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glimepiride 1 mg tablet generic amaryl

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Uses

Diabetes Mellitus

Glimepiride is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Sulfonylureas, including glimepiride, also may be used in combination with one or more other oral antidiabetic agents or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who are unable to achieve adequate glycemic control with oral antidiabetic agent monotherapy. Glimepiride is used in fixed combination with rosiglitazone as an adjunct to diet and exercise in patients with type 2 diabetes mellitus when treatment with both glimepiride and rosiglitazone is appropriate. Glimepiride also is used in fixed combination with pioglitazone in patients with type 2 diabetes mellitus who are already receiving a thiazolidinedione and a sulfonylurea separately or who do not achieve adequate glycemic control with thiazolidinedione or sulfonylurea monotherapy.

The American Diabetes Association (ADA) currently classifies diabetes mellitus as type 1 (immune mediated or idiopathic), type 2 (predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance), gestational diabetes mellitus, or that associated with certain conditions or syndromes (e.g., drug- or chemical-induced, hormonal, that associated with pancreatic disease, infections, specific genetic defects or syndromes). Type 1 diabetes mellitus was previously described as juvenile-onset (JOD) diabetes mellitus, since it usually occurs during youth. Type 2 diabetes mellitus previously was described as adult-onset (AODM) diabetes mellitus. However, type 1 or type 2 diabetes mellitus can occur at any age, and the current classification is based on pathogenesis (e.g., autoimmune destruction of pancreatic β cells, insulin resistance) and clinical presentation rather than on age of onset. Many patients' diabetes mellitus does not easily fit into a single classification. Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents such that 8-45% of children with newly diagnosed diabetes have nonimmune-mediated diabetes mellitus; most of these individuals have type 2 diabetes mellitus, although other types, including idiopathic or nonimmune-mediated type 1 diabetes mellitus, also have been reported.

Patients with type 2 diabetes mellitus have insulin resistance and usually have relative (rather than absolute) insulin deficiency. Most patients with type 2 diabetes mellitus (about 80-90%) are overweight or obese; obesity itself also contributes to the insulin resistance and glucose intolerance observed in these patients. Patients with type 2 diabetes mellitus who are not obese may have an increased percentage of abdominal fat, which is an indicator of increased cardiometabolic risk. While children with immune-mediated type 1 diabetes generally are not overweight, the incidence of obesity in children with this form of diabetes is increasing with the increasing incidence of obesity in the US population. Distinguishing between type 1 and type 2 diabetes in children may be difficult since obesity may occur with either type of diabetes mellitus, and autoantigens and ketosis may be present in a substantial number of children with features of type 2 diabetes mellitus (e.g., obesity, acanthosis nigricans).

Oral antidiabetic agents are not effective as sole therapy for patients with type 1 diabetes mellitus; insulin is necessary in these patients. Sulfonylurea antidiabetic agents are not routinely recommended in hospitalized patients with diabetes mellitus. Because of their long duration of action (24 hours with glimepiride), therapy with sulfonylureas does not allow rapid dosage adjustments to meet changing needs of hospitalized patients. In addition, the risk of hypoglycemia during sulfonylurea therapy is increased in such patients with irregular eating patterns.

Patients with type 2 diabetes mellitus are not dependent initially on insulin (although many patients eventually require insulin for glycemic control) nor are they prone to ketosis; however, insulin may be required for correction of symptomatic or persistent hyperglycemia that is not controlled by dietary regulation or oral antidiabetic agents (e.g., sulfonylureas), and ketosis occasionally may develop during periods of severe stress (e.g., acute infection, trauma, surgery). Type 2 diabetes mellitus is a heterogeneous subclass of the disease; hyperglycemia in these patients often is accompanied by other metabolic abnormalities such as obesity, hypertension, hyperlipidemia, and impaired fibrinolysis. Endogenous insulin is present in type 2 diabetic patients, although plasma insulin concentrations may be decreased, increased, or normal. In type 2 diabetic patients, glucose-stimulated secretion of endogenous insulin is frequently, but not always, reduced and decreased peripheral sensitivity to insulin is almost always associated with glucose intolerance.

Glycemic Control and Microvascular Complications

Current evidence from epidemiologic and clinical studies supports an association between chronic hyperglycemia and the pathogenesis of microvascular complications in patients with diabetes mellitus, and results of randomized, controlled studies in patients with type 1 or 2 diabetes mellitus indicate that intensive management of hyperglycemia with near-normalization of blood glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) concentrations provides substantial benefits in terms of reducing chronic microvascular (e.g., neuropathy, retinopathy, nephropathy) complications associated with the disease. HbA1c reflects the glycosylation of other proteins throughout the body as a result of recent hyperglycemia and is used as a predictor of risk for the development of diabetic microvascular complications. Microvascular complications of diabetes are the principal causes of blindness and renal failure in developed countries and are more closely associated with hyperglycemia than are macrovascular complications.

