VA Class:HS502

ATC Class:A10BX02

AHFS Class:

• Meglitinides 68:20.16

Generic Name(s):

• Repaglinide

Chemical Name:

• ( S )-2-Ethoxy-4-[2-[[methyl-1-[2-(1-piperidinyl)-phenyl]butyl]amino]-2-oxoethyl]-benzoic acid

Repaglinide, a meglitinide (glinide) derivative, is a short-acting, insulinotropic antidiabetic agent.2,6,8,11,12,14,56,57,59,60,61,63,65

Type 2 Diabetes Mellitus

Repaglinide is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,5,61,65 Repaglinide also has been used in combination with metformin and/or other antidiabetic agents for the management of type 2 diabetes mellitus.5,13,59,61,102 Some experts state that glinides (e.g., nateglinide, repaglinide) generally are not preferred as second-line therapy after failure of metformin monotherapy because of their lower effectiveness and comparatively limited clinical data, but may be appropriate choices in selected patients (e.g., as an alternative to sulfonylureas because their lower potency and shorter half-life may be associated with a lower risk of prolonged hypoglycemia).698 Because of its short duration of action, repaglinide may be particularly suited for control of postprandial hyperglycemia in patients with type 2 diabetes mellitus.12,57,59,64

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another agent) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic drug classes with complementary mechanisms of action.698

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,699,704,705,706

When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

Repaglinide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.1,24,25

Repaglinide reduces both fasting and postprandial blood glucose concentrations and HbA_1c 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.1,2,4,5,14,71,80,81,113 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,58,59,64,65 allowing for increased flexibility of meal patterns (e.g., especially in adolescents, who may have an irregular eating schedule)109 and a reduced risk of hypoglycemia between meals or in the event of a missed meal.2,5,10,11,12,14,57,58,59,60,62,64,65,68 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.2,5,14,58,65,67 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.58,59,60,61,64,67,68,71

In controlled clinical trials of 4-24 weeks' duration, repaglinide was more effective than placebo in reducing fasting and postprandial blood glucose concentrations and HbA_1c 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).1,14,80,81 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 (HbA_1c less than 8%) at study entry; the reduction in HbA_1c was 1.7 and 2.1% in the previously treated and treatment-naive groups, respectively.1,14,60,61,80 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.5,12,14,64,71,1,100,114 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.59,61 The hypoglycemic effect of repaglinide does not appear to be influenced by duration of diabetes, race, or age.1,14

While data concerning secondary failure with repaglinide are limited,26,28,39,71 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 [no longer commercially available in the US] 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.84,85 The failure rate at 6 years was 48% among patients receiving glyburide and about 40% among patients receiving chlorpropamide.85 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.82,83,84,85,86,88,89,92 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.82 At diagnosis, risk factors predisposing toward sulfonylurea failure included higher fasting plasma glucose concentrations, younger age, and lower pancreatic β-cell reserve.71,82,85

Repaglinide also has been used concomitantly with metformin and/or other antidiabetic agents for the management of type 2 diabetes mellitus.5,13,59,71,102

In a clinical trial in patients poorly controlled by metformin monotherapy, the combination of repaglinide and metformin reduced fasting plasma glucose concentrations and HbA_1c 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 HbA_1c.1,5,13,14,56,59,60,64,71,102 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.1 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.1 In a clinical trial in patients with inadequate glycemic control (as determined by HbA_1c 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 HbA_1c 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 HbA_1c.1

Administration

Repaglinide is administered orally.1,11,14,11 The manufacturer recommends that patients be instructed to take the drug within 30 minutes before meals.1,59,61 While administration with food has been reported to affect the extent of repaglinide absorption, this effect is not thought to be clinically important.14,59 (See Pharmacokinetics: Absorption.)

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.1,5,14,59,61,62,68 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).2,5,10,11,12,14,57,58,59,60,62,64,65,68 (See Uses: Type 2 Diabetes Mellitus.)

