Amaryl M

Glimepiride, metformin HCl.

Each tablet Amaryl M 1/250 mg contains, as active ingredient, 1 mg glimepiride and 250 mg Metformin Hydrochloride.
Each tablet Amaryl M 2/500 mg contains, as active ingredient, 2 mg glimepiride and 500 mg Metformin Hydrochloride.

Pharmacological Class: Glimepiride: Antidiabetic. Sulfonylurea. Metformin: Antidiabetic. Biguanide. ATC code: A10BD02.
Pharmacology: Glimepiride, the active ingredients of Amaryl M is a blood sugar-lowering agent belonging to the sulfonylurea group. The decrease in blood sugar is achieved principally by means of the stimulation of insulin release from pancreatic β-cells. This effect is predominantly based on improved responsiveness of these cells to the physiological glucose stimulus. Glimepiride augments the normal action of insulin on peripheral glucose uptake. Moreover, it mimics such action as well as the glucose output of the liver. Good metabolic control over 24 hours can be achieved with a single dose of Amaryl M. In patients with insufficient response to the maximum dose, combined use with an additional oral antidiabetic containing metformin or with insulin improves metabolic control.
Metformin, the active ingredients of Amaryl M, is a blood sugar-lowering agent belonging to the biguanide group. The decrease in blood sugar is achieved principally by not increasing insulin secretion. Moreover, metformin is not metabolized in the liver; excretion is through urine and feces.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: 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 900mg/kg/day and 1500mg/kg/day, respectively. These doses are both approximately three times the maximum recommended human daily dose on a body surface area basis. 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. However, an increased incidence of benign stromal uterine polyps was seen in female rats treated with 900 mg/kg/day.
No evidence of a mutagenic potential of metformin was found in the Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), chromosomal aberration test (human lymphocytes), or in vivo micronuclei formation test (mouse bone marrow).
Fertility of male or female rats was unaffected by metformin administration at doses as high as 600 mg/kg/day, or approximately two times the maximum recommended human daily dose on a body surface area basis.
Drug abuse and dependence: Metformin hydrochloride product possesses no pharmacodynamics properties, either primary or secondary, which could be expected to result in abuse as a recreational drug or addiction.

As an adjunct to diet and exercise in NIDDM (type 2) patients: In case that the monotherapy with glimepiride or metformin do not result in adequate glycemic control.
Replacement of glimepiride and metformin combination therapy.

The dosage of anti-diabetic drugs should be individualized based on the patient's blood glucose levels. Generally, it should be recommended to initiate the lowest effective dose and increase the dose depending on the patient's blood glucose levels. Adequate monitoring of blood glucose levels should be performed for this. It should be administered once or twice per day before or with the meals. When switching from combination therapy of glimepiride plus metformin as separate tablets, AMARYL M should be administered on the basis of dosage currently being taken.

Signs and Symptoms: For Glimepiride: Acute overdosage as well as long-term treatment with too high a dose of glimepiride may lead to severe life-threatening hypoglycaemia.
Management: In case of overdosage with glimepiride, a doctor must be notified immediately. At the first signs of hypoglycaemia, the patient must immediately take sugar, preferably glucose, unless a doctor has already started care. Since hypoglycaemia and its clinical symptoms may recur after apparent clinical recovery (even after several days), close and continued medical supervision and possibly referral to a hospital are indicated. In particular, significant overdosage and severe reactions, e.g. with unconsciousness or other neurological dysfunctions, are emergency cases and require immediate care and hospitalization.
If hypoglycaemic coma is diagnosed or suspected, intravenous infusion of a 20 % glucose solution (adults: 40 to 100 ml) is indicated. Alternatively IV, SC, or IM administration of glucagons (adults: 0.5 to 1 mg) may be considered. In infants, glucose must be dosed very carefully and close monitoring of blood glucose is required to minimize the risk of potentially severe hyperglycaemia.
Patients who have ingested life-threatening amounts of glimepiride require detoxification (e.g. by gastric lavage and medicinal charcoal).
After acute glucose replacement has been completed it is usually necessary to give an intravenous glucose infusion in lower concentration so as to ensure that the hypoglycaemia does not recur. The patient's blood glucose level should be carefully monitored for at least 24 hours. In severe cases with a protracted course, hypoglycaemia, or the danger of slipping back into hypoglycaemia, may persist for several days.
For Metformin: Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. Metformin is dialyzable with a clearance of up to 170mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
Pancreatitis may occur in the context of a metformin overdose.