In the Diabetes Control and Complications Trial (DCCT), the reduction in risk of microvascular complications in patients with type 1 diabetes mellitus correlated continuously with the reduction in glycosylated hemoglobin concentration produced by intensive insulin treatment (e.g., a 40% reduction in risk of microvascular disease for each 10% reduction in glycosylated hemoglobin). These data imply that any decrease in glycosylated hemoglobin levels is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic complications. Data from the largest United Kingdom Prospective Diabetes Study (UKPDS) and other smaller studies in patients with type 2 diabetes mellitus are generally consistent with the same benefits on microvascular complications as those observed with type 1 diabetes mellitus in the DCCT study.

Data from long-term follow-up (over 10 years) of UKPDS patients with type 2 diabetes mellitus who received initial therapy with conventional (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations below 270 mg/dL without symptoms of hyperglycemia) antidiabetic treatment or intensive (stepwise introduction of a sulfonylurea [i.e., chlorpropamide, glyburide], then insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentrations of 108 mg/dL) antidiabetic regimens indicate that intensive treatment with monotherapy generally is not capable of maintaining strict glycemic control (i.e., maintenance of blood glucose concentrations of 108 mg/dL or normal values) over time and that combination therapy eventually becomes necessary in most patients to attain target glycemic levels in the long term; in UKPDS , intensive treatment that eventually required combination therapy in most patients resulted in median HbA1c concentrations of 7%. Because of the benefits of strict glycemic control, the goal of therapy for type 2 diabetes mellitus is to lower blood glucose to as close to normal as possible, which generally requires aggressive management efforts (e.g., mixing therapy with various antidiabetic agents including sulfonylureas, metformin, insulin, and/or possibly others) over time.

Glycemic Control and Macrovascular Complications

Current evidence indicates that appropriate management of dyslipidemia, blood pressure, and vascular thrombosis provides substantial benefits in terms of reducing macrovascular complications associated with diabetes mellitus; intensive glycemic control generally has not been associated with appreciable reductions in macrovascular outcomes in controlled trials. Reduction in blood pressure to a mean of 144/82 mm Hg (''tight blood pressure control'') in patients with diabetes mellitus and uncomplicated mild to moderate hypertension in UKPDS substantially reduced the incidence of virtually all macrovascular (e.g., stroke, heart failure) and microvascular (e.g., retinopathy, vitreous hemorrhage, renal failure) outcomes and diabetes-related mortality; blood pressure and glycemic control were additive in their beneficial effects on these end points. While intensive antidiabetic therapy titrated with the goal of reducing HbA1c to near-normal concentrations (6-6.5% or less) has not been associated with appreciable reductions in cardiovascular events during the randomized portion of controlled trials examining such outcomes, results of long-term follow-up (10-11 years) from DCCT and UKPDS indicate a delayed cardiovascular benefit in patients treated with intensive antidiabetic therapy early in the course of type 1 or type 2 diabetes mellitus.

Treatment Goals

The ADA currently states that it is reasonable to attempt to achieve in patients with type 2 diabetes mellitus the same blood glucose and HbA1c goals recommended for patients with type 1 diabetes mellitus. Based on target values for blood glucose and HbA1c used in clinical trials (e.g., DCCT) for type 1 diabetic patients, modified somewhat to reduce the risk of severe hypoglycemia, ADA currently recommends target preprandial (fasting) and peak postprandial (1-2 hours after the beginning of a meal) plasma glucose concentrations of 70-130 and less than 180 mg/dL, respectively, and HbA1c concentrations of less than 7% (based on a nondiabetic range of 4-6%) in general in patients with type 1 or type 2 diabetes mellitus who are not pregnant. HbA1c concentrations of 7% or greater should prompt clinicians to initiate or adjust antidiabetic therapy in nonpregnant patients with the goal of achieving HbA1c concentrations of less than 7%. Patients with diabetes mellitus who have elevated HbA1c concentrations despite having adequate preprandial glucose concentrations should monitor glucose concentrations 1-2 hours after the start of a meal. Treatment with agents (e.g., α-glucosidase inhibitors, exenatide, pramlintide) that principally lower postprandial glucose concentrations to within target ranges also should reduce HbA1c.

