascular collapse (shock), acute myocardial infarction and septicaemia. Congestive heart failure requiring medical treatment; recent myocardial infarction; cardiovascular collapse or respiratory failure. Radiological examinations using intravascular administration of iodinated contrast agents (e.g. intravenous urography, intravenous cholangiography, angiography and computed tomography (CT) with intravascular administration of contrast agents). The use of examination methods with intravascular administration of iodinated contrast agents may lead to acute renal failure and be accompanied by the development of lactic acidosis in patients receiving metformin. Therefore, the use of Duglimax® in patients who are scheduled for any of these examinations should be temporarily discontinued 48 hours before the procedure and resumed no earlier than 48 hours after the procedure and only after re-evaluation of renal function and confirmation that it is within normal limits. Severe infections, conditions before and after surgical interventions. Duglimax® should be temporarily discontinued for the duration of any surgical procedure (except for minor procedures that do not require food or fluid restriction). It should not be resumed until the patient has regained oral intake and renal function has been assessed to be within normal limits. Malnutrition, starvation or exhaustion, as well as hypofunction of the pituitary or adrenal glands. Impaired liver function (since impaired liver function has been associated with isolated cases of lactic acidosis, the use of this drug should be avoided in patients with clinical or laboratory evidence of liver disease), pulmonary infarction, severe pulmonary dysfunction and other conditions likely to be associated with hypoxemia (such as cardiac or respiratory failure, recent myocardial infarction, shock), excessive alcohol consumption, dehydration, gastrointestinal disorders including diarrhea and vomiting.
Interaction with other medicinal products and other types of interactions
Glimepiride.
If a patient taking Duglimax® simultaneously receives certain other drugs or stops taking them, this may lead to both an undesirable increase and a decrease in the hypoglycemic effect of glimepiride. Based on the experience with the use of Duglimax® and other sulfonylurea derivatives, the possibility of interactions of Duglimax® with other drugs should be taken into account.
This drug is metabolized by cytochrome P450 2C9 (CYP2C9). Its metabolism is known to be affected by concomitant administration of CYP2C9 inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole).
Insulin or oral antidiabetic drugs, ACE inhibitors, allopurinol, anabolic steroids, male sex hormones, chloramphenicol, coumarin-derived anticoagulants, cyclophosphamide, disopyramide, fenfluramine, phenyramidol, fibrates, fluoxetine, guanethidine, ifosfamide, MAO inhibitors, miconazole, fluconazole, para-aminosalicylic acid, pentoxifylline (when administered parenterally in high doses), phenylbutazone, probenecid, quinolone antibiotics, salicylates, sulfinpyrazone, sulfonamide, clarithromycin, tetracyclines, tritoqualine, trofosfamide, azapropazone, oxyphenbutazone, sympatholytics.
Medications that reduce the blood sugar-lowering effect.
Acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine (adrenaline) or sympathomimetics, glucagon, laxatives (with prolonged use), nicotinic acid (in high doses), estrogens and progestogens, oral contraceptives, phenothiazines, phenytoin, rifampicin, thyroid hormones, chlorpromazine, isoniazid.
Medications that can both enhance and reduce the blood sugar-lowering effect.
H2 receptor antagonists, clonidine and reserpine.
Beta-blockers reduce glucose tolerance. This may lead to impaired metabolic control. Beta-blockers may increase the risk of hypoglycemia (due to impaired counterregulation).
Drugs that weaken or block the signs of adrenergic counterregulation of hypoglycemia.
Sympatholytic agents (e.g. β-adrenergic blockers, clonidine, guanethidine and reserpine).
Both single and continuous alcohol consumption can increase or decrease the blood sugar-lowering effect of Duglimax® in an unpredictable manner.
This drug can both enhance and weaken the effects of coumarin derivatives.