Insulin-dependent (type I) diabetes (e.g., diabetics with a history of ketonemia), diabetic ketonemia, diabetic coma or precoma, acute or chronic metabolic acidosis.
Known hypersensitivity to any of the excipients of this drug, sulfonylureas, sulfonamides, or biguanide.
There is no experience in patients with severe hepatic dysfunction or hemodialysis. In case of severe hepatic or renal function disorders, a change-over to insulin is required to achieve adequate control of blood glucose.
Pregnant women, women of child-bearing potential, nursing mother.
Patients susceptible to lactic acidosis, patients with a history of lactic acidosis, renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
This drug should be temporarily discontinued in patients being administered iodinated contrast materials intravenously, because use of such products may result in acute alteration of renal function. (See Warnings and Precautions.)
Severe infections, before and after surgery, serious trauma.
Malnourished, starving, or debilitated patients, or patients with pituitary or adrenal insufficiency.
Hepatic dysfunction, severe lung dysfunction, other condition likely to be with hypoxemia, excessive alcohol intake, dehydration, gastrointestinal disturbance including diarrhea and vomiting.
Congestive heart failure requiring pharmacologic treatment.

For Glimepiride: In exceptional stress-situations (e.g., trauma, surgery, febrile infections) blood glucose regulation may deteriorate, and a temporary change to insulin may be necessary to maintain good metabolic control.
For Metformin: Lactic acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with this drug. When it occurs, it 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 levels (>5mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5μ g/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patients-years, with approximately 0.015 fatal cases/1000 patients-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal multiple concomitant medical/surgical problems and multiple concomitant medications.
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 and by use of the minimum effective dose of metformin. In addition, this drug should be withheld in the presence of any condition associated with hypoxemia or dehydration.
Because impaired hepatic function may significantly limit the ability to clear lactate, this drug should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking this drug, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, this drug should be temporarily discontinued prior to any intravascular radio-contrast 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. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur.
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 this drug, gastrointestinal symptoms, which are common during initiation of therapy with metformin, 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 5mmol/L in patients taking this drug 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 (ketouria 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 this drug, the drug should be discontinued immediately and general supportive measures 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.
Administration of iodinated contrast agent: Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with contrast materials): Intravascular contrast studies iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving this drug (see Contraindications). Therefore, in patients in whom any such study is planned, this drug should be discontinued at the time of or prior to the procedure, and withheld for 48hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. See Contraindications and Interactions.
Surgery: This drug therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Increased risk of cardiovascular mortality: The administration of oral hypoglycemic drug has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP) to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes.
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) or phenformin (100 mg/day) had a rate of cardiovascular mortality 2.5 times that of patients treated with diet alone and it resulted in discontinuation of the use of tolbutamide or phenformin. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glimepiride and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) and one drug in the biguanide class (phenformin), it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