Dosage

Type 2 Diabetes Mellitus

Dosage of repaglinide must be individualized carefully based on patient response and tolerance.71,81,99 The goal of therapy should be to reduce both fasting blood (or plasma) glucose and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) 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.14,71,99 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.1,14,109,217 While fasting (preprandial) glucose concentrations are widely used for determination of glycemic control, 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).40,71,109 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.1,14,71

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, HbA_1c values should be monitored at intervals of approximately 3 months to evaluate long-term glycemic control.5,14,40,71,217 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.5,14

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., HbA_1c 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.1,5,14,40,56,61,62,71 For patients whose HbA_1c 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.1,5,14,61,62,71 Approximately 90% of the maximal glucose-lowering effect of repaglinide is achieved with a dosage of 1 mg 3 times daily.56,57,66 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.14

Subsequent dosage of repaglinide should be adjusted according to the patient's therapeutic response and tolerance, using the lowest possible effective dosage.1,14 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.1,3,5,14,27,36,56,59,61,62,71,217 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.14,71 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.14 (See Acute Toxicity.)

Dosage in Renal and Hepatic Impairment

Renal Impairment

Accumulation of repaglinide (as indicated by increased peak plasma concentrations and AUC) occurs in patients with renal impairment.1,5,59,60,61,64,71,104 However, no adjustment in the initial dosage of repaglinide appears to be necessary in patients with mild to moderate renal dysfunction.1 Although the usual initial dosage of repaglinide may be used in these patients, subsequent increases in dosage should be made with caution.1,5,59,61,71,104 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.1 Use of repaglinide in patients with creatinine clearances below 20 mL/minute or in those with renal failure requiring hemodialysis has not been established.1

Hepatic Impairment

Since repaglinide is extensively metabolized by the liver, the drug should be used with caution in patients with hepatic impairment.1,5,59,71 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;1,5,59,61,71,105 however, other clinicians have suggested use of a lower initial dosage in patients with hepatic impairment.64

Dosage Adjustments for Interacting Drugs

Dosage adjustments are recommended when repaglinide is administered with strong inhibitors or inducers of cytochrome P-450 (CYP) 2C8 or 3A4 isoenzymes; concomitant administration of repaglinide and gemfibrozil is contraindicated.1 (See Drug Interactions: Drugs or Foods Affecting Hepatic Microsomal Enzymes.)

Concomitant use of repaglinide and clopidogrel may substantially increase repaglinide exposure and should be avoided.1 If concomitant use cannot be avoided, the initial dosage of repaglinide should not exceed 0.5 mg before each meal and the total daily dosage of repaglinide should not exceed 4 mg.1 (See Drug Interactions: Drugs or Foods Affecting Hepatic Microsomal Enzymes.)

The maximum daily dosage of repaglinide in patients receiving concomitant cyclosporine should not exceed 6 mg.1 (See Drug Interactions: Drugs Transported by Organic Anion-transporting Polypeptide 1B1.)

The overall frequency of adverse effects with repaglinide therapy appears to be similar to that reported with oral sulfonylureas;5,12,14,59,61,99 limited data suggest that repaglinide may be associated with fewer adverse GI effects than metformin.13,64,102 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;64,71,80,81 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.1,5,14,61 The most common effects leading to drug discontinuance were hyperglycemia, hypoglycemia, and related symptoms.1,5,14,61

Hypoglycemia

Hypoglycemia1,5,14,80,81,99,100,101,102,104,105 is the most frequent adverse effect of repaglinide1,100 and may occur shortly after dosing when a meal is delayed or omitted.40,59,68,71 Factors that may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content), changes in physical activity level, changes to coadministered drugs, and concomitant use of other antidiabetic agents.1 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. 1 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.1,5,14,56,59,61,64 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.5,14 In placebo-controlled trials of up to 6 months' duration, 0.6% of patients receiving repaglinide discontinued the drug as a result of hypoglycemia.14 Severe hypoglycemia can cause seizures, may be life-threatening, or cause death.1 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.5,61,71 In placebo-controlled trials, hypoglycemia occurred in 31% of patients treated with repaglinide versus 7% with placebo;1,14,80 however, most of these hypoglycemic episodes occurred in a large, fixed-dose trial80 in which dosage adjustments, if allowed, could potentially have averted such episodes.14,80,81 In this trial,80 patients who had not previously received oral antidiabetic therapy and those with relatively good glycemic control at study entry (HbA_1c less than 8%) had an increased frequency of hypoglycemia during treatment with repaglinide.1,14,80 Patients who had previously received oral antidiabetic therapy and who had a baseline HbA_1c value of at least 8% developed hypoglycemia with similar frequency as those receiving placebo.14,61,80 (See Cautions: Precautions and Contraindications.)

