for medical use
active substances: metformin hydrochloride, glimepiride;
1 tablet contains metformin hydrochloride (long-acting) 500 mg and glimepiride 1 mg or metformin hydrochloride (long-acting) 500 mg and glimepiride 2 mg;
excipients (tablets 500 mg/1 mg):Sodium carboxy methyl cellulose, Hypromellose, Microcrystalline cellulose, Magnesium Stearate, Lactose monohydrate, Croscarmellose Sodium, Hydroxy Propyl cellulose, iron oxide red (E 172);
excipients (tablets 500 mg/2 mg): Sodium carboxy methyl cellulose, Hypromellose, Microcrystalline cellulose, Magnesium Stearate, Lactose monohydrate, Croscarmellose Sodium, Hydroxy Propyl cellulose, Pigment Blend РВ-51323 green.
Pharmacotherapeutic group. Antidiabetic drugs. The combination of oral hypoglycemic drugs. ATC code А10В D02.
Indications. As an adjunct to diet and exercise for patients with insulin-independent type 2 diabetes mellitus:
- if metformin or sulfonylureas monotherapy does not provide an adequate level of glycemic control;
- shifting from combination therapy to metformin and sulfonylureas.
- Insulin-dependent type I diabetes mellitus (e.g., diabetes with ketonemia in anamnesis), diabetic ketonemia, diabetic coma and precoma, acute or chronic metabolic acidosis.
- Hypersensitivity to any of the excipients forming the drug formulation, sulphonylurea, sulfanilamide or biguanide.
- Severe liver function abnormality or hemodialysis (no experience in drug administration). In case of severe renal or hepatic function disorders, a changeover to insulin is required to achieve adequate control of blood sugar level.
- Propensity for lactic acidosis, cases of lactic acidosis in anamnesis, kidney disease or renal dysfunction (as shown, for example, by increasing in plasma creatinine ≥ 1.5 mg/dL in men and ≥ 1.4 mg/dL in women, or decreasing creatinine clearance), which can also be caused by conditions such as cardiovascular collapse (shock), acute myocardial infarction and septicemia.
- Intravenous administration of radiopaque agents containing iodine, because these drugs can cause acute renal failure (the administration of Duglimax® should be suspended) (see section “Peculiarities of use”).
- Severe infections, status before and after surgery, major trauma.
- Undernutrition, abstinence from food or exhaustion of the patient, or patients with pituitary or adrenal hypofunction.
- Abnormal liver function, severe pulmonary function disorder and other conditions, which might be accompanied by hypoxemia, excessive alcohol consumption, dehydration, gastrointestinal disorders, including diarrhea and vomiting.
- Congestive heart failure, which requires drug treatment; recent myocardial infarction, severe circulatory failure or rough breathing.
- Impaired renal function.
Dosage and administration.
The dosage of antidiabetic drugs should be individualized based on the patient's blood glucose levels
It is recommended to initiate the treatment with the lowest effective dose in the following clinical situations.
For patients whose diabetes is not controlled by sulfanilamide or metformin monotherapy the usual starting dose of this drug is 500/1 mg, which is administered 1 time per day and can be adjusted depending on the concomitant treatment with another antihyperglycemic drug, or in accordance with patient's glycemic level. When transferring from sulfonylureas with long half-life (e.g., chlorpropamide), the patient should be carefully monitored in case of hypoglycemia, because hypoglycemia may occur as a result of increasing the effect of drugs.
When transferring from combination therapy with certain tableted drugs: the usual starting dose is already taken dose of glimepiride and metformin
If necessary the dose may be increased to 3 tablets per day, maximum daily dose on the basis of 6 mg of glimepiride per day, given the applied therapy, efficacy or tolerance of the drug. In this regard blood sugar levels should be carefully monitored.
The daily dose of glimepiride over 6 mg is more effective only for a small number of patients.
The drug should be taken 1 time per day before or during breakfast or first main meal.
Mistakes in the drug administration, such as missing of regular dose administration, could never be corrected by the subsequent acceptance of higher dose.
The tablet should be swallowed whole, without breaking or chewing it.