More stringent treatment goals (i.e., an HbA1c concentration less than 6%) can be considered in selected patients. An individualized HbA1c concentration goal that is closer to normal without risking substantial hypoglycemia is reasonable in patients with a short duration of diabetes mellitus, no appreciable cardiovascular disease, and a long life expectancy. Less stringent treatment goals may be appropriate in patients with long-standing diabetes mellitus in whom the general HbA1c concentration goal of less than 7% is difficult to obtain despite adequate education on self-management of the disease, appropriate glucose monitoring, and effective dosages of multiple antidiabetic agents, including insulin. Achievement of HbA1c values of less than 7% is not appropriate or practical for some patients, and clinical judgment should be used in designing a treatment regimen based on the potential benefits and risks (e.g., hypoglycemia) of more intensified therapy.

Considerations in Initiating and Maintaining Antidiabetic Therapy

When initiating therapy for patients with type 2 diabetes mellitus who do not have severe symptoms, most clinicians recommend that diet be emphasized as the primary form of treatment; caloric restriction and weight reduction are essential in obese patients. Although appropriate dietary management and weight reduction alone may be effective in controlling blood glucose concentration and symptoms of hyperglycemia, many patients receiving dietary advice fail to achieve adequate glycemic control with dietary modification alone.

Recognizing that lifestyle interventions often fail to achieve or maintain the target glycemic goal within the first year of initiation of such interventions, many clinicians generally recommend initiation of metformin concurrently with lifestyle interventions at the time of diagnosis of type 2 diabetes mellitus. Other experts suggest concurrent initiation of lifestyle interventions and antidiabetic agents only when HbA1c levels of 9% or greater are present at the time of diagnosis of type 2 diabetes mellitus. ADA and other clinicians state that lifestyle interventions should remain a principal consideration in the management of diabetes even after pharmacologic therapy is initiated. The manufacturer states that patients and clinicians should recognize that dietary management is the principal consideration in the management of diabetes mellitus and that antidiabetic therapy is used only as an adjunct to, and not as a substitute for or a convenient means to avoid, proper dietary management. In addition, loss of blood glucose control on diet alone may be temporary in some patients, requiring only short-term management with drug therapy. The importance of regular physical activity should be emphasized, and cardiovascular risk factors should be identified and corrective measures employed when feasible.

If lifestyle interventions alone are initiated and these interventions fail to reduce symptoms and/or blood glucose concentrations within 2-3 months of diagnosis, initiation of monotherapy with metformin or another oral antidiabetic agent (e.g., a sulfonylurea, acarbose) or insulin should be considered.

Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral sulfonylurea antidiabetic agents. The American Diabetes Association (ADA) currently considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control (e.g., concomitant antihypertensive therapy) in diabetic patients to outweigh the risks overall.

Glimepiride Monotherapy

From dose-ranging studies in patients with type 2 diabetes mellitus, glimepiride appears to reduce both fasting and postprandial blood glucose concentrations and HbA1c; these reductions are dose dependent over a range of 1-4 mg daily. Some patients, particularly those with high fasting plasma glucose concentrations, may benefit from the maximum dosage of glimepiride (8 mg daily). For patients receiving the maximum dosage (8 mg daily) of glimepiride, the average reduction in HbA1c is 2% in absolute units. Clinical studies suggest that glimepiride is as effective as glyburide for the management of hyperglycemia in patients with type 2 diabetes mellitus. The efficacy of glimepiride is not affected by age, gender, weight, or race.

In a comparative, single-blind (patients only), dose titration trial in children and adolescents 8-17 years of age with type 2 diabetes mellitus, glimepiride (titrated to a mean last daily dosage of 4 mg) was as effective as metformin (titrated to a mean last dosage of 1.4 g daily) in reducing HbA1c values from baseline. Patients received an initial glimepiride dosage of 1 mg daily or 500 mg of metformin hydrochloride twice daily, and dosage was titrated until a fasting blood glucose concentration of less than 126 mg/dL was achieved or a maximum dosage of 8 mg daily of glimepiride or 1 g twice daily of metformin hydrochloride was reached. The adverse effect profile in pediatric patients receiving glimepiride was similar to that observed in adults. However, the manufacturer states that data are insufficient to recommend use of glimepiride in pediatric patients.

ADA generally recommends metformin as initial oral antidiabetic therapy because of the absence of weight gain or hypoglycemia, relatively low expense, and generally low adverse effect profile compared with other oral antidiabetic agents.