Concomitant administration of gemfibrozil substantially increases exposure to repaglinide and, consequently, the risk of hypoglycemia.1 Concomitant use of repaglinide and gemfibrozil is contraindicated.1 (See Drug Interactions: Drugs or Foods Affecting Hepatic Microsomal Enzymes.)

Respiratory Effects

Upper respiratory tract infection1,14,80 occurred in 16% of patients receiving repaglinide in placebo-controlled trials.1,14 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).1,14 Sinusitis,1,80 rhinitis,1 or bronchitis1 occurred in 6, 3, or 2%, respectively, of patients receiving repaglinide in placebo-controlled trials1,14 and in 3, 7, or 6%, respectively, of patients receiving the drug in several comparative trials.1,14

Musculoskeletal Effects

Arthralgia1,80,104 or back pain1,80 occurred in 6 or 5% of patients, respectively, receiving repaglinide in placebo-controlled trials of up to 6 months' duration.1,14 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.1,14

GI Effects

Nausea1,14,59,80,81,103,104 or diarrhea1,14,59,80,81 occurred in 5% of patients receiving repaglinide in placebo-controlled trials of up to 6 months' duration.1,14 Dyspepsia1,14 or diarrhea1,14,80,81 occurred in 4% of patients receiving the drug in several long-term, comparative trials;1,14 dyspepsia occurred in 2% of patients receiving repaglinide in placebo-controlled trials.1,14 Constipation1,14,81 or vomiting1,14,81,103 occurred in 3 or 2% of patients receiving repaglinide in placebo-controlled or comparative trials, respectively.1,14 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.64,100

Cardiovascular Effects

Cardiovascular events are more common in patients with type 2 diabetes mellitus than in those without diabetes.5,71 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%).1,71 Cardiac ischemic effects occurred in 2% of patients receiving either repaglinide or a sulfonylurea (glyburide or glipizide) in these comparative trials; myocardial ischemia has been reported in a few patients receiving repaglinide in combination with isophane (NPH) insulin in clinical trials, and isophane (NPH) insulin should not be used concomitantly with repaglinide.1 (See Cautions: Precautions and Contraindications.) Angina1,14 or chest pain1,14,80 occurred in 1.8% of patients receiving repaglinide in 1-year comparative trials with glyburide or glipizide;1,14,71 chest pain was also reported in 3% of patients receiving the drug in placebo-controlled trials.1,14 The overall incidence of other cardiovascular effects, including hypertension, abnormal ECGs, myocardial infarction,81 arrhythmias,81 and palpitations, was 1% or less in comparative trials in patients receiving repaglinide.1,5,14,71 Flushing has been reported rarely with repaglinide therapy.81 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.1,5,14 Repaglinide was not associated with an appreciable excess of cardiovascular mortality (0.5%) compared with glyburide or glipizide (0.4%).1,71

Edema can occur alone and in association with congestive heart failure when repaglinide is used in combination with a thiazolidinedione antidiabetic agent.1 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. 1 Patients receiving repaglinide in combination with a thiazolidinedione experienced more weight gain than has been observed during therapy with repaglinide alone. 1 Edema with congestive heart failure has been reported in 0.8% of patients receiving combined repaglinide and thiazolidinedione therapy.1 Such patients had a prior history of coronary artery disease, and congestive heart failure resolved after treatment with diuretics.1 (See Edema under Warnings/Precautions: General Precautions, in Cautions in Rosiglitazone or Pioglitazone 68:20.28)

The manufacturer states that there have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide.1

Nervous System Effects

Headache1,59,64,67,80,100,103,104 occurred in 11% of patients receiving repaglinide in placebo-controlled trials1,14,59 and in 9% of those receiving the drug in several comparative trials.1,14 Paresthesia1,14,80,81 occurred in 3% of patients receiving repaglinide in placebo-controlled trials1,14 and in 2% of those in several comparative trials.1,14 Other adverse nervous system effects reported with repaglinide therapy include pain,80 hyperesthesia81 or hypoesthesia,81 dizziness,67,80,81,100,101,104 and fatigue.80,81,101

