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Uses

Diabetes Mellitus

Repaglinide is used as monotherapy as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet and exercise alone. Repaglinide also may be used in combination with metformin or a thiazolidinedione antidiabetic agent (e.g., pioglitazone, rosiglitazone) 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 monotherapy with metformin, a sulfonylurea, repaglinide, or a thiazolidinedione antidiabetic agent. Because of its short duration of action, repaglinide may be particularly suited for control of postprandial hyperglycemia in patients with type 2 diabetes mellitus. However, comparative studies are needed to elucidate the relative efficacy of repaglinide versus other short-acting sulfonylureas (e.g., tolbutamide).

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 mellitus 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 in patients with type 1 diabetes mellitus; insulin is necessary in these patients.

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, 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. Although endogenous insulin is present in type 2 diabetic patients, 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 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 nonenzymatic glycosylation of other proteins throughout the body as a result of recent (e.g., previous 6-8 weeks) hyperglycemia; this measure is used as indicator of chronically elevated blood glucose concentrations and as a predictor of risk for the development of diabetic microvascular complications (e.g., neuropathy, retinopathy, nephropathy). 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 HbA1c concentration produced by intensive insulin treatment (e.g., a 40% reduction in risk of microvascular disease for each 10% reduction in HbA1c). These data imply that any decrease in HbA1c concentrations is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic microvascular complications.

The DCCT was terminated prematurely because of the pronounced benefits of intensive insulin regimens, and all treatment groups were encouraged to institute or continue such intensive insulin therapy. In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term, open-label continuation phase of the DCCT, the reduction in the risk of microvascular complications (e.g., retinopathy, nephropathy, neuropathy) associated with intensive insulin therapy has been maintained throughout 7 years of follow-up. In addition, the prevalence of hypertension (an important consequence of diabetic nephropathy) in those receiving conventional therapy has exceeded that of those receiving intensive therapy. Patients receiving conventional insulin therapy in the DCCT were able to achieve a lower HbA1c when switched to intensive therapy in the continuation study, although the average HbA1c values achieved during the continuation study were higher (i.e., worse) than those achieved during the DCCT with intensive insulin therapy. Patients who remained on intensive insulin therapy during the EDIC continuation study were not able to maintain the degree of glycemic control achieved during the DCCT; by 5 years of follow-up in the EDIC study, HbA1c values were similar in both intensive and conventional therapy groups. The EDIC study demonstrated that the greater the duration of chronically elevated plasma glucose concentrations (as determined by HbA1c values), the greater the risk of microvascular complications. Conversely, the longer patients can maintain a target HbA1c of 7% of less, the greater the delay in the onset of these complications.

Data from the United Kingdom Prospective Diabetes Study (UKPDS) and the Action in Diabetes and VAscular disease: preterax and diamicroN modified release Controlled Evaluation (ADVANCE) study in patients with type 2 diabetes mellitus generally are consistent with the same benefits on microvascular complications in type 2 diabetes mellitus as those observed in type 1 diabetes mellitus in the DCCT study.

Data from the long-term UKPDS in middle-aged, newly diagnosed patients with type 2 diabetes mellitus indicate that strict glycemic control (i.e., maintenance of fasting blood glucose concentrations below 108 mg/dL) is not maintained 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. For additional information on clinical studies demonstrating the benefits of strict glycemic control on microvascular complications in patients with type 1 or type 2 diabetes mellitus, .

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. For additional details regarding the effects of intensive antidiabetic therapy on macrovascular outcomes,

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 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. For additional details on individualizing treatment in patients with diabetes mellitus,

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 and maintain 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, ADA currently suggests 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. In addition, loss of blood glucose control on diet alone can be temporary in some patients, requiring only short-term management with drug therapy. The importance of regular physical activity also 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 an oral antidiabetic agent (e.g., metformin, sulfonylurea, acarbose) or insulin. The patient and clinician should recognize that dietary management is the principal consideration in the management of diabetes mellitus and that oral 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 implementing strict glycemic control in patients with type 2 diabetes, antidiabetic therapy should be individualized considering advanced age, comorbid conditions, preexisting clinically relevant microvascular and macrovascular complications or other vascular risk factors, degree of hyperglycemia, and life expectancy. 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 also 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. For more information on the stepwise approach to the management of type 2 diabetes mellitus,

Repaglinide Monotherapy

Repaglinide reduces both fasting and postprandial blood glucose concentrations and HbA1c in patients with type 2 diabetes mellitus; these reductions are superior to those with placebo and are dose-dependent over a range of 0.25-16 mg of repaglinide daily. Because repaglinide therapy produces a more physiologic profile of insulin secretion (i.e., rapid onset and short duration of action) compared with sulfonylureas, repaglinide may be particularly useful for control of postprandial hyperglycemia through use of a ''one meal, one dose; no meal, no dose'' concept, allowing for increased flexibility of meal patterns (e.g., especially in adolescents, who may have an irregular eating schedule) and a reduced risk of hypoglycemia between meals or in the event of a missed meal. Repaglinide is almost as effective as metformin or sulfonylureas in improving glycemic control (approximately 1.5% decrease in HbA1c values), but has a shorter duration of action and is more expensive than metformin. ADA and other clinicians recommend metformin as initial antidiabetic therapy, provided no contraindications exist, because of the absence of weight gain or hypoglycemia, generally low adverse effect profile, and relatively low cost. In a randomized study, patients who ate 2, 3, or 4 meals daily with repaglinide doses prior to each meal achieved similar glycemic control (as assessed by serum glucose profiles and serum fructosamine concentrations) regardless of the number of meals and repaglinide doses daily. In another double-blind, randomized study, mean minimum blood glucose concentrations (obtained between lunch and dinner) were reduced from 77 to 61 mg/dL when lunch was omitted in patients receiving glyburide twice daily (before breakfast and dinner) but were essentially unchanged in those receiving preprandial repaglinide (i.e., dose omitted when lunch omitted); all hypoglycemic events (defined as blood glucose concentrations less than 45 mg/dL) in the study occurred in glyburide-treated patients.

In controlled clinical trials of 4-24 weeks' duration, repaglinide was more effective than placebo in reducing fasting and postprandial blood glucose concentrations and HbA1c in patients with type 2 diabetes mellitus, both in those previously treated with sulfonylureas and treatment-naive patients (i.e., those not previously treated with oral antidiabetic agents). In a 24-week, placebo-controlled trial, repaglinide was most effective in patients not previously treated with oral antidiabetic agents and in those in relatively good glycemic control (HbA1c less than 8%) at study entry; the reduction in HbA1c was 1.7 and 2.1% in the previously treated and treatment-naive groups, respectively. In both short-term and long-term comparative studies, repaglinide (after initial dosage titration) was as effective as glyburide and more effective than glipizide for the management of hyperglycemia in treatment-naive patients with type 2 diabetes mellitus. Similar to sulfonylurea therapy, repaglinide therapy generally increases postprandial plasma insulin concentrations and is associated with weight gain (3.3%) in patients who have not previously received oral sulfonylurea therapy. The hypoglycemic effect of repaglinide does not appear to be influenced by duration of diabetes, race, or age.