For Glimepiride: Careful monitoring should be required during the first treatment week because of increased risk of hypoglycemia. The patients or conditions at risk of hypoglycemia are as follows: Unwillingness or incapacity of the patient to cooperate (more commonly on older patients).
Undernourishment, irregular mealtimes, skipped meals.
Imbalance between physical exertion and carbohydrate intake.
Alterations of diet.
Consumption of alcohol, especially in combination with skipped meals.
Impaired renal function.
Severe impairment of liver function.
Overdosage with glimepiride.
Certain uncompensated disorders of the endocrine system (e.g., disorders of thyroid function and in anterior pituitary or adrenocortical insufficiency): affecting carbohydrate metabolism or counter-regulation of hypoglycemia.
Concurrent administration of certain other medicines.
In these cases, close monitoring of blood glucose is necessary and patients should inform their doctors or pharmacists of these factors and if they had the symptoms of hypoglycemia. If such risk factors of hypoglycemia are present, it may be necessary to adjust the dosage of this drug or the entire therapy. This also applies whenever illness occurs during therapy or the patient's life style changes.
Those symptoms of hypoglycemia which reflect the body's adrenergic counter-regulation (see Adverse reactions) may be milder or absent where hypoglycemia develops gradually, in the elderly, and where there is autonomic neuropathy or where the patient is receiving concurrent treatment with beta-blockers, clonidine, reserpine, guanethidine, or other sympatholytic drugs.
Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.
For Metformin: Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism (see Adverse Reactions).
Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended (see Adverse Reactions).
General precautions: Adequate blood glucose levels should be maintained concomitantly by diet and exercise, if necessary by weight loss as well as by taking this drug regularly. Clinical signs is not adequately controlled blood glucose levels include oliguria, thirst, dipsia, dry skin, and etc.
Patients should be informed of the potential risks and advantage of this drug. They should also be informed about the importance of adherence to dietary instructions and of a regular exercise program. It should be emphasized that patient's positive cooperation is important.
Hypoglycemia can almost always be promptly controlled by immediate intake of carbohydrates (glucose or sugar, e.g., lump sugar, fruit juice including sugar, tea including sugar, and etc). Patients should carry approximately at least 20 g of sugar for this. Other's help may be necessary to avoid the complications. Artificial sweeteners have no effect.
If a patient receives a treatment from other physician or pharmacist (e.g., hospitalization, accident, needed to see a doctor a day off, and etc), he should inform him (or her) of his current diabetic situation and previous treatment.
The dosage of this drug must be the lowest. Treatment with this drug requires regular monitoring of glucose levels in blood and urine. (In addition, determination of the proportion of glycosylated hemoglobin is recommended.) The effectiveness of therapy should be assessed and if not satisfactory, switch to another therapy should be promptly made.
Monitoring of renal function: This drug 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 this drug. In patients with advanced age, this drug 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, this drug should not be titrated to the maximum dose.
Use of concomitant medications that may affect 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 this drug, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.
Hypoxic states: Cardiovascular collapse (shock) from whatever cause, 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 this drug therapy, the drug should be promptly discontinued.
Vitamin B12 levels: A decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, is observed in approximately 7% of patients receiving this drug in controlled clinical trials of 29 weeks duration. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of this drug or vitamin B12 supplementation. Measurement of hematological parameters on an annual basis is advised in patients on this drug 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.
Laboratory Tests: 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. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Therefore, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control. Periodic monitoring of hematological 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 this is suspected, vitamin B12 deficiency should be excluded.
Change in clinical status of previously controlled diabetic: A diabetic patient previously well controlled on metformin hydrochloride tablets 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, this drug must be stopped immediately and other appropriate corrective measures initiated.
Information for patients: Patients should be informed of the potential risks and advantages of this drug and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function and hematological parameters.
The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the Warnings and General precautions previously should be explained to patients. Patients should be advised to discontinue this drug immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of this drug, 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.
Metformin alone does not usually cause hypoglycemia, although it may occur when metformin is used in conjunction with oral sulfonylureas. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients.
Effects on Ability to Drive and Use Machines: For Glimepiride: Alertness and reactions may be impaired due to hypo- or hyperglycaemia, especially when beginning or after altering treatment or when glimepiride is not taken regularly. This may, for example, affect the ability to drive or to operate machinery.
For Metformin: Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.
However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (sulfonylureas, insulin, meglitinide).
Use in Children: Safety and effectiveness in pediatric patients have not been established. Studies in maturity-onset diabetes of the young (MODY) have not been conducted.
Use in Elderly: Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, it should only be used in patients with normal renal function. Because aging is associated with reduced renal function, metformin should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin.

Pregnancy: For Glimepiride: This drug must not be taken during pregnancy. Otherwise there is risk of harm to the child. Pregnant patient or the patient planning a pregnancy must inform their physician. It is recommended that such patients change over to insulin.
For Metformin: A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fetal development, parturition or postnatal development.
However, when the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin should be used to maintain blood glucose levels as close to normal as possible.
Lactation: For Glimepiride: To prevent possible ingestion with the breast milk and possible harm to the child, glimepiride must not be taken by breast-feeding women. If necessary the patient must change over to insulin, or must stop breast-feeding.
For Metformin: Metformin is excreted into milk in lactating rats.
Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision should be made on whether to discontinue nursing or to discontinue metformin, taking into account the benefit and potential risk of adverse effect on the child and importance of the compound to the mother.