Other Adverse Effects

Urinary tract infection1,14 occurred in 2% of patients receiving repaglinide in a placebo-controlled trial and in 3% of those receiving the drug in several comparative trials.1 Increased frequency of micturition81 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.1 Increased appetite80 also has been reported with repaglinide therapy; in addition, as with sulfonylurea antidiabetic agents, some treatment-naive patients receiving repaglinide experienced weight gain;1,14,56,59,71,73,100 the manufacturer states that there was no average gain in body weight when patients previously treated with oral hypoglycemic agents were switched to repaglinide.1 Rash,80 increased appetite,81 and accidental injury80 also have been reported with repaglinide therapy. Adverse effects occurring in less than 1% of patients receiving repaglinide include elevated liver enzymes,68,80 thrombocytopenia, and leukopenia.1,5,14,71 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. 1 Changes in blood glucose concentrations may result in blurred vision and visual disturbances, usually transient, particularly at initiation of treatment with hypoglycemic agents.1 Anaphylactoid reaction has been reported rarely with repaglinide therapy.1,5,14

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.40,71 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.5,38,41,52,71 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.1,5,14 Glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) measurements also are useful, particularly for monitoring long-term control of blood glucose concentration.1,5,14,217 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.1,14 The need for dosage adjustment and adherence to diet should be assessed before determining a patient to be a secondary failure.1

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.18,29,45,71,217 Patients should be informed of the potential risks and advantages of repaglinide therapy and of alternative forms of treatment .1,5 Patients should be instructed that dietary regulation is the principal consideration in the management of diabetes,1,42,43,44 and that repaglinide therapy is used only as an adjunct to,1 and not a substitute for, proper dietary regulation.1,5 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.14,40,68,71,100 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.46,47 Patients receiving repaglinide also should be cautioned that failure to follow an appropriate dosage regimen may result in hypoglycemia or hyperglycemia.14 The possibility of primary and secondary failure of oral antidiabetic agents also should be explained to patients.1

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.1,5,217 Hypoglycemia can impair concentration ability and reaction time, which may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).1 Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual.1 Appropriate patient selection, patient education, and careful attention to dosage are important to avoid hypoglycemic episodes .1 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.1,5 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.1,5,61,71 Debilitated, malnourished, or geriatric patients also may be particularly susceptible to hypoglycemia;1,5,61 this condition may be difficult to recognize in geriatric patients, patients with longstanding diabetes mellitus or diabetic nerve disease, patients who experience recurrent hypoglycemia, or in those receiving β-adrenergic blocking agents or other sympatholytic agents.1,5 Factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content), changes in physical activity level, or changes to coadministered drug therapy.1 Risk of serious hypoglycemia also may be increased in patients with hepatic failure, who may have reduced clearance of repaglinide and diminished gluconeogenic capacity.1,5,61,64 The frequency of hypoglycemia also is increased in patients with type 2 diabetes mellitus who have not been previously treated with oral antidiabetic agents or whose HbA_1c concentration is less than 8%.5

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.1,61,71,217 According to the clinician's judgment, repaglinide therapy may be reinstituted after the acute episode is resolved.40,71

The manufacturer states that repaglinide is not indicated for use in combination with isophane (NPH) insulin .1 (See Cautions: Cardiovascular Effects.)

Repaglinide is contraindicated in patients receiving gemfibrozil.1 (See Drug Interactions.) Repaglinide also is contraindicated in patients with known hypersensitivity to the drug.1,61

Pediatric Precautions

Safety and efficacy of repaglinide in children younger than 18 years of age have not been established,40,71 and the drug has not been studied in type 2 diabetes mellitus of the young, an inherited genetic disorder.1,61,71 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.109

Geriatric Precautions

The safety and efficacy of repaglinide appear to be similar in geriatric and younger patients.1,5,14,101 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.1,5,14 (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.1,5,14 No increase in the frequency and severity of hypoglycemia was observed in geriatric versus younger patients receiving repaglinide.1,14,101

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.1,14

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.1,14 In male rats receiving oral repaglinide dosages up to 120 mg/kg daily, representing 60 times the human exposure on a mg/m² 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/m² basis, respectively).1,14,64 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/m² basis.1,14

Pregnancy, Fertility, and Lactation

Pregnancy

Limited data from case reports and case series of repaglinide use in pregnant women have not revealed a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications.1 Poorly controlled diabetes mellitus also increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.1 Most experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration.14,56,64,71,109

Reproduction studies in rats and rabbits given repaglinide during organogenesis at dosages representing 60 and 1 times, respectively, the maximum daily clinical dosage based on body surface area have not revealed evidence of harm to the fetus.1,64,71