Bile acid sequestrants: Colesevelam binds to glimepiride and reduces the absorption of glimepiride from the gastrointestinal tract. No interaction was observed when glimepiride was administered at least 4 hours before colesevelam. Therefore, glimepiride should be administered at least 4 hours before colesevelam.
Metformin hydrochloride.
When used simultaneously with some medications, the blood sugar-lowering effect may be either increased or decreased. Careful observation of the patient and control of blood sugar levels are necessary in case of simultaneous use with:
drugs that enhance the effect: insulin, sulfonamides, sulfonylureas, alpha-glucosidase inhibitor (acarbose), anabolic steroids, guanethidine, salicylates (aspirin and others), β-adrenoceptor blockers (propranolol and others), MAO inhibitors, angiotensin-converting enzyme inhibitors; drugs that reduce the effect: adrenaline, sympathomimetics, corticosteroids, thyroid hormones, estrogens, oral contraceptives, thiazides or other diuretics, pyrazinamide, isoniazid, nicotinic acid, phenothiazines, phenytoin, calcium channel blockers, beta-agonists such as salbutamol, formoterol.
Glyburide: In a single-dose interaction study in patients with type 2 diabetes, coadministration of metformin and glyburide did not alter the pharmacokinetics or pharmacodynamics of metformin. A decrease in the area under the time-concentration curve (AUC) and maximum serum concentration (Cmax) of glyburide was observed, which was quite variable. Because of the single-dose nature of the study and the lack of correlation between glyburide blood levels and its pharmacodynamic effects, it is uncertain whether this interaction is clinically relevant.
Furosemide: In a single-dose interaction study of metformin and furosemide in healthy volunteers, it was clearly demonstrated that co-administration of these medicinal products affects their pharmacokinetic parameters. Furosemide increased metformin plasma Cmax by 22% and blood AUC by 15% without any significant changes in metformin renal clearance. When used with metformin, furosemide Cmax and AUC decreased by 31% and 12%, respectively, compared with furosemide monotherapy, and the terminal half-life decreased by 32% without any significant changes in furosemide renal clearance. There is no information on interactions between metformin and furosemide with long-term use.
Nifedipine: In a single-dose interaction study between metformin and nifedipine in healthy volunteers, co-administration of nifedipine was shown to increase metformin plasma Cmax and AUC by 20% and 9%, respectively, and to increase the amount of drug excreted in the urine. No changes in Tmax or half-life were observed. Nifedipine did not enhance the absorption of metformin. Metformin had little effect on the pharmacokinetics of nifedipine.
Cationic drugs: Cationic drugs (e.g. amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin) that are excreted by the kidneys by tubular secretion are theoretically capable of interacting with metformin by competing for the common renal tubular transport system. This interaction between metformin and cimetidine when administered orally was observed in studies of interactions between metformin and cimetidine after single and multiple administration of the drugs in healthy volunteers. These studies demonstrated a 60% increase in metformin Cmax in plasma and whole blood, as well as a 40% increase in metformin AUC in plasma and whole blood. No changes in the half-life were observed in a single-dose study. Metformin did not affect the pharmacokinetics of cimetidine. Although such interactions are theoretically possible (with the exception of cimetidine), patients should be carefully monitored and the dose of metformin and/or the interacting drug adjusted when taking cationic drugs that are excreted by the proximal renal tubule.
In a single-dose interaction study in healthy volunteers, the pharmacokinetics of metformin and propranolol, as well as metformin and ibuprofen, were not altered by concomitant administration of these drugs.
The degree of binding of metformin to plasma proteins is insignificant. Therefore, its interaction with drugs that bind well to plasma proteins, such as salicylates, sulfonamides, chloramphenicol, probenecid, is less likely than with sulfonylureas, which have a high degree of binding to serum proteins.
Alcohol.
Increased risk of lactic acidosis in acute alcohol intoxication, especially in the case of:
starvation or malnutrition, liver failure.
It is necessary to avoid the use of alcohol and medications containing alcohol.
