Glimepiride/metformin hydrochloride Overdose
Glimepiride: Acute overdosage as well as long-term treatment with too high a dose of glimepiride may lead to severe life-threatening hypoglycaemia.
Management: As soon as an overdose of glimepiride has been discovered, a physician must be notified without delay. The patient must immediately take sugar, if possible in the form of glucose, unless a physician has already undertaken responsibility for treating the overdose.
Careful monitoring is essential until the physician is confident that the patient is out of danger. It must be remembered that hypoglycaemia may recur after initial recovery.
Admission to hospital may sometimes be necessary even as a precautionary measure. In particular, significant overdoses and severe reactions with signs eg, loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and admission to hospital.
If, for example, the patient is unconscious, an IV injection of concentrated glucose solution is indicated (eg, for adults starting with 40 mL of 20% solution). Alternatively in adults, administration of glucagon eg, in doses of 0.5-1 mg IV, SC or IM may be considered.
In particular, when treating hypoglycaemia due to accidental intake of glimepiride in infants and young children, the dose of glucose given must be very carefully adjusted in view of the possibility of producing dangerous hyperglycaemia and must be controlled by close monitoring of blood glucose.
Patients who have ingested life-threatening amounts of glimepiride require detoxification (eg, gastric lavage and medicinal charcoal).
After acute glucose replacement has been completed, it is usually necessary to give an IV 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 hrs. In severe cases with a protracted course, hypoglycaemia or the danger of slipping back into hypoglycaemia, may persist for several days.
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. The most effective method to remove lactate and metformin is haemodialysis.
Caution when used in patients with CHF especially in those with unstable or acute heart failure. Risk of lactic acid accumulation increases with the degree of renal impairment. May need to discontinue treatment in patients with stress-related states e.g. fever, trauma, infection or surgery. Metformin should be temporarily discontinued for 48 hr in patients undergoing radiologic studies involving intravascular admin of iodinated contrast materials. Elderly. Monitor renal function regularly. May impair ability to drive or operate machinery.
Lactic Acidosis: Lactic acidosis is a serious metabolic complication that can occur due to metformin accumulation during treatment with Glimepiride/metformin hydrochloride and is fatal in approximately 50% of cases. It 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 concentration (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin HCl is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. In >20,000 patient-years exposures to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. Therefore, the risk may be significantly decreased by regular monitoring of renal function in patients taking Glimepiride/metformin hydrochloride. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Glimepiride/metformin hydrochloride treatment should not be initiated in any patient unless measurement of CrCl demonstrates that renal function is not reduced. In addition, Glimepiride/metformin hydrochloride should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration or sepsis.
Because impaired hepatic function may significantly limit the ability to clear lactate, Glimepiride/metformin hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake because alcohol potentiates the effects of metformin on lactate metabolism. In addition, Glimepiride/metformin hydrochloride, should be temporarily discontinued prior to any IV radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate (a carbonic anhydrase inhibitor) in epilepsy and migraine prophylaxis may frequently cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis. The onset of lactic acidosis is often subtle and accompanied only by nonspecific symptoms eg, malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis.
Patient should be educated to promptly report these symptoms should they occur. If present, Glimepiride/metformin hydrochloride should be withdrawn until lactic acidosis is ruled out. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels and blood metformin levels may be useful. Once a patient is stabilized on any dose level of Glimepiride/metformin hydrochloride, GI symptoms which are common during initiation of therapy are unlikely to recur. Later occurrence of GI symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but <5 mmol/L in patients taking Glimepiride/metformin hydrochloride do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms eg, poorly-controlled diabetes or obesity, vigorous physical activity or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking Glimepiride/metformin hydrochloride, the drug should be discontinued immediately and general supportive measures promptly instituted. Because Glimepiride/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.
Hypoglycemia: Glimepiride in combination with insulin or other hypoglycemic agents may increase the risk of hypoglycemia.
Regularly monitor glycemic control and reduce dose during therapy with Glimepiride/metformin hydrochloride in patients susceptible to the hypoglycemic action of these agents (eg, debilitated or malnourished and those with adrenal, liver and kidney dysfunction).
Hypoglycemia may occur in patients when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation or during concomitant use with other glucose-lowering agents (eg, sulfonylureas and insulin) or alcohol.
Despite successful countermeasures, hypoglycemia may recur. Severe or prolonged hypoglycemia may be temporarily controlled by immediate intake of carbohydrates (artificial sweeteners have no effect).
Immediate medical treatment and occasionally, hospitalization may be required.
Loss of Control of Blood Glucose: A loss of control of blood glucose may occur in patients stabilized on any diabetic regimen exposed to stress (eg, fever, trauma, infection or surgery). The efficacy of any oral hypoglycemic drug (including Glimepiride/metformin hydrochloride) may be reduced in many patients over a period of time due to progression of severity of the diabetes or to diminished responsiveness to the drug.