While repaglinide has been used effectively as initial monotherapy in appropriately selected patients with type 2 diabetes mellitus, data are limited concerning use of the drug as monotherapy in patients who did not achieve adequate glycemic control with other oral antidiabetic monotherapy (e.g., glyburide, metformin). In several placebo-controlled trials (12 or 24 weeks' duration) that included a subgroup of patients who had previously received oral antidiabetic therapy, the difference in HbA1c between repaglinide therapy and placebo was 1.6-1.7%, reflecting mainly an increase in HbA1c in the placebo groups (1.4-1.5%) rather than an improvement in glycemic control with repaglinide. In another trial of patients with poorly controlled diabetes mellitus during metformin therapy, switching to repaglinide therapy did not appreciably improve glycemic control; however, repaglinide monotherapy maintained glycemic control with fewer adverse GI effects than metformin monotherapy. Body weight does not change when patients are switched from other oral antidiabetic therapy to repaglinide.

While data concerning secondary failure with repaglinide are limited, interim data from a substudy (UKPDS 26) of UKPDS 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 despite a maximum recommended daily dosage of 20 mg of glyburide or 500 mg of chlorpropamide or symptoms of hyperglycemia) 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 UKPDS, 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 (UKPDS 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.

Repaglinide 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. ADA does not recommend use of meglitinides in hospitalized patients with diabetes mellitus because data on such use are limited in such patients.

Combination Therapy

Repaglinide may be used concomitantly with metformin or a thiazolidinedione (e.g., pioglitazone, rosiglitazone) in patients with type 2 diabetes who do not achieve adequate glycemic control with appropriate diet, exercise, and monotherapy with metformin, a sulfonylurea, repaglinide, or a thiazolidinedione antidiabetic agent. However, ADA and other clinicians 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 therapy with metformin or at any other time when the target HbA1c goal is not achieved). The American Diabetes Association (ADA) generally recommends metformin as initial antidiabetic therapy in patients with type 2 diabetes mellitus, provided no contraindications exist, because of the absence of weight gain or hypoglycemia, generally low adverse effect profile, and relatively low cost.

ADA states that meglitinides may be appropriate choices in selected patients but are not preferred as second-line therapy after failure with metformin monotherapy because of their overall lower effectiveness, limited clinical data, and relative expense.

Data are limited concerning the incidence of primary failure (lack of glycemic response after 1-3 months of therapy with fasting blood glucose concentrations exceeding 140 mg/dL) or secondary failure (progressively decreasing diabetic control following 1 month to several years of good control) with repaglinide therapy. In several comparative clinical trials in which fixed dosages of repaglinide or glyburide were used after initial dosage titration, glycemic control (as determined by fasting plasma glucose and HbA1c concentrations) was maintained for the first 6-9 months of the studies but gradually declined (i.e., fasting glucose and HbA1c values increased) thereafter. Although not representative of clinical practice because of the fixed dosages used in these studies, the percentage of patients who withdrew because of ineffective therapy was 3.3% among both treatment groups in one study, 8-12% among repaglinide-treated patients in another study, and 18% in each treatment group in the third study; whether these figures represent primary or secondary failure of oral antidiabetic therapy was not reported. In a clinical trial in patients poorly controlled by metformin monotherapy, the combination of repaglinide and metformin reduced fasting plasma glucose concentrations and HbA1c by 39.2 mg/dL and 1.41%, respectively, compared with reductions of 4.5 mg/dL and 0.33%, respectively, with metformin alone; patients receiving repaglinide therapy alone had an increase in fasting glucose concentrations of 8.8 mg/dL and a reduction of 0.38% in HbA1c. In this study, the dosage of metformin hydrochloride was kept constant (final median dosage of 1.5 g either as monotherapy or as a component of combination therapy), and the dosage of repaglinide was titrated for 4-8 weeks followed by a 3-month maintenance period. Greater glycemic control was achieved with combined repaglinide and metformin therapy at half the median daily dosage of repaglinide compared with that used for repaglinide monotherapy. In a clinical trial in patients with inadequate glycemic control (as determined by HbA1c values exceeding 7%) while receiving metformin or sulfonylurea monotherapy, the combination of repaglinide (6 mg daily) and rosiglitazone (4 mg daily) reduced fasting plasma glucose concentrations and HbA1c by 94 mg/dL and 1.43%, respectively, at 24 weeks compared with reductions of 54 mg/dL and 0.17%, respectively, with repaglinide (12 mg daily) alone; patients receiving rosiglitazone monotherapy (8 mg daily) had a decrease in fasting glucose concentrations of 67 mg/dL and a reduction of 0.56% in HbA1c.

Combined therapy with repaglinide and other oral antidiabetic agents (e.g., metformin) in patients not adequately controlled with monotherapy may reduce symptoms and delay or avoid institution of insulin.

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. However, other options in patients not adequately controlled on 2 oral antidiabetic agents include addition of a third oral agent, addition of a bedtime dose of a long-acting (e.g., isophane) insulin, or switching to a multiple-injection insulin regimen. 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. However, triple combination oral antidiabetic therapy is more costly and potentially not as effective as adding insulin therapy to dual combination oral antidiabetic therapy. Repaglinide has been used in combination with isophane (NPH) insulin to improve glycemic control in patients with type 2 diabetes mellitus who no longer respond adequately to therapy with one or more oral antidiabetic agents. In a placebo-controlled trial, therapy with repaglinide alone or combined with NPH insulin at bedtime improved glycemic control (as measured by a reduction in fasting blood glucose concentrations and HbA1c) in patients inadequately controlled with sulfonylurea therapy with or without metformin. Pooled analysis of data from a number of clinical trials, each evaluating the combination of repaglinide and isophane insulin a limited number of patients, revealed myocardial ischemia in a small number of such patients; repaglinide is not indicated for use in such a combination regimen. 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.

Dosage and Administration

Administration

Repaglinide is administered orally. The manufacturer states that the drug generally is given within 15 minutes of each meal but may be given as early as 30 minutes prior to each meal up to immediately preceding each meal. While administration with food has been reported to affect the extent of repaglinide absorption, this effect is not thought to be clinically important.(See Pharmacokinetics: Absorption.)

Because repaglinide has a short half-life, current pharmacodynamic data suggest that the use of pre-meal doses may enhance glycemic control compared with twice-daily dosing at breakfast and dinner using the same total daily dosage of repaglinide. Depending on the patient's meal patterns, repaglinide should be given prior to each meal, with a total dosing frequency of 2-4 times daily; patients who skip a meal or add an extra meal should be instructed to skip or add a dose, respectively, for that meal. Meal-related dosing of repaglinide allows patients to maintain glycemic control and to avoid hypoglycemic episodes even when eating patterns are varied (e.g., skipped meals).(See Diabetes Mellitus: Repaglinide Monotherapy in Uses.)