Iodinated contrast agents.
Intravascular administration of iodinated contrast media may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis.
Metformin should be discontinued prior to or during the procedure and not resumed for 48 hours after the procedure until renal function has been fully assessed and normal renal function has been confirmed (see section: Precautions).
Application features
General precautions
Patients should be advised that the tablet of this drug should be swallowed whole, without crushing or chewing, and that the inactive ingredients may sometimes be excreted in the feces as a soft mass that may resemble a tablet.
Hypoglycemia
Since the drug lowers blood sugar levels, it may lead to the development of hypoglycemia, which, based on the experience of using other sulfonylureas, may recur. Therefore, the patient should remain under close medical supervision. Possible symptoms of hypoglycemia include headache, a strong feeling of hunger ("wolf" appetite), nausea, vomiting, apathy, falling asleep, restlessness, sleep disturbances, anxiety, aggressiveness, impaired concentration, decreased alertness and reaction, depression, confusion, speech disorders, aphasia, visual impairment, tremor, paresis, sensory disorders, dizziness, helplessness, loss of self-control, delirium, central convulsions, drowsiness and loss of consciousness up to coma, shallow breathing and bradycardia. In addition, signs of adrenergic counterregulation may occur: excessive sweating, clammy skin, feelings of anxiety, tachycardia, hypertension, palpitations, angina attacks and cardiac arrhythmias.
The clinical picture of a severe hypoglycemic attack may resemble a stroke. Patients with severe hypoglycemia require immediate medical treatment and examination, and in some cases, hospitalization. Hypoglycemia can almost always be controlled quickly by immediate ingestion of carbohydrates (glucose or sugar, e.g., a sugar cube, fruit juice with sugar, tea with sugar). Patients should carry at least approximately 20 g of sugar for such cases. Patients and their family members should be informed about the risk of hypoglycemia, its symptoms, treatment, and factors that contribute to its occurrence. Assistance from others may be needed to prevent complications. Artificial sugar substitutes are ineffective for controlling hypoglycemia.
unwillingness or inability of the patient to cooperate with the doctor (especially in the elderly); malnutrition, irregular eating, skipping meals; imbalance between physical activity and carbohydrate intake; changes in diet; alcohol consumption, especially in combination with skipping meals; impaired renal function (patients with impaired renal function may be more sensitive to the glucose-lowering effect of this drug); overdose of the drug; certain non-metabolic diseases of the endocrine system (for example, thyroid dysfunction and adenohypophyseal or adrenocortical insufficiency), which affect carbohydrate metabolism and counterregulation of hypoglycemia;
simultaneous use of certain other medicines (see section "Interaction with other medicines and other types of interactions").
In the presence of factors that increase the risk of hypoglycemia, the dose of Duglimax® or the entire treatment regimen should be adjusted. This should also be done in the event of any disease or change in the patient's lifestyle. Symptoms of hypoglycemia, reflecting adrenergic counterregulation, may be smoothed out or completely absent in cases where hypoglycemia develops gradually: in elderly patients, in patients with autonomic neuropathy or in those who are simultaneously receiving treatment with sympatholytics.
Lactic acidosis.
Lactic acidosis is a rare but serious metabolic complication that develops as a result of metformin accumulation during treatment with this drug. If this condition occurs, it is fatal in almost 50% of cases. Lactic acidosis can also occur in certain pathophysiological conditions, such as diabetes mellitus, as well as in any condition accompanied by significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by an increase in blood lactate levels (≥ 5 mmol/L), a decrease in blood pH, electrolyte imbalance, an increase in the anion gap, and an increase in the lactate/pyruvate ratio. In cases where lactic acidosis is caused by metformin, the level of metformin in plasma is usually greater than 5 μg/mL.