Taking into account the experience of using the drug Duglimax® and the data about other sulphonylurea derivatives, the possibility of the following adverse effects should be considered.
Lactic acidosis: see section “Peculiarities of use”.
Hypoglycemia: see section “Peculiarities of use”.
Visual disturbance: during treatment (especially at the beginning) transitory visual disturbances due to the changes in blood sugar level may be observed.
Gastrointestinal disorders: gastrointestinal symptoms, including diarrhea, nausea, vomiting, abdominal distension, flatulence and anorexia are the most common reactions to this drug and occur about 30% more often in patients taking metformin, compared to those taking placebo, especially at the beginning of therapy with this drug. Usually, these symptoms are self-treated. Sometimes dose reduction is necessary. As the gastrointestinal symptoms at the beginning of treatment are dose-dependent, their severity may be reduced during the gradual increase of dosage by taking the drug with meal. As severe diarrhoea and/or vomiting may cause dehydration and extrarenal azotemia, the drug should be suspended in such case. For patients whose condition has been stabilized by the drug, nonspecific gastrointestinal symptoms should not be associated with the therapy, but with the intercurrent disease and lactic acidosis.
Nervous system disorders: about 3% of patients may complain of unpleasant or metallic taste at the beginning of drug therapy, but usually it is self-treated.
Hypersensitivity: sometimes – allergic or pseudoallergic reactions (such as itching, urticaria or rash). Almost in all cases such reactions are moderate, but they may progress and be accompanied by shortness of breath and arterial blood pressure fall, until the emergence of shock. In case of urticaria, seek medical attention immediately.
Blood system: there may be changes in blood picture; rarely – thrombocytopenia, in exceptional cases – leukopenia, hemolytic anemia, or erythrocytopenia, granulocytopenia, agranulocytosis, or pancytopenia. Close monitoring of the patient’s condition is required, as during the therapy with sulphonylurea there were cases of aplastic anemia and pancytopenia. In case of development of any of these phenomena, the drug should be stopped, and appropriate treatment should be started.
Asymptomatic reduction of vitamin В12 in blood serum was observed (folic acid levels in serum were not significantly decreased). Despite this, only megaloblastic anemia was registered during the drug therapy, there was no increase in the incidence of neuropathy. Therefore, careful control of level of vitamin В12 in blood serum or periodic additional parenteral administration of vitamin B12 is recommended.
Liver and biliary tract disorders: in isolated cases, increase of liver enzymes activity and liver function impairment (cholestasis and jaundice) are possible, as well as hepatitis which may progress to liver failure.
Other: in isolated cases, allergic vasculitis, photosensitization and decreased serum sodium may be observed.
In case of the above stated adverse reactions, other adverse reactions or unexpected changes, the patients should inform their physician immediately. Certain adverse reactions, including severe hypoglycemia, special hematologic changes, severe allergic and pseudoallergic reactions, and renal failure may be life-threatening if accompanied by some diseases, and in case of such reactions, the patients should inform their physician immediately and stop the drug till further medical instructions.
Overdose.As this drug contains glimepiride, its overdose may cause hypoglycemia. In case of glimepiride overdose, inform your physician immediately. If the physician has not yet prescribed the treatment of overdose, the patient should immediately take sugar, preferably in the form of glucose. The therapeutic measures mainly consist in prevention of absorption through inducing vomiting and prescription of lemonade with activated carbon (adsorbent) and sodium sulfate (laxative) to the patient
Significant overdose and severe reactions with such symptoms as loss of consciousness or other serious neurological disorders are the life-threatening conditions. In such case, urgent medical treatment and hospitalization are necessary. If hypoglycemic coma is diagnosed or suspected due to the serious overdose, it is necessary to administer for instance, a rapid intravenous injection of 40 mL of glucose 20% solution to the patient. Then, less concentrated (10%) glucose solution should be administered in the form of infusion in a quantity which permits to maintain the blood glucose level over 100 mg/dL. Alternatively, in adults glucagon may be used, for instance, in doses ranging from 0.5 mg to 1 mg intravenously, subcutaneously or intramuscularly. The patient should be constantly monitored for 24-48 hours as after the visible clinical recovery a recurrent episode of hypoglycemia is possible.