Primary or secondary failure to sulfonylureas has been attributed to a progressive decline in pancreatic beta-cell function, but data are limited concerning the incidence of failure with glimepiride. Secondary failure to sulfonylurea drugs is characterized by progressively decreasing diabetic control following 1 month to several years of good control. Interim data from a substudy (UKPD 26) of the UKPD study in newly diagnosed type 2 diabetic patients receiving intensive therapy (maintenance of fasting plasma glucose in a range from 108 mg/dL to less than 270 mg/dL by increasing doses of either a sulfonylurea [i.e., glyburide or chlorpropamide] to maximum recommended dosage) showed that secondary failure (defined as fasting plasma glucose exceeding 270 mg/dL or symptoms of hyperglycemia despite maximum recommended daily dosage of 20 mg of glyburide or 500 mg of chlorpropamide) occurred overall at about 7% per year. The failure rate at 6 years was 48% among patients receiving glyburide and about 40% among patients receiving chlorpropamide. In the UKPD studies, stepwise addition of insulin or metformin to therapy with maximal dosage of a sulfonylurea was required periodically over time to improve glycemic control. In another substudy (UKPD 49), progressive deterioration in diabetes control was such that monotherapy was effective in only about 50% of patients after 3 years and in only about 25% of patients after 9 years; thus, most patients require multiple-drug antidiabetic therapy over time to maintain such target levels of disease control. At diagnosis, risk factors predisposing toward sulfonylurea failure included higher fasting plasma glucose concentrations, younger age, and lower pancreatic β-cell reserve.

Glimepiride is not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma; management of these conditions requires the use of insulin.

Combination Therapy with Metformin or Other Oral Antidiabetic Agents

Sulfonylureas also may be used in combination with one or more other oral antidiabetic agents (e.g., metformin, thiazolidinedione derivatives, α-glucosidase inhibitors) as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy. Combined therapy with metformin or other oral antidiabetic agents generally is used in patients with longstanding type 2 diabetes mellitus who have poor glycemic control with monotherapy.

Glimepiride may be used in combination with metformin in patients in whom adequate glycemic control can no longer be achieved by monotherapy with the maximal dosage of either oral antidiabetic agent (i.e., secondary failure). Because of differences in the mechanisms of antidiabetic effects, adequate glycemic control can be achieved in some patients exhibiting secondary failure to one oral antidiabetic agent (e.g., sulfonylurea) by adding a second oral antidiabetic agent from another class (e.g., metformin, acarbose). While data are limited concerning use of glimepiride in combination with metformin, such use is based on clinical data regarding the use of other sulfonylureas (e.g., glyburide, glipizide, chlorpropamide, tolbutamide) with metformin. The sequence in which metformin or a sulfonylurea is used at initiation of therapy does not appear to alter the effectiveness of combined therapy with the drugs. However, ADA and other clinicians currently recommend initiating therapy with metformin and adding another antidiabetic agent, such as a sulfonylurea, insulin, or a thiazolidinedione, if patients fail to achieve or maintain target HbA1c goals. Optimal benefit generally is obtained by addition of a second antidiabetic agent as soon as monotherapy with metformin at the maximum tolerated dosage no longer provides adequate glycemic control (i.e., when the target glycemic goal is not achieved within 2-3 months of initiation of metformin therapy or at any other time when the HbA1c goal is not achieved). Should secondary failure occur with glimepiride and metformin combination therapy, institution of insulin therapy may be necessary. Although combined therapy with glimepiride and metformin is one of several options for the management of hyperglycemia in patients not responding adequately to oral monotherapy, such combined therapy may increase the risk of hypoglycemic reactions.

Glimepiride is used in fixed combination with rosiglitazone when treatment with both glimepiride and rosiglitazone is indicated in patients with type 2 diabetes mellitus. Glimepiride also is used in fixed combination with pioglitazone in patients with type 2 diabetes mellitus who are already receiving pioglitazone and a sulfonylurea separately or whose hyperglycemia is inadequately controlled on a sulfonylurea or pioglitazone alone.

For additional information on combination therapy with sulfonylureas and other oral antidiabetic agents, see the sections on combination therapy in Uses in the individual monographs in 68:20.

When lifestyle interventions, metformin, and a second oral antidiabetic agent are not effective in maintaining the target glycemic goal in patients with type 2 diabetes mellitus, ADA and other clinicians generally recommend the addition of insulin therapy. In patients whose HbA1c is close to the target level (less than 8%) on metformin and a second oral antidiabetic agent, addition of a third oral antidiabetic agent instead of insulin may be considered. ADA states that triple combination oral antidiabetic therapy is more costly and potentially not as effective as adding insulin therapy to dual combination oral antidiabetic therapy.