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).1,14,64

Lactation

Nursing pups of rat dams receiving repaglinide at 15 times the human exposure on a mg/m² basis during days 17-22 of gestation and throughout lactation developed shortening, thickening, and bending of the humerus during the postnatal period.1,14,64,71 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.1,14,71 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.14 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/m² basis during days 1-22 of gestation or at higher dosages given during days 1-16 of pregnancy.1,14,71 Similar studies in humans have not been conducted, and the safety of repaglinide administration throughout pregnancy or lactation cannot be established.1,14,71

Because of the potential for repaglinide to cause hypoglycemia and 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.1,14,71 If repaglinide is discontinued and diet therapy alone does not provide adequate glycemic control, insulin therapy should be instituted.1,14,71

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.1,5,14,61,62,64,71,104,107,200 Caution should be used during concomitant administration of repaglinide and inhibitors or inducers of CYP2C8 and 3A4 isoenzymes.1,200 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.1,40,59,71,120,200 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.1,200

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 CYP3A4.1,14,59,62,64,71,200 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.1 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.1 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. 1,200 The appreciable increase in repaglinide plasma concentrations observed during concomitant administration of clarithromycin may necessitate an adjustment in the dosage of repaglinide.1,120,200 Other drugs or foods that inhibit CYP3A4, such as HIV protease inhibitors or grapefruit juice, may inhibit the metabolism of repaglinide,71,201,202 although limited data suggest that the interaction with grapefruit juice is unlikely to be of clinical importance.200 Coadministration of repaglinide and cimetidine, another inhibitor of the hepatic microsomal enzyme system,49,64,106,120 does not appreciably alter the absorption or disposition of repaglinide.1,14,64,71,106,120

Concomitant administration of repaglinide with drugs that induce the CYP3A4 or 2C8 isoenzymes (e.g., rifampin, barbiturates, carbamazepine) may theoretically increase repaglinide metabolism.1,14,59,62,64,71,200 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.123 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. 1 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.1 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.1,123 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.123

Concomitant administration of repaglinide with drugs that inhibit the CYP2C8 isoenzyme, such as gemfibrozil,1,200 trimethoprim,1,200 deferasirox,1 or clopidogrel,1,200 may increase the drug's plasma concentrations and the risk of hypoglycemia.1 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.1,200 When both gemfibrozil and itraconazole were co-administered with repaglinide, the AUC and peak plasma concentration of repaglinide were increased 19- and 28-fold, respectively.1,200 Gemfibrozil is contraindicated in patients taking repaglinide.1,200 Addition of a single 0.25-mg dose of repaglinide in healthy individuals receiving trimethoprim 160 mg twice daily for the previous 2 days increased AUC and peak plasma concentrations of repaglinide by 61 and 41%, respectively.1,121,200 Concomitant administration of deferasirox (30 mg/kg daily for 4 days) and repaglinide (single 0.5-mg dose) increased repaglinide AUC by 2.3-fold and peak plasma concentration by 62%.1

In a study in healthy individuals, concomitant administration of clopidogrel (300 mg on day 1, then 75 mg once daily for 2 days) and repaglinide (0.25 mg on days 1 and 3) increased the peak plasma concentration and AUC of repaglinide.1 The AUC of repaglinide was increased 5.1-fold on day 1 and 3.9-fold on day 3, and the peak plasma concentration of repaglinide was increased by 2.5-fold on day 1 and 2-fold on day 3.1 Concomitant use of clopidogrel and repaglinide should be avoided or, if not possible, repaglinide dosage should be reduced.1 (See Dosage Adjustments for Interacting Drugs, under Dosage and Administration.)