In particular, during the treatment of hypoglycemia arising from accidental intake of glimepiride in children, the prescribed dose of glucose should be carefully calculated, and the blood glucose level should be constantly monitored.
In case of intake of a big quantity of the drug, gastric lavage is recommended with subsequent use of activated carbon and sodium sulfate.
Since this drug contains metformin, it may cause lactic acidosis. In case of intake of up to 85 g of metformin hydrochloride, hypoglycemia was not observed, though the development of lactic acidosis is possible after such a dose. The drug is excreted during hemodialysis with a clearance up to 170 mL/min on condition of satisfactory hemodynamics. Therefore, hemodialysis may be used for excretion of the cumulated drug in patients with suspected overdose.
Using during pregnancy and breast-feeding. Duglimax® must not be used during pregnancy due to the possibility of adverse effects on the child. The pregnant women and the patients attempting to conceive should inform their physician. Such patients should be transferred to insulin.
To avoid getting the drug Duglimax® into the body of a child with the breast milk, women should not take the drug during breast-feeding. If it is necessary, the patient should use insulin or completely stop breast-feeding.
Children. The safety and efficacy of using the drug in children have not been ascertained.
Special precautions for use.
Precautions. Serious lactic acidosis may occur (see section “Peculiarities of use”) or hypoglycemia.
During the first week of treatment, close monitoring of the patient’s condition is required due to the high risk of hypoglycemia. The risk of hypoglycemia exists in patients with the following conditions:
- unwillingness or inability of the patient to cooperate with the physician (especially in the elderly);
- malnutrition, irregular meals, skipping meals;
- imbalance between physical activity and consumption of carbohydrates;
- changes in diet;
- using alcohol, especially accompanied by skipping meals;
- renal dysfunction (patients with renal dysfunction may be more sensitive to the glucose-lowering effect of the drug);
-severe liver dysfunction;
- overdose of the drug;
-certain decompensated diseases of endocrine system (such as thyroid dysfunction and adenohypophysis or adrenocortical failure) which affect carbohydrate metabolism and counterregulation of hypoglycemia;
- co-administration of some other drugs (see section “Interaction with other medicinal products and other types of interaction”).
In such cases close monitoring of blood sugar level is necessary, and the patient should inform his physician about the above factors and the episodes of hypoglycemia, if there were such. If there are risk factors of hypoglycemia, the dose of Duglimax® or the whole treatment regimen should be adjusted. This should also be done in case of any disease or changes in the lifestyle of the patient. The symptoms of hypoglycemia which reflect adrenergic counterregulation may be slight or absent if the development of hypoglycemia is gradual: in elderly patients, in patients with autonomic neuropathy or in those concomitantly treated with beta adrenoreceptor antagonists, clonidine, reserpine, guanethidine or other sympatholytic agents.
High risk of cardiovascular mortality. There have been reports about the connection between the use of antidiabetic drugs and the risk of cardiovascular mortality, which is higher than when using only diet therapy or diet therapy combined with insulin. This observation is based on the data of a long-term prospective clinical trial conducted within the University Group Diabetes Program (UGDP), which involved the efficacy evaluation of the glucose-lowering drugs, on prevention or delay of development of vascular complications in patients with insulin-independent diabetes. According to the data of UGDP, in patients receiving diet therapy plus treatment with a fixed dose of tolbutamide (1.5 g/day) or diet therapy plus treatment with a fixed dose of phenformin (100 mg/day) during 5-8 years cardiovascular mortality was 2.5 times higher than in patients receiving only diet therapy, which was the reason for cessation of therapy in both cases during the UGDP study. Despite the controversy in the interpretation of these data, the information received during the UGDP study provides an appropriate background for such warning. The patient should be informed about the possible risk and benefit of using metformin and about the alternative ways of treatment. Although this study involved only one drug from the group of sulfonylureas (tolbutamide) and one drug from the group of biguanide (phenformin), in terms of safety, it is appropriate to consider that this warning may also refer to other antidiabetic drugs due to the similar action and chemical structure of the drugs of each group.
