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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.