Drugs Affecting Organic Anion-transporting Polypeptide 1B1

Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion-transporting polypeptide 1B1 [OATP1B1]).1,200 Drugs that inhibit OATP1B1 (e.g., cyclosporine) may have the potential to increase plasma concentrations of repaglinide.1 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.1 Blood glucose should be monitored more frequently in patients receiving concomitant cyclosporine and repaglinide, and the maximum daily dosage of repaglinide should be limited to 6 mg.1

Protein-bound Drugs

Because protein binding of repaglinide is reported to be high (exceeding 98%),1,5,14,61,64,71,104 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 (statins), and β-adrenergic blocking agents.14,71 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.1,200 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.5,14,71 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.64,200

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, atypical antipsychotics (e.g., olanzapine, clozapine), danazol, glucagon, HIV protease inhibitors, somatropin, estrogens, phenytoin, phenothiazines, calcium-channel blocking agents, and isoniazid.1,14,61,71 Conversely, drugs such as antidiabetic agents, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIAs), pentoxifylline, pramlintide, propoxyphene (no longer commercially available in the US), salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics may enhance the hypoglycemic effect of repaglinide.1,71,117,200 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.1,5,14,71

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.1,200 The AUC was increased by 20% for the ethinyl estradiol component, while this parameter remained unchanged for repaglinide and the levonorgestrel component.1,200

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.1,200

Studies in healthy individuals indicate that repaglinide has no clinically relevant effect on the pharmacokinetics of digoxin, theophylline, nifedipine, or warfarin,1,14,61,64,71,106,200 and the manufacturer states that no dosage adjustment is necessary when these drugs are given concurrently with repaglinide.1,71

Acute Toxicity

Limited information is available on the acute toxicity of repaglinide.40,64,71,108

Manifestations

In a clinical trial, patients receiving increasing doses of repaglinide up to 80 mg daily (20 mg 4 times daily) for 14 days experienced no acute drug-related adverse events, including hypoglycemia, changes in hepatic enzymes, arrhythmias, or other cardiovascular manifestations, provided the drug was given with meals.1,5,71 However, acute repaglinide overdosage is manifested principally as hypoglycemia, which may be severe.1 Severe repaglinide-induced hypoglycemia with neurologic signs (coma, seizures) occurs infrequently but constitutes a medical emergency requiring immediate hospitalization and treatment.1,5,40,71 If hypoglycemic coma is diagnosed or suspected, 50% dextrose injection (e.g., 50 mL) should be administered IV rapidly, followed immediately by a continuous IV infusion of 10% dextrose injection at a rate sufficient to maintain a blood glucose concentration of about 100 mg/dL.1,5,71 While repaglinide has a short half-life (about 1 hour), studies in dogs indicate that the drug has the potential to produce prolonged hypoglycemia (e.g., for up to 24 hours after dosing) similar to that with the sulfonylureas.108 Treatment of mild hypoglycemic symptoms (i.e., loss of consciousness or neurologic findings) consists principally of administration of oral glucose and supportive therapy.1,5

Treatment

Adjustment of repaglinide dosage or meal patterns should be considered and patients should be monitored closely for a minimum of 24-48 hours until complete recovery is ensured since hypoglycemic episodes may recur after apparent clinical recovery.1,5 Repaglinide does not appear to be removed by hemodialysis.1,104

Pharmacology

Repaglinide lowers fasting and postprandial blood glucose concentrations in animals, healthy individuals, and patients with diabetes mellitus.1,12,14,56,57,58,59,60 Repaglinide produces reductions in fasting plasma glucose and hemoglobin A_1c (HbA_1c) values that are similar to those with sulfonylurea antidiabetic agents.56 In animals, repaglinide is associated with a greater and more rapid elevation in plasma insulin concentrations and an earlier decrease in glucose concentrations than glyburide or glimepiride.60,61,64,77 As with sulfonylurea antidiabetic agents, functioning pancreatic β-cells are required for repaglinide's hypoglycemic activity since the drug lowers blood glucose concentrations principally by augmenting endogenous insulin secretion from the pancreas in response to a meal.1,5,14,56,57,58,59,60,61,62,64,67,71

Insulin release by pancreatic β-cells is controlled in part by the cellular membrane potential, which depends on the activity of ATP-sensitive potassium channels in the plasma membrane and on extracellular glucose concentrations.9,14 At low glucose concentrations, ATP-sensitive potassium-channel activity is high and the membrane on pancreatic β-cells is repolarized and electrically inactive.9 At higher glucose concentrations, ATP-sensitive potassium channels close, depolarizing the β-cell membrane and opening voltage-dependent L-type calcium channels.1,2,3,5,7,9,59,61,71 The increased calcium influx induces insulin secretion through facilitation of calcium-dependent exocytosis of insulin granules.2,5,7,9,60 In vitro studies in mouse and rat pancreatic β-cells indicate that repaglinide is at least as potent as glyburide in inhibiting ATP-sensitive potassium channels, increasing intracellular concentrations of calcium, and stimulating insulin release.2,5,7,8,9,14,60,61,64 The minimum effective glucose-lowering dose of repaglinide in animals has been reported to be 18 or 25 times less than that of glimepiride or glyburide, respectively.64