Peculiarities of use.
Patients should be warned that this drug should be swallowed whole, without breaking or chewing the tablet and that the inactive ingredients can sometimes be excreted with feces in the form of mash that may resemble a tablet.
As the drug reduces blood sugar levels, it can lead to hypoglycemia, which can last for a long time, taking into account the experience of other sulfonylureas administration. Possible symptoms of hypoglycemia include headache, strong feeling of hunger (canine appetite), nausea, vomiting, apathy, drowsiness, fatigue, anxiety, disorientation, sleep disturbance, apprehension, aggressiveness, clouded sensorium, decrease in vigilance and reaction, depression, confusion, speech disturbance, aphasia, visual disturbances, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, convulsions of central genesis, drowsiness and loss of consciousness up to coma, shallow breathing and bradycardia. Moreover, there may be symptoms of adrenergic counter-regulation: hyperhidrosis, clammy skin, anxiety, tachycardia, arterial hypertension, palpitations, angina attacks and cardiac arrhythmia.
The clinical presentation of a severe attack of hypoglycemia may resemble a stroke. Patients with severe hypoglycemia require immediate therapy and medical examination, in some cases hospitalizing. Almost always it is possible to put the hypoglycemia under control by immediate carbohydrate intake (glucose or sugar, for example, a lump of sugar, fruit juice with sugar, tea with sugar, etc.). For such cases, patients should always have at least 20 g of sugar. Family members should also be informed about the risk of hypoglycemia, symptoms, treatment, and factors contributing its emergence. To prevent the risk of complications, the help of others may be needed. Artificial sweeteners are not effective to control hypoglycemia.
Lactic acidosis is a rare, but serious metabolic complication that can occur due to metformin accumulation during the drug therapy. If this condition occurs, it's fatal in 50% of cases. Lactic acidosis may also occur under certain pathophysiological conditions such as diabetes mellitus. It is always accompanied by a significant hypoperfusion of tissues and hypoxemia. Lactic acidosis is characterized by increased plasma lactate levels (>5 mmol/L), decreased blood pH, electrolyte imbalance, increased anion gap and lactate/pyruvate ratio. If lactic acidosis occurs due to metformin, metformin plasma levels are generally greater than 5 µ/ml.
The frequency of reported cases of lactic acidosis in patients receiving metformin hydrochloride is very low (0.03 cases/1000 patient-years, including about 0.015 fatal cases/1000 patient-years). The reported cases occurred primarily in diabetic patients with frank renal failure caused by renal disease as well as by decreased renal hemodynamics, very often at the background of a numerous concomitant therapeutic/surgical pathologies and administration of large amount of drugs.
The risk of lactic acidosis increases in proportion to severity of renal dysfunction and patient’s age. However, the risk of lactic acidosis in patients taking metformin can be significantly reduced by constant monitoring of kidney function and administration of the minimum effective dose of metformin.
Besides, in case of any conditions accompanied by hypoxemia or dehydration, the drug administration should be discontinued.
Due to the fact that with abnormal liver function the ability to excrete lactate may decrease, the drug should not be administrated in patients with clinical or laboratory features of liver disease. Patients should be cautioned against excessive consumption of alcohol (both single and chronic) during treatment with this drug, as alcohol increases the effect of metformin hydrochloride on lactate metabolism. What is more, the drug administration should be suspended before any studies with intravascular administration of radiocontrast dye and before any surgical intervention.
Quite often, lactic acidosis begins hardly noticeable, and is accompanied only by nonspecific symptoms, such as discomfort, myalgia, respiratory distress syndrome, hypersomnia and nonspecific abdominal syndrome. With more severe acidosis hypothermia, hypotension and resistant bradyarrhythmia may occur. Both patient and physician must be aware of how important such symptoms are. Therefore, the patient should be instructed to report immediately about the emergence of such symptoms. Investigation of such indicators as electrolytes and ketone bodies in the blood plasma, blood sugar level, blood pH, lactate and metformin concentration in the blood may also be useful. Once a patient is stabilized on any dose level of Duglimax®, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. 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 this drug do not necessarily indicate impending lactic acidosis. It 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 and lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In patients with lactic acidosis taking Duglimax®, the drug should be discontinued immediately and general supportive measures promptly instituted. As metformin hydrochloride is dialyzable (with 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.