Combination Therapy with Insulin

Glimepiride may be used in combination with insulin in patients who experience secondary failure with glimepiride monotherapy. ADA and other clinicians state that combined therapy with insulin and metformin with or without other antidiabetic agents is one of several options for the management of hyperglycemia in patients not responding adequately to oral monotherapy with metformin, the preferred agent for initiation of oral antidiabetic therapy. In patients with an HbA1c concentration exceeding 8.5% or symptoms secondary to hyperglycemia despite metformin monotherapy, ADA states that consideration should be given to adding insulin. When patients are not controlled with metformin with or without other oral antidiabetic agents (i.e., a sulfonylurea, a thiazolidinedione) and basal insulin (e.g., given as intermediate- or long-acting insulin at bedtime or in the morning), therapy with insulin should be intensified by adding additional short-acting or rapid-acting insulin injections at mealtimes. Therapy with insulin secretagogues (i.e., sulfonylureas, meglitinides) should be tapered and discontinued when intensive insulin therapy is initiated, as insulin secretagogues do not appear to be synergistic with such insulin therapy. The manufacturer recommends that addition of insulin to glimepiride be considered if fasting glucose concentrations continue to exceed 150 mg/dL in plasma or serum despite appropriate sulfonylurea monotherapy.

Combined therapy with insulin and oral antidiabetic agents may be useful in some patients with type 2 diabetes mellitus whose blood glucose concentrations are not adequately controlled with maximal dosages of the oral agent and/or as a means of providing increased flexibility with respect to timing of meals and amount of food ingested. In general, combined sulfonylurea and insulin therapy for type 2 diabetes mellitus results in glycemic control comparable to that achieved with insulin alone but at substantially reduced (e.g., by 40-50%) insulin dosage. For example, combined therapy with insulin (a mixture of 70% isophane insulin and 30% regular insulin) and glimepiride in obese patients with secondary failure to oral antidiabetic agents resulted in glycemic control comparable to that achieved with insulin alone but at insulin dosages of approximately 38% lower than those required with monotherapy. However, such combined therapy may increase the risk of hypoglycemic reactions.

Precautions about Hypoglycemia

Patients should be advised fully and completely about the nature of diabetes mellitus, what they must do to prevent and detect complications, and how to control their condition.Patients should be informed of the potential risks and advantages of glimepiride therapy and of alternative forms of treatment. Patients should be instructed that dietary regulation is the principal consideration in the management of diabetes and that glimepiride therapy only is used as an adjunct to, and not a substitute for, proper dietary regulation.Patients also should be advised that they should not neglect dietary restrictions, develop a careless attitude about their condition, or disregard instructions about body-weight control, exercise, hygiene, and avoidance of infection. The possibility of primary and secondary failure to glimepiride therapy also should be explained to patients.

Hypoglycemia, which may be severe, may occur in patients receiving glimepiride alone or in combination with metformin or insulin. Appropriate patient selection and careful attention to dosage are important to avoid glimepiride-induced hypoglycemia. Hypoglycemia may occur as a result of excessive glimepiride dosage; however, since the development of hypoglycemia is a function of many factors, including diet, exercise without adequate caloric supplementation, and alcohol ingestion, this effect may occur in some patients receiving usual dosages of the drug. Hypoglycemia (i.e., blood glucose concentrations less than 60 mg/dL) has occurred in 0.9-1.7% of patients receiving glimepiride in long-term (1 year) controlled clinical trials. Geriatric patients, debilitated or malnourished patients, or those with adrenal, pituitary, renal, or hepatic impairment may be particularly susceptible to hypoglycemia induced by sulfonylureas, including glimepiride. Hypoglycemia may be more difficult to recognize in geriatric patients and in patients who also are receiving β-adrenergic blocking agents or other sympatholytic agents.

Management of glimepiride-induced hypoglycemia depends on the severity of the reaction; severe reactions (e.g., coma, seizures) occur infrequently but require immediate hospitalization and treatment and observation until complete recovery is ensured. Hypoglycemia is usually, but not always, readily controlled by administration of glucose. If hypoglycemia occurs during therapy with the drug, immediate reevaluation and adjustment of glimepiride dosage and/or the patient's meal and exercise pattern are necessary.

Patients and responsible family members should be informed of the risks of hypoglycemia, symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of such reactions, since these reactions may occur during therapy with glimepiride. Patients should be advised fully and completely about the nature of diabetes mellitus, what they must do to prevent and detect complications, and how to control their condition.