Monitoring of Renal Function: Impaired renal function would increase the risk of metformin accumulation and lactic acidosis. Patients with serum creatinine levels higher than the normal range should not initiate therapy with Glimepiride/metformin hydrochloride.
Renal function should be assessed and verified as normal before initiation of Glimepiride/metformin hydrochloride therapy especially in elderly patients because aging is associated with reduced renal function.
Medications which may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin (ie, cationic drugs) should be used with caution since these drugs are eliminated by renal tubular secretion.
Impaired Hepatic Function: Glimepiride/metformin hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic disease since impaired hepatic function has been associated with lactic acidosis.
Hematologic: Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylureas (eg, glimepiride) can lead to hemolytic anemia. Use with caution in these patients and consider a nonsulfonylurea alternative.
Parenteral iodinated contrast media may alter renal function and increase the risk of lactic acidosis in patients receiving metformin, including Glimepiride/metformin hydrochloride. Temporarily discontinue Glimepiride/metformin hydrochloride prior to or at the time of any procedure requiring parenteral iodine contrast media. Do not initiate treatment with Glimepiride/metformin hydrochloride until 48 hrs after such procedures and until renal function has been re-evaluated and found to be normal.
Surgical Procedures: Temporarily discontinue Glimepiride/metformin hydrochloride use in patients undergoing surgery associated with restricted food or fluid intake. Therapy may be reinstituted when the patient's oral intake has resumed and renal function has been found normal.
Alcohol: Combined use of alcohol and metformin may increase the risk of hypoglycemia and lactic acidosis since alcohol decreases lactate clearance and hepatic gluconeogenesis and may increase insulin secretion. Excessive alcohol intake on an acute or chronic basis should be avoided in patients receiving Glimepiride/metformin hydrochloride.
Vitamin B12 Levels: Evaluate hematologic parameters prior to initiation of Glimepiride/metformin hydrochloride therapy and at least annually since decrease in serum vitamin B12 have been associated with metformin use.
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. Promptly discontinue Glimepiride/metformin hydrochloride when such events occur.
Macrovascular Outcomes: Although the United Kingdom Prospective Diabetes Study (UKPDS) showed that HbA1c lowering results in reduced microvascular disease in patients with newly diagnosed type 2 diabetes treated with metformin, sulfonylureas and/or insulin, the 10-year follow-up post-trial monitoring showed a continued benefit of metformin in microvascular disease. In addition, reduction in myocardial infarction (macrovascular disease) and death from any cause after the end of the intervention period were reported.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride. Glimepiride/metformin hydrochloride should not be prescribed to lower the risk of cardiovascular disease (ie, myocardial infarction and stroke) or to lower cardiovascular mortality for there is no study conducted using the combination.
Increased Risk of Cardiovascular Mortality:
Oral hypoglycemic drugs have been associated with increased cardiovascular mortality compared to treatment with diet alone or diet plus insulin.
In a study by the University Group Diabetes Program (UGDP), patients treated for 5-8 years with diet plus a fixed dose of tolbutamide had a rate of cardiovascular mortality approximately 2.5 times of patients treated with diet alone. Although this study only included tolbutamide, this warning may also apply to other oral hypoglycemic drugs in the sulfonylurea class including glimepiride, in view of their close similarities in mechanism of action and chemical structure. Inform patients of the potential risks and advantages of glimepiride and of alternative modes of therapy.
Effects on the Ability to Drive and Operate Machinery: Although no studies have been conducted, patients who need to perform activities requiring mental alertness or physical coordination should avoid Glimepiride/metformin hydrochloride since it may cause visual impairment as a result of hypoglycemia or hyperglycemia.
Use in pregnancy: Current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Glimepiride/metformin hydrochloride should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
Use in lactation: In studies performed on the individual components, metformin HCl and glimepiride have been shown to be secreted in human breast milk and in the milk of rats and serum of the pups. Discontinue use in breastfeeding mothers because of potential hypoglycemia in breastfeeding infants. Consider insulin therapy if diet and exercise is inadequate to control blood glucose.
Use in children: The safety and efficacy of Glimepiride/metformin hydrochloride have not been established in children.
Use in the elderly: There are no significant differences in glimepiride pharmacokinetics in patients with type 2 diabetes ≤65 and >65 years. Although no dosage adjustment is necessary, elderly patients are more susceptible to the hypoglycemic action of glucose-lowering agents. To avoid hypoglycemia, carefully adjust the initial dose, dose increments and maintenance dose based on blood glucose levels.
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Information checked by Dr. Sachin Kumar, MD Pharmacology