- Optimal blood sugar level should be maintained by simultaneous dieting and physical exercise and, if necessary, by reducing body weight and with a regular administration of Duglimax®. Clinical symptoms of insufficient reduction in blood sugar levels include increasing of the urinary frequency (oliguria), excessive thirst, dry mouth and dry skin.
- The patients should be informed of the potential risks and benefits of Duglimax® administration, and of the importance of diet and regular physical exercise.
- Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. At the beginning of treatment, during the initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control.
- If the patient is treated by another physician (e.g., during hospitalization, accident, necessity to seek health care at the weekend), he must necessarily inform him about his diabetes and previous treatment.
- In exceptional stress situations (such as trauma, surgery or infection with fever), a temporary loss of glycemic control may occur, and to establish metabolic control, it may be necessary to withhold metformin and temporarily administer insulin.
- Duglimax® treatment should be started with the minimum dose. During this drug treatment it is necessary to monitor the sugar level in blood and urine. Besides, it is recommended to determine the glycosylated hemoglobin level. It is also necessary to evaluate the effectiveness of treatment, and if it is not enough, it is necessary to transfer the patient to other therapy immediately.
- Monitoring of renal function: Duglimax® 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. Therefore, the patients with serum creatinine levels above the upper limit of normal for their age should not receive this drug. In elderly patients, Duglimax® should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, renal function should be monitored regularly and generally, metformin should not be titrated to the maximum dose.
Before starting this drug and minimum every 6 months renal function should be assessed and verified as being within normal range. In patients with the anticipated development of renal dysfunction renal function should be assessed more frequently and metformin discontinued if evidence of renal impairment is present. Special caution should be exercised in the beginning of treatment with antihypertensive agents or diuretics, as well as in cases when renal function may decrease in the beginning of using NSAIDs.
- Hypoxic conditions: cardiovascular collapse (shock) of any genesis, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia may be associated with lactic acidosis and may also cause prerenal azotemia. In case of such event in patients on Duglimax® therapy, the drug should be promptly discontinued.
- Alcohol intake. Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Duglimax®.
- Liver function impairment. Since there were cases of lactic acidosis in liver impairment, this drug should generally be avoided in patients with clinical or laboratory features of hepatic disease.
- Vitamin B12 levels. During the controlled 29-weeks’ clinical trials, in almost 7% of patients receiving Duglimax® there was a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations. Such decrease might be due to interference with B12 absorption from B12-intrinsic factor complex but 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 Duglimax®, 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. For such patients, regular monitoring of vitamin B12 serum level would be useful.
- Change in clinical status of previously a controlled diabetic patient. A diabetic patient previously well controlled on metformin 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 appropriate corrective measures initiated
- Loss of control of blood glucose level: when a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. In such cases, it may be necessary to withhold metformin and temporarily administer insulin. Treatment with insulin may be started after ineffective therapy with metformin hydrochloride and sulfonylurea. Metformin hydrochloride should be stopped 48 hours before surgical operation, which requires general anesthesia. Normally metformin may be reinstituted not earlier than 48 hours after it.
- Individuals performing specific tasks. In patients working in a state of hypoxia or drive a car, the drug should be administered with caution, as lactic acidosis or serious delayed hypoglycemia may occur. To exercise caution, the patient and his family should receive complete information on the risk of lactic acidosis and hypoglycemia. Moreover, they should be informed on the importance of following the instructions on diet, regular program of physical activity and regular checks of glucose level, glycosylated hemoglobin, renal function and hematological parameters.
- The use of sulfonylureas in patients with G6PD deficiency may cause hemolytic anemia. As glimepiride belongs to sulfonylurea derivatives, caution should be exercised when using it in patients with G6PD deficiency, and the possibility of using alternative means other than sulfonylurea derivatives should be taken into account.