Dosage

Diabetes Mellitus

Dosage of repaglinide must be individualized carefully based on patient response and tolerance. The goal of therapy should be to reduce both fasting blood (or plasma) glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) values to normal or near normal using the lowest effective dosage of repaglinide, either when used as monotherapy or in combination with metformin or a thiazolidinedione. (Glucose concentrations in plasma generally are 10-15% higher than those in whole blood; glucose concentrations also may vary according to the method and laboratory used for these determinations.) Patients should be monitored with regular laboratory evaluations, including fasting blood (or plasma) glucose determinations, to assess the therapeutic response and the minimum effective dosage of repaglinide. While fasting (preprandial) glucose concentrations are widely used for determination of glycemic control, the American Diabetes Association (ADA) and some clinicians currently suggest that routine blood glucose monitoring individualized to the patient's needs probably should include determination of postprandial glucose concentrations as well (e.g., fasting and 2-hour postprandial blood glucose concentrations). Postprandial blood glucose determinations may be helpful in patients whose preprandial blood glucose concentrations are satisfactory but whose overall glycemic control (as determined by HbA1c values) is inadequate. Glucose concentrations 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) of drug therapy. If inadequate glycemic control and/or secondary failure occurs during maintenance therapy with repaglinide, a sulfonylurea, a thiazolidinedione, or metformin alone, combined therapy with metformin or a thiazolidinedione and repaglinide may result in an adequate response. If secondary failure occurs with combined metformin and repaglinide therapy, most clinicians currently recommend discontinuance of oral antidiabetic agents and initiation of insulin therapy. However, some clinicians suggest other options such as addition of a third oral antidiabetic agent (e.g., acarbose, a thiazolidinedione) before switching to insulin therapy.(See Diabetes Mellitus: Combination Therapy, in Uses.)

During initiation of therapy and titration of dosage, fasting and postprandial blood glucose determinations should be performed to determine therapeutic response weekly and the minimum effective dosage of repaglinide; thereafter, HbA1c values should be monitored at intervals of approximately 3 months to evaluate long-term glycemic control. In patients usually well controlled by dietary management alone, short-term therapy with repaglinide may be sufficient during periods of transient loss of diabetic control.

Initial Dosage

For the management of type 2 diabetes mellitus in patients not previously treated with oral antidiabetic agents or in those who have relatively good glycemic control (i.e., HbA1c less than 8%), the usual initial adult dosage of repaglinide is 0.5 mg (the minimum effective dosage) given preprandially (see Dosage and Administration: Administration) for a total dosing frequency of 2-4 times daily, depending on the patient's meal patterns. For patients whose HbA1c remains 8% or greater despite treatment with other oral antidiabetic agents, the initial adult dosage of repaglinide is 1 or 2 mg with or preceding each meal. Approximately 90% of the maximal glucose-lowering effect of repaglinide is achieved with a dosage of 1 mg 3 times daily. A lower initial starting dosage may be needed in patients who have not received oral antidiabetic therapy previously or in those with relatively good glycemic control at treatment initiation, as an increase in hypoglycemic symptoms was noted in such patients receiving repaglinide during clinical trials.

Subsequent dosage of repaglinide should be adjusted according to the patient's therapeutic response and tolerance, using the lowest possible effective dosage. Dosage of repaglinide may be doubled at no less than weekly intervals until the desired fasting blood glucose concentration (e.g., 80-140 mg/dL with infrequent hypoglycemic episodes) is achieved or a maximum daily dosage of 16 mg (e.g., 4 mg four times daily depending on meal patterns) is attained. Some patients have received higher dosages of repaglinide (8-20 mg 3-4 times daily before meals), but the safety and efficacy of such dosages have not been established. If fasting blood glucose concentrations fall below 80 mg/dL or symptoms of hypoglycemia occur, the dosage of repaglinide should be reduced and therapeutic measures instituted to treat hypoglycemia if necessary.(See Acute Toxicity.)

Transferring from Therapy with Other Antidiabetic Agents

When transferring from most other oral antidiabetic agents to repaglinide, a transition period generally is not required, and administration of the other oral antidiabetic agent may be abruptly discontinued and repaglinide initiated the day after the final dose of the other oral antidiabetic agent. Because an exaggerated hypoglycemic response may occur in some patients during transition from a long-acting sulfonylurea antidiabetic agent (e.g., chlorpropamide) to repaglinide, close monitoring for the occurrence of hypoglycemia may be necessary for one week or longer after switching to repaglinide.

Concomitant Therapy with Repaglinide and Metformin or a Thiazolidinedione

If monotherapy with repaglinide does not result in adequate glycemic control (i.e., fasting blood glucose concentrations between 80 and 140 mg/dL with infrequent hypoglycemic episodes), metformin or a thiazolidinedione may be added to therapy. Likewise, repaglinide in combination with metformin and thiazolidinedione may be used in patients who have inadequate glycemic control after 2-3 months with initial metformin, sulfonylurea, or thiazolidinedione monotherapy. Titration of the initial dosage of repaglinide during combination therapy is the same as with repaglinide monotherapy. With concomitant metformin or thiazolidinedione and repaglinide therapy, dosage of each drug should be adjusted to obtain adequate glycemic control (as determined by fasting plasma glucose and HbA1c concentrations) using the minimum effective dosage of each drug. Failure to titrate the dosage of each drug to the minimum effective level could result in an increased risk of hypoglycemic episodes. When hypoglycemia occurs in patients receiving combination therapy with repaglinide and a thiazolidinedione or metformin, the dosage of repaglinide should be reduced. Indicators of glycemic control (fasting blood glucose concentrations, HbA1c) also should be monitored to detect the development of secondary failure of antidiabetic therapy. In patients who do not respond to 3 months of concomitant therapy at the maximum dosage of each oral antidiabetic agent, therapy with oral antidiabetic agents generally should be discontinued and insulin therapy instituted although other therapeutic options also have been suggested.(See Diabetes Mellitus: Combination Therapy, in Uses.)

Special Populations

Renal Impairment

Accumulation of repaglinide (as indicated by increased peak plasma concentrations and AUC) occurs in patients with renal impairment. However, no adjustment in the initial dosage of repaglinide appears to be necessary in patients with mild to moderate renal dysfunction. Although the usual initial dosage of repaglinide may be used in these patients, subsequent increases in dosage should be made with caution. The manufacturer states that patients with severe renal impairment (e.g., creatinine clearance of 20-40 mL/minute) should initiate therapy with a repaglinide dose of 0.5 mg, with subsequent careful dosage titration. Use of repaglinide in patients with creatinine clearances below 20 mL/minute or in those with renal failure requiring hemodialysis has not been established.