Glimepiride: Metabolism and nutrition disorders: Hypoglycemia: As a result of the blood-glucose-lowering action of this drug, hypoglycemia may occur, which-based on what is known of other sulfonylureas- may also be prolonged. Possible symptoms of hypoglycemia include headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, impaired alertness and reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, pareses, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to and including coma, shallow respiration and bradycardia.
In addition, signs of adrenergic counter-regulation may be present such as sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris, and cardiac arrhythmias.
The clinical picture of a severe hypoglycemic attack may resemble that of a stroke. The symptoms nearly always subside when hypoglycemia is corrected.
Eye disorders: Especially at the start of treatment, there may be temporary visual impairment due to the change in blood glucose levels. The cause is a temporary alteration in the turgidity and hence the refractive index of the lens, this being dependent on blood glucose level.
Gastrointestinal disorders: Occasionally, gastrointestinal symptoms such as nausea, vomiting, sensations of pressure or fullness in the epigastrium, abdominal pain and diarrhoea may occur.
Hepatobiliary: In cases, elevation of liver enzymes levels and impairment of liver function (e.g., cholestasis and jaundice) may occur, as well as hepatitis which may progress to liver failure.
Dysgeusia (frequency not known).
Blood and lymphatic system disorders: Changes in the blood picture may occur: Rarely, thrombocytopenia and, in isolated cases, leucopenia, haemolytic anaemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop. Because it is reported that aplastic anemia and pancytopenia may occur in sulfonylureas, careful monitoring should be performed. If these occur, the medication should be discontinued and adequate treatment taken. Cases of severe thrombocytopenia with platelet count less than 10,000/μl and thrombocytopenic purpura have been reported in post-marketing experience (frequency not known).
Skin and subcutaneous tissue disorders: Alopecia (frequency not known).
General disorders: Occasionally, allergic or pseudoallergic reactions. Occasionally, allergic or pseudo-allergic reactions (e.g., itching, urticaria, or rashes) may occur. These reactions are almost mild but may develop into serious reactions with dyspnoea and a fall in blood pressure, sometimes progressing to shock. In the event of urticaria a physician must therefore be notified immediately.
In isolated cases, a decrease in serum sodium concentration and allergic vasculitis or hypersensitivity of the skin to light may occur.
Investigations: Glimepiride, like all sulfonylureas, can cause weight gain (frequency not known).
Metformin: Hypoglycemia.
Gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal bloating, flatulence, and anorexia) are the most common reactions to this drug and are approximately 30% more frequent in patients on monotherapy than in placebo-treated patients, particularly during initiation of this drug therapy. These symptoms are generally transient and resolve spontaneously during continued treatment. Occasionally, temporary dose reduction may be useful. In clinical trials, this drug was discontinued due to GI reactions in approximately 4% of patients. Because GI symptoms during therapy initiation appear to be dose-related, they may be decreased by gradual dose escalation and by having patients take this drug with meals.
Because significant diarrhea and/or vomiting may cause dehydration and prerenal azotemia, under such circumstances, this drug should be temporarily discontinued. For patients who have been stabilized on this drug, nonspecific GI symptoms should not be attributed to therapy unless intercurrent illness or lactic acidosis has been excluded.
Special senses: During initiation of this drug therapy, approximately 3% of patients may complain of an unpleasant or metallic taste, which usually resolve spontaneously.
Skin reactions such as erythema, pruritus, urticarial are very rare.
Rarely, anemia, leukocytopenia, or thrombocytopenia may occur. Approximately 9% of patients on this drug monotherapy and 6% of patients on this drug/sulfonylurea monotherapy developed asymptomatic subnormal serum vitamin B12 levels; serum folic acid levels did not decrease significantly. Only megaloblastic anemia have been reported with this drug administration. Therefore, serum B12 levels should be appropriately monitored or periodic parenteral B12 supplementation considered. However, cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in post-marketing experience (frequency not known) (see Precautions).
Lactic acidosis is very rare.
Hemolytic anemia (frequency unknown).
Reduction of thyrotropin level in patients with hypothyroidism (see Precautions) (frequency unknown).
Hypomagnesemia in the context of diarrhea (frequency unknown).
Encephalopathy (frequency unknown).
Photosensitivity (frequency unknown).
Hepatobiliary disorders: Reports of liver function tests abnormalities and hepatitis resolving upon metformin discontinuation.
If the adverse reactions mentioned previously, other undesirable reactions, or unexpected changes may occur, patients should promptly notify their health practitioner. Certain adverse reactions including severe hypoglycemia, special hematological change, severe allergic or pseudo-allergic reactions, and hepatic insufficiency may be life-threatening in certain conditions, and if these reactions occur, patients should promptly inform their physician and stop taking the drug until physician's instructions.
In local phase 1 and open phase 3 clinical trials, unexpected adverse reactions of this drug except for those of glimepiride and metformin already known have not been observed.