Studies in pancreatic islet-cell cultures indicate a glucose-dependent relationship for the insulinotropic action of repaglinide.63,64,71,80 Unlike sulfonylurea antidiabetic agents, repaglinide does not stimulate insulin release in the absence of glucose, and insulin release is diminished at low glucose concentrations.2,5,7,9,14,60,64,71 Therefore, repaglinide has little effect on serum insulin concentrations between meals and overnight.71 As blood glucose concentrations increase, repaglinide augments the glucose-induced closure of ATP-sensitive potassium channels and, thereby, the release of insulin.5,8,9,58,59,60,61,63 However, repaglinide exerts most of its insulinotropic activity at intermediate glucose concentrations (54-180 mg/dL).9,60,63 At high glucose concentrations (exceeding 270 mg/dL), addition of repaglinide does not augment the insulin release already stimulated by high extracellular glucose concentrations.9,60,63 The effect of repaglinide on potassium and calcium channels is somewhat selective for pancreatic β-cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue.1,5,14,71,80

Limited data in animals suggest that long-term administration of repaglinide may be associated with some improvement in β-cell responsiveness (as determined by an increase in basal and glucose-stimulated insulin output); however, additional studies are required to confirm such an effect.63,71

Repaglinide does not appear to appreciably affect blood lipids (total, HDL-, or LDL-cholesterol) or fibrinogen concentrations.2,14,56,71,81,100 In patients previously treated with oral antidiabetic agents, body weight does not change during repaglinide therapy.14,56,64,100 In therapy-naive patients receiving repaglinide in clinical trials, body weight increased by 3.3%.1,14,56,64,80,100 Although the exact mechanisms associated with such alterations in weight have not been established, suggested mechanisms include an increase in insulin secretion (which may increase appetite), stimulation of lipogenesis in fat tissue, or resistance to the actions of leptin (which decreases appetite and increases energy expenditure).13,50,56,74,111,112

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.64,65 Limited data from studies in whites and African Americans suggest no differences in the pharmacokinetics of repaglinide according to race.64

Absorption

Repaglinide is rapidly and completely absorbed from the GI tract following oral administration.1,14,56,59,60,71,107 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).1,10,14,56,59,60,61,62,64,65,68,71,100,107 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.107 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.1,4,5 Following once-daily administration (not currently recommended), plasma repaglinide concentrations are dose-proportional within the range of 0.25-16 mg.2,4,60,61,113

The absolute bioavailability of repaglinide averages approximately 56%.1,5,14,61,71 Considerable intraindividual and interindividual variation in areas under the plasma concentration-time curve (AUCs) have been reported over the therapeutic dosage range of repaglinide.1,5,64,113

Serum insulin concentrations begin to increase within 30 minutes following administration of repaglinide and reach a peak approximately 1.5 hours after a dose.113 Following acute oral administration of repaglinide or glyburide in healthy individuals, the maximal glycemic effect for both drugs occurs within 3-3.5 hours.2,61,79 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.10 Plasma insulin concentrations increase in proportion to dose with repaglinide and return toward premeal concentrations between meals and at bedtime.1,2,5,11,14,61,64,71 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).61,79 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.12 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.1,5,11,14,61,65,71,80,113

The pharmacokinetics of repaglinide are affected by gender, administration with food,1,59 and hepatic or renal impairment,1,14,71,104,105 but do not appear to be influenced by age.1,14,101,103 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.1,14,61,78,113 In some studies, administration of repaglinide with food reduced the extent of GI absorption59 (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.1,5,14,61,71 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.60,61,64 The clinical importance of these effects has not been determined.59

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.1,5,14,61,71,105 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;1,5,59,60,61,105 however, these drug concentrations did not exceed concentrations that were well tolerated in a dose-escalation study.1,5 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.1,105

Renal impairment also is associated with increases in plasma concentrations of repaglinide.1,104 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.1,5,14,61,64 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.1,5,71,104

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.1,5,14,101 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.103

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.1,5,14,61 Protein binding (e.g., to albumin and α₁-acid glycoprotein) of repaglinide exceeds 98%.1,5,14,64,71,104,105,106 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.107