Hepatic Impairment

Since repaglinide is extensively metabolized by the liver, the drug should be used with caution in patients with hepatic impairment. The manufacturer and some clinicians state that the usual initial dosage of repaglinide may be given to these patients, but subsequent dosage adjustments should be made at longer than usual intervals (e.g., 3 months) to allow full assessment of response; however, other clinicians have suggested use of a lower initial dosage in patients with hepatic impairment.

Cautions

Repaglinide shares the toxic potential of other oral antidiabetic agents, and the usual precautions of oral antidiabetic therapy should be observed with repaglinide. When repaglinide is used in combination with metformin or a thiazolidinedione (e.g., rosiglitazone), the cautions, precautions, and contraindications associated with these concomitant agents must be considered in addition to those associated with repaglinide. The overall frequency of adverse effects with repaglinide therapy appears to be similar to that reported with oral sulfonylureas; limited data suggest that repaglinide may be associated with fewer adverse GI effects than metformin. In addition to hypoglycemia, the most common adverse effects in clinical trials of repaglinide were headache and dizziness, which may have been related to changes in glycemic control; data from several comparative one-year trials indicate that 13 or 14% of patients receiving repaglinide or oral sulfonylureas (i.e., glyburide or glipizide), respectively, discontinued the drug as a result of adverse effects. The most common effects leading to drug discontinuance were hyperglycemia, hypoglycemia, and related symptoms.

Hypoglycemia

Hypoglycemia is the most frequent adverse effect of repaglinide and may occur shortly after dosing when a meal is delayed or omitted. Hypoglycemia is more likely to occur after severe or prolonged exercise, or during concurrent use of alcohol or other antidiabetic agents. Based on pooled data from several comparative trials evaluating combination therapy of repaglinide and thiazolidinediones (i.e., pioglitazone, rosiglitazone), the incidence of hypoglycemia was 7, 7, or 2% in patients receiving combination therapy, repaglinide alone, or a thiazolidinedione alone. Pooled data from long-term (1-year) comparative clinical trials in patients with type 2 diabetes mellitus indicate that mild to moderate hypoglycemia occurred in 16% of patients receiving repaglinide, 20% of patients receiving glyburide, and 19% of those receiving glipizide. In several long-term (1-year) comparative trials, drug discontinuance as a result of hypoglycemia occurred in half as many patients (1.4 versus 2.8%) receiving repaglinide as in sulfonylurea-treated patients. In placebo-controlled trials of up to 6 months' duration, 0.6% of patients receiving repaglinide discontinued the drug as a result of hypoglycemia. Of patients in comparative clinical trials who developed symptomatic hypoglycemia during antidiabetic therapy, none of the episodes in those receiving repaglinide was severe (i.e., no patient developed coma or required hospitalization) while several patients receiving sulfonylureas developed severe hypoglycemia. In placebo-controlled trials, hypoglycemia occurred in 31% of patients treated with repaglinide; however, most of these hypoglycemic episodes occurred in a large, fixed-dose trial in which dosage adjustments, if allowed, could potentially have averted such episodes. In this trial, patients who had not previously received oral antidiabetic therapy and those with relatively good glycemic control at study entry (HbA1c less than 8%) had an increased frequency of hypoglycemia during treatment with repaglinide. Patients who had previously received oral antidiabetic therapy and who had a baseline HbA1c value of at least 8% developed hypoglycemia with similar frequency as those receiving placebo.(See Cautions: Precautions and Contraindications.)

Severe hypoglycemia has been reported rarely during postmarketing surveillance in patients receiving concomitant therapy with repaglinide and gemfibrozil.(See Drug Interactions: Drugs or Foods Affecting Hepatic Microsomal Enzymes.) Repaglinide and gemfibrozil should not be used concomitantly.(See Cautions: Precautions and Contraindications.)

Respiratory Effects

Upper respiratory tract infection occurred in 16% of patients receiving repaglinide in placebo-controlled trials. Pooled data from several comparative trials indicate that upper respiratory tract infection occurred in 10% of patients receiving either repaglinide or a sulfonylurea (i.e., glyburide, glipizide). Sinusitis, rhinitis, or bronchitis occurred in 6, 3, or 2%, respectively, of patients receiving repaglinide in placebo-controlled trials and in 3, 7, or 6%, respectively, of patients receiving the drug in several comparative trials.

Musculoskeletal Effects

Arthralgia or back pain occurred in 6 or 5% of patients, respectively, receiving repaglinide in placebo-controlled trials of up to 6 months' duration. Pooled data from several long-term, comparative (with glipizide or glyburide) trials indicate that arthralgia or back pain occurred in 3 or 6%, respectively, of patients receiving repaglinide.

GI Effects

Nausea or diarrhea occurred in 5% of patients receiving repaglinide in placebo-controlled trials of up to 6 months' duration. Dyspepsia or diarrhea occurred in 4% of patients receiving the drug in several long-term, comparative trials; dyspepsia occurred in 2% of patients receiving repaglinide in placebo-controlled trials. Constipation or vomiting occurred in 3 or 2% of patients receiving repaglinide in placebo-controlled or comparative trials, respectively. In a multicenter, comparative study in poorly controlled, obese patients with type 2 diabetes mellitus, monotherapy with repaglinide maintained glycemic control with fewer adverse GI effects than metformin monotherapy.

Cardiovascular Effects

Cardiovascular events are more common in patients with type 2 diabetes mellitus than in those without diabetes. In long-term (1-year) comparative clinical trials, the incidence of serious cardiovascular effects with repaglinide was similar (4%) to that with glyburide or glipizide (3%). Cardiac ischemic effects occurred in 2% of patients receiving either repaglinide or a sulfonylurea (glyburide or glipizide) in these comparative trials. Angina or chest pain occurred in 1.8% of patients receiving repaglinide in 1-year comparative trials with these sulfonylureas; chest pain was also reported in 3% of patients receiving the drug in placebo-controlled trials. The overall incidence of other cardiovascular effects, including hypertension, abnormal ECGs, myocardial infarction, arrhythmias, and palpitations, was 1% or less in comparative trials in patients receiving repaglinide. Flushing has been reported rarely with repaglinide therapy. Pooled data from several comparative trials indicate that the incidence of serious cardiovascular effects is lower with repaglinide therapy than with glipizide therapy and slightly higher with repaglinide than with glyburide; risk appears to be related to age of the patient and previous cardiovascular history. Repaglinide was not associated with an appreciable excess of cardiovascular mortality (0.5%) compared with glyburide or glipizide (0.4%).