Use in elderly patients
Metformin is known to be substantially excreted by the kidneys. As the risk of serious adverse reactions to Duglimax® is greater in patients with impaired renal function, it should only be used in patients with normal renal function. As aging is associated with reduced renal function, metformin should be used with caution as age increases. Care should be taken in dose selection, and careful and regular monitoring of renal function is necessary.
Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if it is suspected, vitamin B12 deficiency should be excluded.
Effect on reaction rate when driving motor transport or operating other mechanisms.
Patients should be advised to take precautions whilst driving or operating mechanisms. Hypo- and hyperglycemia may decrease attention level and reaction rate, especially at the beginning of treatment or after switching to the drug, and when irregular use of this drug. This may affect the ability to drive and use mechanisms.
Interaction with other medicinal products and other forms of interaction.
If Duglimax® is taken simultaneously with certain other medicinal products, or stops them; it can lead to undesirable increase or decrease of the hypoglycemic action of glimepiride. On the basis of experience of using Duglimax® and other sulphonylureas, the possibility of interaction with other drugs should be taken into account.
This drug is metabolized by cytochrome P-450 2C9 (CYP2C9). Its metabolism is known to be influenced by concomitant administration of CYP2C9 inducers (e.g., rifampicin) or inhibitors (e.g., fluconazole).
Drugs that potentiate hypoglycemic effect.
Insulin or oral antidiabetic drugs, ACE inhibitors, allopurinol, anabolic steroids, male hormones, chloramphenicol, anticoagulants, which are derivatives of coumarin, cyclophosphamide, disopyramide, fenfluramine, phenyramidol, fibrates, fluoxetine, guanethidine, iphosphamide, MAO inhibitors, miconazole, fluconazole, para-aminosalicylic acid, pentoxifylline (in case of parenteral administration of high doses), phenylbutazone, probenecid, quinolone antibiotics, salicylates, sulfinpyrazone, sulfonamides, clarithromycin, tetracyclines, tritoqualine, trophosphamide, azapropazon, oxyphenbutazone.
Drugs that weaken hypoglycemic effect.
Acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine (adrenaline) or sympathomimetic means, glucagon, laxatives (with prolonged use), nicotinic acid (in high doses), estrogen and progestogen, oral contraceptives, phenothiazines, phenytoin, rifampicin, thyroid hormones.
Drugs that may lead to either potentiation or weakening of hypoglycemic effect.
H2 antagonists, β-blockers, clonidine and reserpine.
β-adrenoceptor blockers reduce glucose tolerance. This may result in violation of metabolic control. β-adrenoceptor blockers may increase the risk of hypoglycemia (due to violation of counter regulation).
Drugs that weaken or block the signs of adrenergic counter regulation to hypoglycemia.
Sympatholytic agents (clonidine, guanethidine and reserpine).
Single and chronic intake of alcohol may potentiate or weaken the hypoglycemic action of Duglimax®.
This drug may either potentiate or weaken the effects of coumarin derivatives.
With the simultaneous use of some drugs, hypoglycemia effect may both increase and decrease. Careful observation of patients and monitoring of blood glucose level are required in case of simultaneous use with:
- drugs that potentiate the effect: insulin, sulfonamides, sulfonylurea drugs, anabolic steroids, guanethidine, salicylates (aspirin, etc.), β-adrenoceptor blockers (propranolol, etc.) MAO inhibitors;
- drugs that weaken effect: epinephrine, sympathomimetics, corticosteroids, thyroid hormones, estrogens, oral contraceptives, thiazides and other diuretics, pyrazinamide, isoniazid, nicotinic acid, phenothiazines, phenytoin, calcium channel blockers, beta-2 agonists such as salbutamol, formotherol.
Glyburide. during the study of interactions by introducing a single dose to patients with diabetes mellitus type II, simultaneous administration of metformin and glyburide did not cause any changes in either the pharmacokinetics or in pharmacodynamics of metformin. There were reductions of the area under the curve time/concentration (AUC) and maximum serum concentration (Cmax) of glyburide, which was quite variable. Due to the fact that during the study a single dose was administered, and due to the absence of correlation between the glyburide levels in blood and its pharmacodynamic effects, there is no assurance that this interaction has clinical significance.