The incidence of reported cases of lactic acidosis in patients taking metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, including approximately 0.015 fatalities/1000 patient-years). The reported cases occurred predominantly in diabetic patients with severe renal insufficiency, caused by both renal damage and decreased renal hemodynamics, very often with multiple concomitant therapeutic/surgical pathologies and the use of a large number of drugs.
The risk of lactic acidosis increases with the severity of renal dysfunction and the age of the patient. However, the risk of lactic acidosis in patients taking metformin can be significantly reduced by continuous monitoring of renal function and the use of the minimum effective dose of metformin.
In addition, if any conditions accompanied by hypoxemia or dehydration occur, this medication should be discontinued.
Since the ability to excrete lactate may be reduced in patients with impaired liver function, the drug should not be used in patients with clinical or laboratory evidence of liver disease. Patients should be advised against excessive alcohol consumption (both occasional and chronic) during treatment with this drug, as alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, the drug should be temporarily discontinued before any studies involving intravascular administration of radiocontrast agents and before any surgical intervention.
The occurrence of lactic acidosis should be suspected in any diabetic patient who has metabolic acidosis and no signs of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a condition requiring urgent inpatient treatment. In patients with lactic acidosis receiving Duglimax®, it should be immediately discontinued and the necessary general supportive measures should be immediately taken. Due to the fact that metformin hydrochloride is dialyzable (with a clearance of up to 170 ml/min under adequate hemodynamic conditions), immediate hemodialysis is recommended to correct the acidosis and remove accumulated metformin. Such therapeutic measures quite often contribute to the rapid disappearance of symptoms and recovery of the patient.
Optimal blood sugar levels should be maintained through diet and exercise, and when necessary, weight loss, and regular use of this medication. Clinical symptoms of insufficient blood sugar control include increased frequency of urination, excessive thirst, polydipsia, and dry skin.
Patients should be informed of the benefits and potential risks associated with the use of this drug, as well as the importance of diet and regular exercise. The importance of positive patient cooperation with the healthcare professional should be emphasized.
Response to all diabetes treatments should be monitored by periodic determinations of fasting glucose and glycosylated hemoglobin levels with the aim of reducing these levels to normal. At the beginning of treatment with an established dose, fasting glucose levels can be used to determine therapeutic response. Both glucose and glycosylated hemoglobin concentrations should be monitored thereafter. Glycosylated hemoglobin determinations may be particularly useful in assessing long-term control.
If the patient receives treatment prescribed by another doctor or pharmacist (for example, during hospitalization, accident, need to seek medical attention on weekends), he must inform him about his diabetes and previous treatment.
In exceptional stressful situations (e.g. trauma, surgery, infectious disease with fever), blood sugar regulation may be impaired, and temporary transfer to insulin may be necessary to ensure adequate metabolic control.
Treatment should be initiated at the lowest effective dose. During treatment with this drug, blood and urine sugar levels should be monitored regularly. In addition, it is recommended to determine the level of glycosylated hemoglobin. It is also necessary to assess the effectiveness of treatment, and if it is insufficient, the patient should be immediately transferred to another therapy.
Monitoring of renal function: Duglimax® is known to be excreted primarily by the kidneys, therefore the risk of metformin accumulation and lactic acidosis increases in proportion to the severity of renal pathology. Therefore, patients with serum creatinine levels above the upper limit of normal for their age should not take this drug. Elderly patients require careful titration of the dose of Duglimax® in order to determine the minimum dose that exhibits an adequate glycemic effect, since renal function decreases with age. In elderly patients, renal function should be monitored regularly, and this drug should usually not be titrated to the maximum dose.
Before starting treatment with this drug, and at least once a year, it is necessary to assess renal function and confirm their normal functioning. In patients who are expected to develop renal dysfunction, renal function should be assessed more frequently and if there are signs of renal failure, treatment with the drug should be discontinued. Particular caution is required at the beginning of treatment with antihypertensive drugs or diuretics, as well as in cases where renal function may decrease at the beginning of taking non-steroidal anti-inflammatory drugs.