Edema can occur alone and in association with congestive heart failure when repaglinide is used in combination with a thiazolidinedione antidiabetic agent. Based on pooled data from several clinical trials, peripheral edema occurred in 5% of patients receiving repaglinide and thiazolidinedione combination therapy and in 4% of patients receiving thiazolidinedione monotherapy. Patients receiving repaglinide in combination with a thiazolidinedione experienced more weight gain than has been observed during therapy with repaglinide alone. Edema with congestive heart failure has been reported in 0.8% of patients receiving combined repaglinide and thiazolidinedione therapy. Such patients had a prior history of coronary artery disease, and congestive heart failure resolved after treatment with diuretics. (See Edema under Warning/Precautions: General Precautions, in Cautions in or 68:20.28)

Nervous System Effects

Headache occurred in 11% of patients receiving repaglinide in placebo-controlled trials and in 9% of those receiving the drug in several comparative trials. Paresthesia occurred in 3% of patients receiving repaglinide in placebo-controlled trials and in 2% of those in several comparative trials. Other adverse nervous system effects reported with repaglinide therapy include pain, hyperesthesia or hypoesthesia, dizziness, and fatigue.

Other Adverse Effects

Urinary tract infection occurred in 2% of patients receiving repaglinide in a placebo-controlled trial and in 3% of those receiving the drug in several comparative trials. Increased frequency of micturition also has been reported with repaglinide therapy.

Tooth disorder or allergy occurred in 2% of patients receiving repaglinide in placebo-controlled trials and in less than 1 or 1%, respectively, of those in several comparative trials. Increased appetite also has been reported with repaglinide therapy; in addition, as with sulfonylurea antidiabetic agents, some treatment-naive patients receiving repaglinide experienced weight gain. Rash, increased appetite, and accidental injury also have been reported with repaglinide therapy. Adverse effects occurring in less than 1% of patients receiving repaglinide include elevated liver enzymes, thrombocytopenia, and leukopenia. Hemolytic anemia, alopecia, pancreatitis, Stevens-Johnson syndrome, or severe hepatic dysfunction, including jaundice and hepatitis, has been reported rarely during postmarketing experience with the drug. Changes in blood glucose concentrations may result in blurred vision and visual disturbances, usually transient, particularly at initiation of treatment with hypoglycemic agents. Anaphylactoid reaction has been reported rarely with repaglinide therapy.

Precautions and Contraindications

The diagnostic and therapeutic measures for managing diabetes mellitus that are necessary to ensure optimum control of the disease with insulin generally are necessary with repaglinide. Clinicians who prescribe repaglinide should be familiar with the indications, limitations, and patient-selection criteria for therapy with oral antidiabetic agents to ensure appropriate patient management, including management of hypoglycemic episodes. Patients receiving repaglinide should be monitored with regular laboratory evaluations, including blood glucose determinations, to determine the minimum effective dosage of repaglinide when used either as monotherapy or in combination with metformin. Glycosylated hemoglobin (hemoglobin A1c [HbA1c]) measurements also are useful, particularly for monitoring long-term control of blood glucose concentration. Blood glucose determinations are important to detect primary failure (inadequate lowering of blood glucose concentration at the maximum recommended dosage) or secondary failure (loss of control of blood glucose concentration following an initial period of effectiveness) to the drug. The need for dosage adjustment and adherence to diet should be assessed before determining a patient to be a secondary failure.

Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral antidiabetic agents. In 1970, the University Group Diabetes Program (UGDP) reported that administration of oral antidiabetic agents (i.e., tolbutamide or phenformin) was associated with increased cardiovascular mortality compared with treatment with dietary regulation alone or with dietary regulation and insulin. The UGDP reported that type 2 diabetic patients who were treated for 5-8 years with dietary regulation and a fixed dose (1.5 g daily) of tolbutamide or dietary regulation and a fixed dose (100 mg daily) of phenformin (currently not commercially available in the US) had a cardiovascular mortality rate approximately 2.5 times that of patients treated with dietary regulation alone; although a substantial increase in total mortality was not observed, the use of tolbutamide was discontinued because of the increase in cardiovascular mortality, thereby limiting the ability of the study to show an increase in total mortality. The results of the UGDP study have been analyzed exhaustively, and there has been general disagreement in the scientific and medical communities regarding the study's validity and clinical importance. However, recent results from the United Kingdom Prospective Diabetes Study (UKPDS), a large, long-term (over 10 years) study in newly diagnosed type 2 diabetic patients, did not confirm an increase in cardiovascular events or mortality in the group treated intensively with sulfonylureas, insulin, or combination therapy compared with less intensive conventional antidiabetic therapy.

In UKPDS, the overall aggregate rates of death from macrovascular diseases such as myocardial infarction, sudden death, stroke, or peripheral vascular disease were not appreciably different among either intensive therapies (stepwise introduction of a sulfonylurea [i.e., chlorpropamide, glyburide] followed by insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentration of 108 mg/dL) or less intensive conventional therapy (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations below 270 mg/dL without symptoms of hyperglycemia). However, a trend in reduction in fatal and nonfatal myocardial infarction with intensive therapy was noted with sulfonylurea or insulin, and epidemiologic analysis of the data indicate that each 1% decrease in HbA1c was associated with an 18% reduction in fatal and nonfatal myocardial infarction. Among the single end points, the incidence of angina increased among patients receiving chlorpropamide, and blood pressure also was higher with chlorpropamide compared with glyburide or insulin intensive therapies. As a result of these and other findings (e.g., beneficial effects on microvascular [retinopathy, nephropathy, and possibly neuropathy] complications, confirmation of the beneficial effects of concomitant antihypertensive therapy and blood pressure lowering) of UKPDS, the American Diabetes Association (ADA) currently considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control in diabetic patients to outweigh the risks overall. ADA currently recommends that clinicians continue to emphasize dietary management and weight reduction as the principal therapy for the management of type 2 diabetes mellitus and that oral antidiabetic agents or insulin be used only after these measures have failed; the decision to use an oral antidiabetic agent or insulin should be made by the clinician in consultation with the patient. While the manufacturer of repaglinide states that it is prudent from a safety standpoint to consider that the potential increase in cardiovascular risk seen with tolbutamide in the UGDP study also may apply to repaglinide because of similarities in mechanisms of actions, pooled data from several comparative trials suggest that the incidence of cardiovascular mortality with repaglinide (0.5%) is not appreciably different from that reported with other sulfonylureas (i.e., glyburide, glipizide) (0.4%).(See Cautions: Cardiovascular Effects).

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 repaglinide 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 repaglinide therapy is used only as an adjunct to, and not a substitute for, proper dietary regulation. Patients who do not comply with prescribed dietary regimens are more likely to have an unsatisfactory response to oral antidiabetic drug therapy and are more susceptible to hypoglycemia. Patients also should be advised that they should not neglect dietary restrictions, develop a careless attitude about their condition, or disregard instructions about weight control, exercise, hygiene, and avoidance of infection. Patients receiving repaglinide also should be cautioned that failure to follow an appropriate dosage regimen may result in hypoglycemia or hyperglycemia. The possibility of primary and secondary failure of oral antidiabetic agents also should be explained to patients.