Furosemide. During the study of interactions between metformin and furosemide by introducing a single dose in healthy volunteers, it has been clearly demonstrated that the simultaneous use of these medical compounds affects their pharmacokinetic parameters. Furosemide increased Cmax of metformin in plasma by 15% without any significant changes in metformin renal clearance. When used with metformin, Cmax and AUC of furosemide decreased by 31% and 12%, respectively, compared to monotherapy with furosemide; and terminal half-life decreased by 32% without any significant change in furosemide renal clearance. There is no information on interaction between metformin and furosemide, when simultaneously used for a long time.
Nifedipine. During the study of interactions between metformin and nifedipine by introducing a single dose in healthy volunteers it has been clearly demonstrated that the simultaneous use of nifedipine improves Cmax and AUC of metformin in plasma by 20% and 9%, respectively, and increases the quantity of drug excreted with the urine. Metformin had almost no effect on the pharmacokinetics of nifedipine.
Cationic drugs. Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin) that are eliminated by renal tubular secretion, theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such an interaction has been observed between metformin and oral cimetidine in normal healthy volunteers in both single and multiple-dose, metformin-cimetidine drug interaction studies. In these studies, a 60% increase in peak metformin plasma concentrations, and a 40% increase in plasma metformin AUC were observed. During the single-dose study, there were no changes in half-life. Metformin had no effect on cimetidine pharmacokinetics. Despite the fact that such interactions are theoretically possible (except for cimetidine), careful patient monitoring and dose adjustment of metformin or the interfering drug is recommended in patients who are taking cationic medications that are excreted via renal tubular secretion.
Other. Somedrugs tend to produce hyperglycemia and may lead to a loss of blood sugar control. These include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to patients receiving metformin, the patient should be closely observed to maintain adequate glycemic control.
During the study of interactions by introducing a single dose in healthy volunteers, there have been no changes in pharmacokinetics of simultaneously used metformin and propranolol, and metformin and ibuprofen.
The degree of binding of metformin to plasma proteins is negligible. Therefore, its interaction with drugs that are well bound to plasma proteins, such as salicylates, sulfonamides, chloramphenicol, probenecid, is less likely than interaction with sulfonylurea, which has an extremely high degree of serum protein binding.
Metformin hydrochloride has neither primary nor secondary pharmacodynamic properties, which could lead to its non-medical use as a recreational drug or to addiction.
Glimepiride – is a substance having hypoglycemic activity when administered orally and is classified as sulfonylureas. It can be administered in insulin-independent diabetes mellitus.
The influence of glimepiride is realized by stimulating insulin release from the pancreatic β-cells. Like the other sulfonylureas, it increases the sensitivity of the pancreatic β-cells to the physiological glucose stimulation. Furthermore, glimepiride, like other sulfonylureas is likely to have a significant extrapancreatic effect.
Sulfonylurea regulates insulin secretion by closing the ATP-sensitive potassium channels in the β-cell membrane. Closing the potassium channel induces depolarization of the cell membrane and results by opening of calcium channels in an increased influx of calcium into the cell.
This leads to insulin release through exocytosis.
Glimepiride binds with a high exchange rate to a β-cell membrane protein which is associated with the ATP-sensitive potassium channel but which is different from the usual sulfonylurea binding site.
The extrapancreatic effects are for example an improvement of the sensitivity of the peripheral tissue for insulin and a decrease of the insulin uptake by the liver.
The uptake of glucose from blood into peripheral muscle and fat tissues occurs via special transport proteins located in the cells membrane. The transport of glucose in these tissues is the rate-limiting step in the use of glucose. Glimepiride increases very rapidly the number of active glucose transport molecules in the plasma membranes of muscle and fat cells, resulting in stimulated glucose uptake.
Glimepiride increases the activity of the glycosyl-phosphatidylinositol-specific phospholipase-C which may be correlated with the drug-induced lipogenesis and glycogenesis in isolated fat and muscle cells.