This medicinal product should only be prescribed to patients who have been diagnosed with diabetes mellitus. They should be distinguished from patients with diseases accompanied by diabetes-like symptoms (renal diabetes, impaired glucose metabolism of the elderly, thyroid dysfunction), including impaired glucose tolerance or positive results of the analysis for the presence of glucose in the urine.
For some patients, oral antidiabetic agents may no longer be needed or the dose may need to be reduced. In many patients, the effectiveness of oral antidiabetic agents decreases over time due to progression of the underlying disease or infectious complications. Therefore, the question of continued therapy with such agents, their doses, and concomitant therapies should be determined in the light of food intake, changes in body weight, blood glucose levels, and the presence of infections.
Alcohol consumption: Alcohol is known to potentiate the effects of metformin on lactate metabolism. Therefore, patients should be cautioned against excessive, single or chronic alcohol consumption while taking Duglimax®.
Hepatic impairment: Since cases of lactic acidosis have been observed in patients with hepatic impairment, this drug should generally not be prescribed to patients with clinical or laboratory evidence of liver disease.
Vitamin B12 levels: In controlled clinical trials lasting 29 weeks, approximately 7% of patients taking the combination of metformin hydrochloride and glimepiride experienced a decrease in serum vitamin B12 levels below normal, without any clinical manifestations. This decrease is likely due to the effect of the vitamin B12-intrinsic factor complex on vitamin B12 absorption, but is very rarely associated with anemia and resolves relatively quickly upon discontinuation of this drug or administration of vitamin B12.
Patients taking Duglimax® are recommended to have a blood test annually, and if abnormalities are detected, undergo the necessary examination and treatment.
Some individuals (with inadequate intake or absorption of vitamin B12 or calcium) are prone to low vitamin B12 levels. For such patients, regular determination of serum vitamin B12 levels every 2-3 years may be beneficial.
Change in clinical status of a patient with previously controlled diabetes mellitus: If laboratory abnormalities or clinical signs of the disease (especially if they are vague) occur in a patient previously controlled on metformin hydrochloride tablets, the patient should be evaluated immediately for ketoacidosis and lactic acidosis. Serum electrolytes and ketone bodies, blood sugar levels, and, if indicated, blood pH, lactate, pyruvate, and metformin levels should be determined. If any form of acidosis occurs, Duglimax should be discontinued immediately and other appropriate corrective measures initiated.
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients should be warned about the need to be careful when driving a vehicle and operating machinery. Hypo- and hyperglycemia may reduce alertness and reaction speed, especially at the beginning or after a change in treatment and in case of irregular administration of this drug. This may affect the ability to drive a vehicle and operate machinery.
Use during pregnancy or breastfeeding
Duglimax should not be taken during pregnancy. Animal studies have shown teratogenicity of the combination of metformin with glimepiride, and a risk of lactic acidosis has been reported. Pregnant women and patients planning to become pregnant should inform their doctor. Such patients should be transferred to insulin to maintain blood glucose levels as close to normal as possible to reduce the risk of fetal malformations associated with abnormal blood glucose levels.
Studies in lactating rats have shown that metformin and glimepiride are excreted in breast milk. The drug should not be taken by women who are breastfeeding. If necessary, the patient should use insulin or completely stop breastfeeding.
Method of administration and doses
The dose of antidiabetic drugs should be selected individually, taking into account the patient's blood sugar level.
It is recommended that the starting dose of this drug be administered at the lowest effective dose in the clinical situations listed below.
For patients whose diabetes is not controlled with sulfonylurea or metformin monotherapy: the usual starting dose of this drug is 1 mg/500 mg, administered once daily, which may be adjusted depending on concomitant therapy with another hypoglycemic agent or according to the patient's glycemia level. When transferring from sulfonylureas with a long half-life (e.g. chlorpropamide), the patient should be carefully observed for hypoglycemia, as m