Precautions Relating to Heart Failure

Because thiazolidinediones (i.e., pioglitazone, rosiglitazone) can cause or exacerbate congestive heart failure (CHF), use of these agents is not recommended or is contraindicated in certain patients with heart failure. Initiation of therapy with glimepiride in fixed combination with pioglitazone or rosiglitazone is contraindicated in patients with New York Heart Association (NYHA) class III or IV heart failure. Patients with NYHA class III or IV heart failure were not studied in clinical trials; use of glimepiride in fixed combination with pioglitazone or rosiglitazone is not recommended in these patients. Use of glimepiride in fixed combination with pioglitazone or rosiglitazone is not recommended in patients with symptomatic heart failure.

Dosage and Administration

Administration

Glimepiride is administered orally. The drug usually is administered alone or in fixed combination with rosiglitazone or pioglitazone as a single daily dose given each morning with breakfast or with the first main meal. Although food slightly decreases the extent and slightly delays absorption of glimepiride, the manufacturer recommends that the drug be taken with the first meal of the day. Once-daily dosing of glimepiride provides adequate control of blood glucose concentration throughout the day.

Dispensing and Administration Precautions

Because of similarity in spelling between Amaryl (the trade name for glimepiride) and Reminyl (the former trade name for galantamine hydrobromide, an acetylcholinesterase inhibitor used for treatment of Alzheimer's dementia), dispensing errors involving these drugs have occurred. These medication errors were associated with serious adverse events (e.g., severe hypoglycemia, death) because of the use of glimepiride in patients for whom the drug was not prescribed. In 2005, the manufacturer of Reminyl changed the trade name for galantamine hydrobromide from Reminyl to Razadyne to avoid future dispensing errors.

Dosage

The manufacturer states that data are insufficient to recommend use of glimepiride in pediatric patients. Although no overall differences in safety or efficacy were observed between geriatric and younger adults in clinical studies, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Dosage of glimepiride must be individualized carefully based on patient response and tolerance. The goal of therapy should be to reduce both fasting glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) values to normal or near normal using the lowest effective dosage of glimepiride, when used either as monotherapy or combined with metformin or insulin. Patients should be monitored with regular laboratory evaluations, including fasting blood (or plasma) glucose determinations, to determine therapeutic response and the minimum effective dosage of glimepiride either when used as monotherapy or when used in combination with insulin. Any change in drug therapy should be undertaken with care, and patients should be monitored appropriately. (Glucose concentrations in plasma generally are 10-15% higher than glucose concentrations in whole blood; glucose concentrations also may vary according to the method and laboratory used for these determinations.) Glucose determinations also should be monitored to detect primary failure (inadequate lowering of glucose concentration at the maximum recommended dosage) or secondary failure (loss of glycemic control following an initial period of effectiveness) to the drug. If inadequate glycemic control and/or secondary failure occurs during therapy with glimepiride, combined therapy with metformin or insulin may be initiated; use of glimepiride with metformin or acarbose has not been evaluated, but these drugs have been used safely and effectively in combination with other sulfonylureas. Following initiation of glimepiride therapy and dosage titration, determination of HbA1c values at intervals of approximately 3-6 months may be useful for determining the patient's continued response to therapy. In patients usually well controlled by dietary management alone, short-term therapy with glimepiride may be sufficient during periods of transient loss of diabetic control. If appropriate glimepiride dosage regimens are not followed, hypoglycemia may be precipitated.

Initial Dosage in Previously Untreated Patients

For the management of type 2 diabetes mellitus in patients not previously receiving insulin or another sulfonylurea antidiabetic agent, the usual initial adult dosage of glimepiride is 1-2 mg once daily administered with breakfast or the first main meal. In debilitated, malnourished, or geriatric patients and in other patients at increased risk of hypoglycemia, the initial dosage of glimepiride should be 1 mg once daily.

Initial Dosage in Patients Transferred from Other Antidiabetic Agents

When transferring from most sulfonylurea antidiabetic agents to glimepiride, a transition period generally is not required, and administration of the sulfonylurea antidiabetic agent may be discontinued abruptly. Because an exaggerated hypoglycemic response may occur in some patients during the transition from a sulfonylurea antidiabetic agent with a prolonged half-life (e.g., chlorpropamide) to glimepiride, patients being transferred from such agents should be monitored closely for the occurrence of hypoglycemia during the initial 1-2 weeks of the transition period.

For the management of type 2 diabetes mellitus in adults previously receiving other sulfonylurea antidiabetic agents, the initial dosage of glimepiride should be 1-2 mg once daily. Even in patients being transferred from the maximum dosage of another sulfonylurea, the initial dosage of glimepiride should not exceed 2 mg daily since exact dosage relationships have not been established and hypoglycemia may be precipitated if this dosage is exceeded.