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 occasionally may occur during therapy with repaglinide.Appropriate patient selection, patient education, and careful attention to dosage are important to avoid hypoglycemic episodes. However, hypoglycemia may occur when the drug is used concomitantly with another oral antidiabetic agent and/or insulin; if needed, patients should be instructed in concomitant use of other antidiabetic agents. In addition, certain other factors (e.g., deficient caloric intake, strenuous exercise not compensated by caloric supplementation, alcohol ingestion, adrenal or pituitary insufficiency) may predispose patients to the development of hypoglycemia. Debilitated, malnourished, or geriatric patients also may be particularly susceptible to hypoglycemia; this condition may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents or other sympatholytic agents. Risk of serious hypoglycemia may be increased in patients with hepatic failure, who may have reduced clearance of repaglinide and diminished gluconeogenic capacity. The frequency of hypoglycemia is increased in patients with type 2 diabetes mellitus who have not been previously treated with oral antidiabetic agents or whose HbA1c concentration is less than 8%.

To maintain control of diabetes during periods of stress (e.g., fever of any cause, trauma, infection, surgery), temporary discontinuance of repaglinide and administration of insulin may be required. According to the clinician's judgment, repaglinide therapy may be reinstituted after the acute episode is resolved.

Repaglinide is contraindicated as sole therapy in patients with type 1 diabetes and in patients with diabetes complicated by acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma; insulin should be used to treat these conditions. Repaglinide also is contraindicated in patients receiving gemfibrozil.(See Drug Interactions.) Repaglinide is contraindicated in patients with known hypersensitivity to the drug.

Pediatric Precautions

Safety and efficacy of repaglinide in children younger than 18 years of age have not been established, and the drug has not been studied in type 2 diabetes mellitus of the young, an inherited genetic disorder. However, the American Diabetes Association (ADA) states that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater patient compliance and convenience for the patient's family and a lack of evidence demonstrating better efficacy of insulin as initial therapy for type 2 diabetes mellitus.

Geriatric Precautions

The safety and efficacy of repaglinide appear to be similar in geriatric and younger patients. No pharmacokinetic differences were noted in healthy geriatric individuals (65 years of age or older) versus healthy younger individuals receiving repaglinide 2 mg before each meal.(See Pharmacokinetics: Absorption.) Subgroup analyses of clinical trials have not revealed evidence of altered effectiveness or safety of repaglinide based on age other than the expected age-related increase in cardiovascular morbidity observed with repaglinide and other comparative oral antidiabetic agents. No increase in the frequency and severity of hypoglycemia was observed in geriatric versus younger patients receiving repaglinide.

Mutagenicity and Carcinogenicity

Repaglinide showed no evidence of genotoxicity in a number of in vitro and in vivo tests, including bacterial mutagenesis (Ames test), chromosomal aberrations in human lymphocytes, forward cell mutation assay in V79 cells (HGPRT), unscheduled and replicating DNA synthesis assay in rat hepatocytes, and in vivo mouse and rat micronucleus tests.

Although the relevance to long-term use in humans is not known, long-term (i.e., 2 years) studies in rodents have revealed some carcinogenic potential associated with high dosages of repaglinide. In male rats receiving oral repaglinide dosages up to 120 mg/kg daily, representing 60 times the human exposure on a mg/m basis, an increased incidence of benign hepatocellular and thyroid adenomas was observed; similar changes were not observed in male rats at oral dosages of 30 or 60 mg/kg daily for thyroid adenomas or hepatocellular adenomas, respectively (representing 15 or 30 times the human exposure on a mg/m basis, respectively). No increase in these adenomas was seen in female rats receiving the same dosage or in mice of either sex receiving 500 mg/kg daily, representing 125 times the human clinical exposure on a mg/m basis.

Pregnancy, Fertility, and Lactation

Pregnancy

The safety of repaglinide in pregnant women has not been established, and the drug should be used during pregnancy only when clearly needed. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, most experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration.

Reproduction studies in rats and rabbits given repaglinide at dosages representing 40 times or 0.8 times the human clinical exposure based on body surface area, respectively, have not revealed evidence of harm to the fetus.

Fertility

No evidence of impaired fertility was observed in male or female rats following administration of repaglinide dosages of 300 mg/kg daily or 80 mg/kg daily, respectively (representing over 40 times the human exposure based on body surface area).

Lactation

Nursing pups of rat dams receiving repaglinide at 15 times the human exposure on a mg/m basis during days 17-22 of gestation and throughout lactation developed shortening, thickening, and bending of the humerus during the postnatal period. Cross-fostering studies indicate that such skeletal changes could be induced in control pups nursed by treated dams, although skeletal changes occurred to a lesser degree than in pups exposed to repaglinide in utero. Lowered blood glucose concentrations were found in nursing pups of rat dams treated with repaglinide, and skeletal effects were similar to those observed in rat pups subjected to hypoglycemia during pregnancy. These nonteratogenic effects were not seen in nursing pups of rat dams receiving repaglinide dosages of up to 2.5 times the human exposure on a mg/m basis during days 1-22 of gestation or at higher dosages given during days 1-16 of pregnancy. Similar studies in humans have not been conducted, and the safety of repaglinide administration throughout pregnancy or lactation cannot be established.

Because of the potential for repaglinide to cause hypoglycemia and resultant skeletal changes in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. If repaglinide is discontinued and diet therapy alone does not provide adequate glycemic control, insulin therapy should be instituted.

Drug Interactions

Drugs or Foods Affecting Hepatic Microsomal Enzymes

Repaglinide is metabolized by multiple cytochrome P-450 (CYP) microsomal isoenzymes, including 3A4 and 2C8, and drugs that induce or inhibit these isoenzymes may alter the metabolism of the drug. Caution should be used during concomitant administration of repaglinide and inhibitors or inducers of CYP2C8 and 3A4 isoenzymes. Some clinicians suggest that blood glucose concentrations be monitored closely and that dosage adjustment of repaglinide may be necessary in patients receiving strong inducers or inhibitors of these microsomal isoenzymes concomitantly with repaglinide. If repaglinide is administered concomitantly with several inhibitors affecting either CYP2C8 (e.g., gemfibrozil) or 3A4 isoenzymes (e.g., itraconazole), simultaneous inhibition of these multiple isoenzymes may result a substantial increase in the plasma concentrations of repaglinide.(See Cautions: Precautions and Contraindications.)

In vitro data suggest that antifungal agents such as itraconazole, ketoconazole and miconazole; antibacterial agents such as erythromycin; and cyclosporine can inhibit the metabolism of repaglinide, probably via inhibition of the CYP3A4. Concomitant administration of a single 2-mg dose of repaglinide in patients receiving ketoconazole 200 mg daily for 4 days resulted in a 15% increase in the area under the blood concentration-time curve (AUC) and a 16% increase in peak blood concentrations of repaglinide. Addition of a single 0.25-mg dose (dosage strength not commercially available in the US) of repaglinide in healthy individuals receiving itraconazole 100 mg twice daily for 3 days (following an initial 200-mg dose of itraconazole) resulted in a 1.4-fold increase in the AUC of repaglinide. Addition of a single 0.25-mg dose of repaglinide following 4 days of therapy with clarithromycin 250 mg twice daily resulted in a 40 and 67% increase in the AUC and peak plasma concentrations, respectively, of repaglinide. The appreciable increase in repaglinide plasma concentrations observed during concomitant administration of clarithromycin may necessitate an adjustment in the dosage of repaglinide. Other drugs or foods that inhibit the CYP3A4 isoenzyme, such as protease inhibitors or grapefruit juice, may potentially inhibit the metabolism of repaglinide. However, coadministration of repaglinide and cimetidine, another inhibitor of the hepatic microsomal enzyme system, does not appreciably alter the absorption or disposition of repaglinide.