Glimepiride inhibits the glucose production in the liver by increasing the intracellular concentration of fructose-2.6-bisphosphate, which in its turn inhibits the gluconeogenesis.
Metformin is a biguanide with hypoglycemic effect, which manifests itself in lowering both basal level of glucose in plasma and its level in plasma after a meal. It does not stimulate insulin production; therefore, it does not provoke hypoglycemia.
Metformin may act via 3 mechanisms:
- reducing liver glucose production by inhibiting gluconeogenesis and glycogenolysis;
- in muscles: by increasing insulin sensitivity, improving of peripheral glucose uptake and utilization;
- delay of intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis, affecting glycogen synthase.
Metformin increases the ability of specific membrane transport of glucose carriers (GLUT-1 and GLUT-4).
In humans, depending on blood glucose level, metformin affects lipid metabolism. This has been shown when using the drug in therapeutic doses during controlled medium-or long-term clinical trials: metformin decreases total cholesterol level, LDL (low density lipoproteins) and triglycerides.
The bioavailability of glimepiride after oral administration is complete. Food intake has no relevant influence on absorption, only absorption rate is slightly diminished. Maximum serum concentrations (Cmax) are reached approximately 2.5 hrs. after oral intake (mean 0.3 mcg/mL during multiple dosing of 4 mg daily) and there is a linear relationship between dose and both Cmax and area under the time-concentration curve (AUC).
Glimepiride has a very low distribution volume (~8.8 L) which is roughly equal to the albumin distribution space, high protein binding (>99%), and a low clearance (~48 mL/min).
In animals, glimepiride is excreted in milk. Glimepiride is transferred to the placenta. Passage of the blood brain barrier is low.
Biotransformation and Elimination.
Mean dominant serum half-life, which is of relevance for the serum concentrations under multiple-dose conditions, is about 5-8 hrs. After high doses, slightly longer half-lives were noted.
After a single dose of radiolabelled glimepiride, 58% of the radioactivity was recovered in the urine, and 35% in the faeces. No unchanged substance was detected in the urine. Two metabolites, most probably resulting from hepatic metabolism (major enzyme is CYP2C9) were identified both in urine and faeces; the hydroxy derivative and the carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3-6 hrs. and 5-6 hrs, respectively.
Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics and the intraindividual variability was very low. There was no relevant accumulation.
Pharmacokinetics were similar in males and females, as well as in young and elderly (>65 years) patients. In patients with low creatinine clearance, there was a tendency for glimepiride clearance to increase and for average serum concentrations to decrease, most probably resulting from a more rapid elimination because of lower protein binding. Renal elimination of the 2 metabolites was impaired. Overall, no additional risk of accumulation is to be assumed in such patients.
Pharmacokinetics in 5 nondiabetic patients after bile duct surgery was similar to that in healthy persons.
After an oral dose of metformin, the time to maximum plasma concentration (Tmax) is reached in 2.5 hrs. Absolute bioavailability of metformin 500 mg is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is linear. At the recommended metformin doses and usual dosing schedules, steady-state plasma concentrations are reached within 24-48 hrs. and are generally
Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg with food, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35-min prolongation of time to peak plasma concentration were observed. The clinical relevance of such changes is unknown.
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells probably represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 L.
Biotransformation and elimination.
Metformin is excreted unchanged with the urine. No metabolites were found in humans.
Renal clearance of metformin is >400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hrs. If renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Basic physical and chemical properties:
Duglimax® (500 mg/ 1 mg): double-layer, capsule form, biconvex tablets with one pink layer and one white layer, plain on both sides; marbling is permitted;
Duglimax ® (500 mg/ 2 mg): double-layer, capsule form, biconvex tablets with one green layer and one white layer, plain on both sides; marbling is permitted.
Store below 25°С in a dark and dry place. Keep it out of reach of children.
15 tablets in blister; 2 or 4 blisters in a carton box.
Conditions of supply.
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54, Skryabina Str., Sumy, 40020, Ukraine.
Last revision date.