Maintenance Dosage

The usual maintenance dosage of glimepiride for the management of type 2 diabetes mellitus ranges from 1-4 mg once daily. In patients receiving 1 mg of glimepiride daily, the dosage may be increased to 2 mg daily if adequate glycemic control has not been achieved after 1-2 weeks. After reaching the 2-mg dosage, subsequent dosage should be adjusted according to the patient's tolerance and therapeutic response, increasing the dosage in increments of no more than 2 mg daily at 1- to 2-week intervals. Maintenance dosage of glimepiride should be conservative in debilitated, malnourished, or geriatric patients and in patients with impaired hepatic or renal function because of an increased risk of hypoglycemia in such patients.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) The maximum recommended dosage of glimepiride is 8 mg daily.

Concomitant Glimepiride and Metformin Therapy

Combined therapy with glimepiride and metformin may be used in patients who no longer respond adequately to either oral antidiabetic agent, despite appropriate oral antidiabetic monotherapy, diet, and exercise. With concomitant glimepiride and metformin therapy, glycemic control may be obtained by adjusting the dosage to the minimum effective dosage for each drug.

Glimepiride/Pioglitazone Fixed-Combination Therapy

The initial dosage of glimepiride in fixed combination with pioglitazone should be based on the patient's current regimen with a sulfonylurea and/or pioglitazone. Bioequivalence has been demonstrated between the fixed combination of glimepiride and pioglitazone and each drug given concurrently at the currently approved dosage strengths (2 or 4 mg of glimepiride and 30 mg of pioglitazone). When the commercially available preparation containing pioglitazone in fixed combination with glimepiride is used in patients currently receiving glimepiride monotherapy, the usual initial dosage of the glimepiride component is 2 or 4 mg with 30 mg of pioglitazone once daily.

The usual initial dosage in patients transferring from monotherapy with a sulfonylurea other than glimepiride is 2 mg of glimepiride and 30 mg of pioglitazone once daily. Because an exaggerated hypoglycemic response may occur in some patients during the transition from a sulfonylurea antidiabetic agent with a prolonged half-life (e.g., chlorpropamide) to glimepiride in fixed combination with pioglitazone, patients being transferred from such agents should be monitored closely for the occurrence of hypoglycemia during the initial 1-2 weeks of the transition period. The usual initial dosage in patients previously receiving pioglitazone monotherapy is 2 mg of glimepiride and 30 mg of pioglitazone once daily.

When the fixed-combination preparation is used to replace concurrent therapy with separate tablets of glimepiride and pioglitazone, therapy may be initiated with 2 or 4 mg of glimepiride in fixed combination with 30 mg of pioglitazone once daily based on the patient's current dosage of glimepiride and pioglitazone. Patients who were not controlled with 15 mg of pioglitazone once daily given concurrently with glimepiride as separate tablets should be carefully monitored during transfer to the fixed-combination preparation.

Following initiation of therapy in patients previously receiving monotherapy with pioglitazone or a sulfonylurea or combination therapy with each component given separately, subsequent dosage should be adjusted according to the patient's therapeutic response. Sufficient time should be allowed to assess full therapeutic response (approximately 8-12 weeks) unless glycemic control (as measured by fasting plasma glucose concentrations) deteriorates. If additional glycemic control is needed, the dosage of glimepiride and pioglitazone may be increased to a maximum total daily dosage of 8 mg of glimepiride and 45 mg of pioglitazone.

As geriatric patients, debilitated or malnourished patients, and those with renal or hepatic insufficiency are particularly susceptible to hypoglycemia, such patients should receive initial therapy with glimepiride at a dosage of 1 mg once daily prior to receiving the fixed-combination preparation, followed by conservative initial and maintenance dosages of glimepiride in fixed combination with pioglitazone. Blood glucose concentrations of such patients should be closely monitored prior to and after initiation of therapy to avoid hypoglycemia.

As fluid retention and CHF have been reported with pioglitazone, patients with systolic dysfunction should receive pioglitazone 15 mg once daily as monotherapy and safely tolerate dosage titration to 30 mg once daily as monotherapy before receiving the fixed-combination preparation consisting of glimepiride 2 mg and pioglitazone 30 mg. If subsequent dosage adjustment is necessary with the fixed-combination preparation, patients should be closely monitored for weight gain, edema, or other signs or symptoms of exacerbation of CHF.