Concomitant administration of repaglinide with drugs that induce the CYP3A4 or 2C8 isoenzymes (e.g., troglitazone [no longer commercially available in the US], rifampin, barbiturates, carbamazepine) may theoretically increase repaglinide metabolism. Rifampin also may be a substrate for the these microsomal enzymes and may act as a competitive inhibitor with repaglinide in binding to these isoenzymes. Concomitant administration of a single 4-mg dose of repaglinide and 600 mg of rifampin in healthy individuals receiving rifampin 600 mg daily for the previous 6 days resulted in a 32 and 26% decrease in the AUC and peak plasma concentrations of the drug, respectively. In another study in healthy individuals receiving rifampin 600 mg daily for 6 days, coadministration of a single 4-mg dose of repaglinide and rifampin 600 mg on day 6 resulted in a 48 and 17% decrease in the median AUC and peak plasma concentrations of repaglinide, respectively. When repaglinide was given to healthy individuals 24 hours after receiving rifampin 600 mg once daily for the previous 7 days, an even greater reduction in the median AUC (80%) and peak plasma concentrations (79%) of repaglinide was observed. As rifampin was not administered concomitantly with repaglinide in this study, rifampin was not able to act as a competitive inhibitor with repaglinide for CYP enzyme binding, and the full inductive effect of rifampin on these enzymes could be observed.

Concomitant administration of repaglinide with drugs that inhibit the CYP2C8 isoenzyme, such as gemfibrozil, trimethoprim, or montelukast, may increase the drug's plasma concentrations. Concomitant administration of gemfibrozil 600 mg and a single 0.25-mg dose of repaglinide (dosage strength not commercially available in the US) in healthy individuals receiving gemfibrozil 600 mg twice daily for 3 days increased repaglinide AUC by 8.1-fold and prolonged the half-life of repaglinide from 1.3 to 3.7 hours. When both gemfibrozil and itraconazole were co-administered with repaglinide, the AUC of repaglinide was increased 19-fold and repaglinide half-life was prolonged to 6.1 hours. Plasma repaglinide concentration at 7 hours increased 28.6-fold with concomitant gemfibrozil administration and 70.4-fold with concomitant gemfibrozil-itraconazole administration. Gemfibrozil therapy should not be initiated in patients taking repaglinide, and those taking gemfibrozil should not begin therapy with repaglinide, since such concomitant use may enhance and prolong the hypoglycemic effects of repaglinide. Addition of a single 0.25-mg of repaglinide in healthy individuals receiving trimethoprim 160 mg twice daily for the previous 2 days resulted in a 61 and 41% increase in AUC and peak plasma concentrations, respectively, of repaglinide.

Drugs Transported by Organic Anion-transporting Polypeptide 1B1

Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion-transporting polypeptide 1B1 [OATP1B1]). Drugs that inhibit OATP1B1 (e.g., cyclosporine) may have the potential to increase plasma concentrations of repaglinide. In a drug interaction study in healthy individuals, co-administration of cyclosporine 100 mg and a single 0.25-mg dose of repaglinide (after 2 doses of cyclosporine 100 mg given 12 hours apart) increased the peak plasma repaglinide concentration by 1.8-fold and AUC by 2.5-fold.

Protein-bound Drugs

Because protein binding of repaglinide is reported to be high (exceeding 98%), the drug could be displaced from binding sites by, or could displace from binding, other protein-bound drugs such as salicylates or other nonsteroidal anti-inflammatory agents (NSAIAs), sulfonamides, probenecid, chloramphenicol, oral anticoagulants (e.g., warfarin), monoamine oxidase (MAO) inhibitors, certain HMG-CoA reductase inhibitors, and β-adrenergic blocking agents. Coadministration of simvastatin (20 mg once daily for 4 days) and repaglinide (2 mg 3 times daily for 4 days) at steady state resulted in a 26% increase in peak blood concentrations of repaglinide. When such drugs are initiated or withdrawn in patients receiving repaglinide, the patient should be observed for evidence of hypoglycemia or loss of glycemic control. In vitro studies indicate that warfarin, furosemide, or tolbutamide decrease protein binding of repaglinide; however, the increase in free repaglinide concentration is not thought to be clinically important.

Other Drugs

Drugs that cause hyperglycemia and may exacerbate glycemic control in patients with diabetes mellitus include corticosteroids, niacin, thiazides and other diuretics, oral contraceptives, sympathomimetics, thyroid preparations, estrogens, phenytoin, phenothiazines, calcium-channel blocking agents, and isoniazid. Conversely, certain drugs (e.g., clofibrate) may enhance the hypoglycemic effect of repaglinide. When such drugs are added or withdrawn from therapy in patients receiving oral antidiabetic agents, close monitoring for evidence of altered glycemic control is recommended.

Concomitant use of repaglinide (2 mg 3 times daily for 4 days) and a course (21 days) of levonorgestrel (0.15 mg once daily) in fixed combination with ethinyl estradiol (0.03 mg once daily) resulted in a 20% increase in the peak blood concentrations of repaglinide and the oral contraceptive components. The AUC was increased by 20% for the ethinyl estradiol component, while this parameter remained unchanged for repaglinide and the levonorgestrel component.

Concomitant administration of fenofibrate 200 mg with a single 0.25-mg dose of repaglinide (after 5 days of once-daily fenofibrate 200 mg) did not alter AUC or peak plasma concentrations of either drug. Studies in healthy individuals indicate that repaglinide has no clinically relevant effect on the pharmacokinetics of digoxin, theophylline, nifedipine, or warfarin, and the manufacturer states that no dosage adjustment is necessary when these drugs are given concurrently with repaglinide. However, when these drugs are initiated or discontinued in patients receiving repaglinide, the patient should be observed closely for hypoglycemia or loss or glycemic control.

Pharmacokinetics

The pharmacokinetics of repaglinide appear to be similar in healthy individuals and patients with type 2 diabetes mellitus in the absence of renal or hepatic impairment. Limited data from studies in whites and African Americans suggest no differences in the pharmacokinetics of repaglinide according to race.