Glimepiride: When other drugs are concomitantly administered to or withdrawn from a patient receiving this drug, both undesired increases and decreases in the hypoglycemic action of glimepiride can occur.
Based on experience with glimepiride and other sulfonylureas, the following interactions must be considered: Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). Its metabolism is known to be influenced by concomitant administration of CYP2C9 inducers (e.g., rifampicin) or inhibitors (e.g., fluconazole).
Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may occur when one of the following drugs is taken, for example: insulin and other oral antidiabetics; ACE inhibitors; allopurinol; anabolic steroids and male sex hormones; chloramphenicol; coumarin derivatives; cyclophosphamide; disopyramide; fenfluramine; fenyramidol; fibrates; fluoxetine; guanethidine; ifosfamide; MAO inhibitors; miconazole; fluconazole; para-aminosalicylic acid; pentoxifylline (high dose parenteral); phenylbutazone; azapropazone; oxyphenbutazone; probenecid; quinolones; salicylates; sulfinpyrazone; clarithromycin; sulfonamide antibiotics; tetracyclines; tritoqualine; trofosfamide.
Weakening of the blood-glucose-lowering effect and, thus raised blood glucose levels may occur when one of the following drugs is taken, for example: acetazolamide; barbiturates; corticosteroids; diazoxide; diuretics; epinephrine (adrenaline) and other sympathomimetic agents; glucagon; laxatives (long term use); nicotinic acid (in high doses); oestrogens and progestogens; phenothiazines; phenytoin; rifampicin; thyroid hormones.
H2 receptor antagonists, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect.
Beta-blockers reduce glucose tolerance. Reduction of glucose tolerance may change metabolic control. Beta-blockers may increase the risk of hypoglycemia (due to failure of counter-regulation).
Under the influence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent.
Both acute and chronic alcohol intake may potentiate or weaken the blood-glucose-lowering action of glimepiride in an unpredictable fashion.
The effect of coumarin derivatives may be potentiated or weakened.
Bile acid sequestrant: Colesevelam binds to glimepiride and reduces glimepiride absorption from the gastro-intestinal tract. No interaction was observed when glimepiride was taken at least 4 hours before colesevelam. Therefore glimepiride should be administered at least 4 hours prior to colesevelam.
Metformin: Concomitant use not recommended: Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting, malnutrition or hepatic insufficiency. Avoid consumption of alcohol and alcohol-containing medications.
Iodinated contrast agents: Metformin should be discontinued at the time of or prior to the procedure, and withheld for 48hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. (See Contraindications and Warnings).
Combinations requiring precautions for use: Medicinal products with intrinsic hyperglicaemic activity (e.g. glucocorticoids and tetracosactides (systemic and local routes), beta-2-agonists, danazol, and chlorpromazine at high dosages of 100 mg per day, diuretics): More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon its discontinuation.
Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to their potential to decrease renal function (further to their intrinsic hyperglycaemic effect, see previous text).
ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.
Others: Lactic acidosis may occur by concomitant administration with antibiotics having strong nephrotoxicity (gentamicin, etc).
The hypoglycemic action of co-administration with the following drugs may be potentiated or weakened. When these drugs are administered, the blood glucose level and patient should be observed closely.
Drugs potentiating the effect Insulin, sulfonamides, and sulfonylureas products, Anabolic steroids, guanethidine, salicylates (aspirin, etc), beta-blockers(propranolol, etc), MAO inhibitors.
Drugs weakening the effect. Epinephrine, corticosteroids, thyroid hormones, estrogens, diuretics, pyrazinamide, isoniazid, nicotinic acid, phenothiazines.
Glyburide: In a single-dose interaction study in type 2 diabetes subjects, co-administration of metformin and glyburide did not result on any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamics effects, makes the clinical significance of this interaction uncertain.
Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.
Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Metformin had minimal effects on nifedipine.
Cationic drugs: Cationic drugs (e.g. amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and 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 interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple- dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Other: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs 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 a patient receiving metformin, the patient should be closely observed to maintain adequate glycemic control.
In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.
Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, a close monitoring of the INR is recommended.
Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin must be adjusted if necessary.
Organic caution transporters (OCT): Metformin is a substrate of both transporters OCT1 and OCT2.
Co-administration of metformin with: Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.
Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.
Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.
Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.
Caution is therefore advised, especially in patients with renal impairment, when these drugs are coadministered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.

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Antidiabetic Agents

A10BD02 - metformin and sulfonylureas ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.

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