Glimepiride/Rosiglitazone Fixed-Combination Therapy

The initial dosage of glimepiride in fixed combination with rosiglitazone should be based on the patient's current regimen with a sulfonylurea and/or rosiglitazone. Bioequivalence has been demonstrated between the fixed combination of glimepiride and rosiglitazone and each drug given concurrently at a dosage of 4 mg of glimepiride and 4 mg of rosiglitazone. When the commercially available fixed-combination preparation containing glimepiride and rosiglitazone (Avandaryl) is used in appropriately selected patients with type 2 diabetes mellitus, the recommended initial dosage is 1 mg of glimepiride and 4 mg of rosiglitazone once daily. An initial dosage of 4 mg of rosiglitazone and 2 mg of glimepiride once daily may be considered in those already receiving rosiglitazone or a sulfonylurea.

In patients previously receiving rosiglitazone monotherapy, sufficient time (approximately 1-2 weeks) should be allowed to assess therapeutic response; dosage titration of the glimepiride component is recommended if adequate glycemic control is not achieved after this time. If additional glycemic control is needed, dosage of the glimepiride component may be increased in increments not exceeding 2 mg. Therapeutic response to an increase in the glimepiride component should be assessed after 1-2 weeks to determine the need for further dosage adjustment.

In patients previously receiving sulfonylurea monotherapy who are switched to the fixed combination of glimepiride and rosiglitazone, 2 weeks may be required to observe a reduction in blood glucose concentrations and 2-3 months to observe full therapeutic response to the rosiglitazone component. If additional glycemic control is needed after 8-12 weeks, the dosage of the glimepiride component may be increased; rosiglitazone dosage should not exceed 8 mg daily. Further dosage titration of the fixed combination is recommended if therapeutic response is not achieved 2-3 months after an increase in dosage of the rosiglitazone component. When transferring from most sulfonylurea agents to the fixed combination of glimepiride and rosiglitazone, a transition period generally is not required. However, because an exaggerated hypoglycemic response may occur in some patients during transition from a long-acting sulfonylurea antidiabetic agent (e.g., chlorpropamide) to the fixed combination of glimepiride and rosiglitazone, close monitoring for the occurrence of hypoglycemia may be necessary for 1-2 weeks after switching to the fixed combination.

When the fixed-combination preparation of glimepiride and rosiglitazone is used to replace concurrent therapy as separate tablets, the dosage of the fixed combination is based on the patient's current dosage of glimepiride and rosiglitazone. If hypoglycemia occurs, reduction of the dosage of the glimepiride component should be considered.

As geriatric patients, debilitated or malnourished patients, and patients with renal, hepatic, or adrenal insufficiency are particularly susceptible to hypoglycemia, dosage should be carefully titrated; conservative initial and maintenance dosages are recommended.

Concomitant Glimepiride and Insulin Therapy

Combined therapy with glimepiride and insulin may be used in patients who no longer respond adequately to oral antidiabetic agents. The manufacturer recommends that such combination therapy be considered when the fasting plasma or serum glucose concentration continues to exceed 150 mg/dL despite appropriate oral antidiabetic monotherapy, diet, and exercise. In such patients, the manufacturer recommends an initial glimepiride dosage of 8 mg once daily with the first main meal and an initially low insulin dosage. Insulin dosage then may be adjusted upward at approximately weekly intervals until adequate glycemic control is achieved; patients should be monitored closely (e.g., with determination of fasting glucose concentrations) during the dosage titration. Once glycemic control has been achieved, patients should monitor their capillary blood glucose concentrations, preferably daily. Periodic adjustments in insulin dosage may be necessary during continued combination therapy, as guided by monitoring of fasting glucose and/or HbA1c concentrations.

Dosage in Renal and Hepatic Impairment

Because glimepiride is eliminated by renal excretion following metabolism in the liver, the manufacturer states that initial dosing of the drug in patients with renal or hepatic impairment should be conservative to avoid hypoglycemic reactions; adults initially should receive 1 mg of glimepiride once daily. The dosage may be titrated upward based on fasting glucose concentrations; patients with creatinine clearance of less than 22 mL/minute may not need further dosage titration. Because geriatric patients may have decreased renal function, the manufacturer states that monitoring renal function may be useful and dosage should be selected with care in these patients. Patients with renal impairment should be closely monitored for hypoglycemia during initiation and subsequent dosage adjustment of such combination therapy.

No studies have been performed in patients with type 2 diabetes mellitus and hepatic impairment; however, initial and maintenance dosage should be conservative to avoid potential hypoglycemic reactions. In patients receiving glimepiride in fixed combination with pioglitazone or rosiglitazone, combination therapy should not be initiated in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT more than 2.5 times the upper limit of normal).

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