Absorption

Repaglinide is rapidly and completely absorbed from the GI tract following oral administration. Following single and multiple oral doses of repaglinide in healthy individuals or patients with type 2 diabetes mellitus, peak plasma drug concentrations are attained within approximately 1 hour (range: 0.5-1.4 hours). In healthy men who received a 2-mg radiolabeled dose of repaglinide during a multiple-dose study (2 mg 4 times daily for 13 days), the peak plasma concentration of repaglinide averaged 27.7 ng/mL with an average time to peak concentration of 0.5 hours. In patients with type 2 diabetes mellitus receiving 0.5, 1, 2, or 4 mg of repaglinide, peak plasma concentrations of the drug averaged 8-9.8, 18.3-21, 26-29, or 65.8-69 ng/mL, respectively. Following once-daily administration (not currently recommended), plasma repaglinide concentrations are dose-proportional within the range of 0.25-16 mg.

The absolute bioavailability of repaglinide averages approximately 56%. Considerable intraindividual and interindividual variation in areas under the plasma concentration-time curve (AUCs) have been reported over the therapeutic dosage range of repaglinide.

Serum insulin concentrations begin to increase within 30 minutes following administration of repaglinide and reach a peak approximately 1.5 hours after a dose. Following acute oral administration of repaglinide or glyburide in healthy individuals, the maximal glycemic effect for both drugs occurs within 3-3.5 hours. In patients with type 2 diabetes mellitus receiving repaglinide or glyburide, plasma insulin concentrations remain elevated for 4 or 10 hours, respectively, after each meal. Plasma insulin concentrations increase in proportion to dose with repaglinide and return toward premeal concentrations between meals and at bedtime. In a euglycemic clamp study in healthy individuals, there was a 2.5-fold increase in maximal hypoglycemic effect between repaglinide doses of 1 and 4 mg, which was similar to that observed between glyburide doses of 1.75 and 7 mg (2.3-fold increase). In comparative clinical trials, patients receiving repaglinide before each meal had lower 2-hour postprandial blood glucose concentrations than those receiving glyburide once or twice daily before a meal. Most of the effect of repaglinide on fasting glucose concentrations occurs within 1-2 weeks of initiation of therapy; mean blood glucose concentrations stabilize at week 2 with a repaglinide dosage of 0.5 mg before each meal and at week 3 with preprandial dosages of 1 or 4 mg.

The pharmacokinetics of repaglinide are affected by gender, administration with food, and hepatic or renal impairment, but do not appear to be influenced by age. In patients with type 2 diabetes mellitus, bioavailability (as determined by AUC) of repaglinide over the therapeutic dosage range (0.5-4 mg) was 15-70% higher in females than in males, although this difference disappeared when normalized for dosage and weight. In some studies, administration of repaglinide with food reduced the extent of GI absorption (as determined by AUC) by up to 12.4%; time to peak plasma concentration and mean peak plasma concentration were reduced by up to 30 and up to 20%, respectively. Administration of the drug with a high-fat meal reportedly reduced peak plasma concentration and AUC slightly but did not affect time to peak concentration. The clinical importance of these effects has not been determined.

Since repaglinide is eliminated principally by the liver, patients with hepatic impairment have greater systemic exposures (as determined by peak plasma concentrations and AUCs) to repaglinide as compared with healthy individuals. In a small, open study in nondiabetic patients with chronic liver disease (as determined by caffeine clearance), higher and more prolonged serum concentrations of both total and unbound repaglinide and its metabolites were found in patients with moderate to severe hepatic dysfunction than in healthy individuals; however, these drug concentrations did not exceed concentrations that were well tolerated in a dose-escalation study. Peak plasma drug concentrations following a single 4-mg dose of repaglinide were 105.4 or 46.7 ng/mL in patients with chronic liver disease or healthy individuals, respectively.

Renal impairment also is associated with increases in plasma concentrations of repaglinide. Because plasma drug concentrations are highly variable in individuals with renal impairment, AUC for repaglinide does not correlate or correlates only weakly with creatinine clearance. In patients with type 2 diabetes mellitus receiving repaglinide, increases in peak plasma concentrations and AUC were noted in patients with severe renal impairment (creatinine clearance 20-40 mL/minute; such alterations in the pharmacokinetics of the drug were not found in patients with mild to moderate renal impairment.

No pharmacokinetic differences (peak plasma concentration, AUC) were observed between healthy geriatric individuals (65 years of age or older) and healthy younger individuals receiving repaglinide 2 mg before each of 3 meals in a clinical trial. In another clinical trial in a limited number of geriatric patients with type 2 diabetes, the pharmacokinetic profiles of repaglinide following single or multiple doses were comparable and the drug was well tolerated.

Distribution

The apparent steady-state volume of distribution of repaglinide in healthy individuals following IV administration (an IV preparation currently is not commercially available in the US) reportedly averages 31 L. Protein binding (e.g., to albumin and α1-acid glycoprotein) of repaglinide exceeds 98%. In a study in healthy men, approximately 20% of a radiolabeled dose of the drug (parent drug and metabolites) was distributed into erythrocytes; however, no radioactivity was detectable in whole blood samples 6 hours after dosing.

Studies in rats indicate that repaglinide is distributed into breast milk.(See Pregnancy, Fertility, and Lactation.)

Elimination

Unlike sulfonylureas, many of which are excreted partially or principally by the kidneys, repaglinide is extensively metabolized in the liver and excreted into bile. Repaglinide is rapidly metabolized by the cytochrome P-450 (CYP) microsomal isoenzymes 3A4 and 2C8, principally via oxidation and dealkylation to the major dicarboxylic acid derivative (M2) and by further oxidation to an aromatic amine derivative (M1). An acyl glucuronide metabolite (M7) is formed from the carboxylic acid group of repaglinide; a number of other unidentified metabolites also have been detected. The metabolites of repaglinide do not have clinically important hypoglycemic activity. In a dose-response study in patients with type 2 diabetes mellitus, repaglinide did not accumulate over a 4-week course of therapy when administered in recommended doses.

The elimination half-life of repaglinide is about 1 hour when the drug is given in doses of 0.5-4 mg in healthy individuals and patients with type 2 diabetes mellitus. Total body clearance following IV administration of repaglinide (an IV preparation currently is not commercially available in the US) in healthy individuals is 38 L/hour; a plasma clearance of 33 L/hour also has been reported following IV administration of the drug. Clearance of oral repaglinide is constant over the 0.5-4 mg dosage range, indicating a linear correlation between dose and peak plasma drug concentration.

Within 96 hours following oral administration of a dose of radiolabeled repaglinide in healthy men, approximately 90% of the dose was excreted in feces (less than 2% as repaglinide) and 8% was excreted in urine (0.1% as repaglinide). The major metabolite, the dicarboxylic acid derivative, accounts for about 60% of the administered radiolabeled dose.

In patients with hepatic impairment, elimination of unbound repaglinide is reduced, resulting in higher plasma concentrations of unbound and total repaglinide, higher AUC, and longer mean residence time compared with that in healthy individuals.(See Hepatic Impairment under Dosage and Administration: Special Populations.)

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