Studies in rats indicate that repaglinide is distributed into breast milk.1,14 (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.1,3,5,14,40,59,61,64,71,73,107 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).1,5,14,61,62,64,71,104,107 An acyl glucuronide metabolite (M7) is formed from the carboxylic acid group of repaglinide;1,5,61,64,71,104,107 a number of other unidentified metabolites also have been detected.107 The metabolites of repaglinide do not have clinically important hypoglycemic activity.1,5,14,59,64,65,67,71,80,81,99,100,101,104,105,107 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.1,5,14,61,64,65,71,113

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.1,3,5,14,59,61,62,64,65,68,101,107 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;1,14,61 a plasma clearance of 33 L/hour also has been reported following IV administration of the drug.60,64 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.1,61

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).1,5,14,56,59,60,61,64,65,68,80,99,104,106,107 The major metabolite, the dicarboxylic acid derivative, accounts for about 60% of the administered radiolabeled dose.1,5,14

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.14,71,105 (See Hepatic Impairment under Dosage and Administration: Special Populations.)

Chemistry and Stability

Chemistry

Repaglinide, a carbamoylmethyl benzoic acid derivative, is a short-acting, insulinotropic antidiabetic agent.2,11,12,14,56,57,60,61,65 Like nateglinide, repaglinide is a meglitinide-derivative antidiabetic agent; meglitinide is the nonsulfonylurea moiety of glyburide.2,6,8,57,59,61,63 Meglitinide, repaglinide, and certain sulfonylurea agents (e.g., glyburide, glimepiride, glipizide) have in common a hydrophobic aromatic ring, a peptide bond linked to an aliphatic chain, and another hydrophobic aromatic ring; these moieties contribute to the lipophilicity of repaglinide.1,9,15,61,63

Three repaglinide binding sites have been found on pancreatic β-cells, one of which is on what is referred to as the sulfonylurea receptor.14,56,59,60,71 Binding sites on the sulfonylurea receptor for repaglinide or sulfonylureas (i.e., glyburide) are distinct but similar; either drug may displace the other from a binding site.2,5,9,14,58,59,60,61,64,63 Meglitinides and certain sulfonylurea agents have a similar U-shaped conformation, with the 2 hydrophobic rings forming the extremities of each branch of the U and the peptide bond and aliphatic chain forming the bottom of the U; this conformation is postulated to fit into the β-pancreatic plasma membrane receptor.2,6,61,63,64 Commercially available repaglinide is the S ⁺-enantiomer, which has approximately 100 times the glucose-lowering activity64 of the S ^- enantiomer.1,2,6,14,61,62,64,107 The S ^- enantiomer of repaglinide does not have a pronounced U-shaped conformation, which may account for its lack of hypoglycemic activity.6,61

Repaglinide occurs as a white to off-white powder.1,14 The drug is lipophilic and has pK_a values of 3.9 and 6.40,71

Stability

Commercially available repaglinide tablets should be stored in well-closed containers at a temperature not exceeding 25°C and should be protected from moisture;1 repaglinide tablets reportedly are stable for at least 12 months in the original container at 25°C and 60% relative humidity.71

1. Perrigo. Repaglinide tablets prescribing information. Minneapolis, MN; 2019 Dec.

2. Anon. Repaglinide. Drugs Future . 1996; 21: 694-9.

3. Wolffenbuttel BHR, Nijst L, Sels JPE et al. Effects of a new oral hypoglycaemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM. Eur J Clin Pharmacol . 1993; 45: 113-6.

4. Perentesis GP, Damsbo P, Muller PG et al. Single dose pharmacokinetics and pharmacodynamics of repaglinide in type II diabetic patients. J Clin Pharmacol . 1994; 34: 1021.

5. NovoNordisk. Product information form for American hospital formulary service: Prandin^® (repaglinide tablets). Princeton, NJ.

6. Lins L, Brasseur R, Malaisse WJ. Conformational analysis of non-sulfonylurea hypoglycemic agents of the meglitinide family. Biochem Pharmacol . 1995; 50: 1879-84. [PubMed 8615868]

7. Gromada J, Dissing S, Kofod H et al. Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in β TC3 cells and rat pancreatic beta cells. Diabetologia . 1995; 38: 1025-32. [PubMed 8591815]

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