Pharmacology: Repaglinide is an oral blood glucose-lowering drug of the meglitinide class used in the management of type 2 diabetes mellitus (also known as non-insulin dependent diabetes mellitus or NIDDM).
Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (β) cells in pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations.
Repaglinide closes ATP-dependent potassium channels in the β-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the β-cell, which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion-channel mechanism is highly tissue-selective with low affinity for heart and skeletal muscle.
Pharmacokinetics: Absorption: After oral administration, repaglinide is rapidly and completely absorbed from the gastrointestinal tract. After single and multiple oral doses in healthy subjects or in patients, peak plasma drug levels (Cmax) occur within 1 hour (Tmax). Repaglinide is rapidly eliminated from the bloodstream with a half-life of approximately 1 hour. The mean absolute bioavailability is 56%. When repaglinide was given with food, the mean Tmax was not changed, but the mean Cmax and AUC (area under the time/plasma concentration curve) were decreased 20% and 12.4%, respectively.
Distribution: After intravenous (IV) dosing in healthy subjects, the volume of distribution at steady-state (Vss) was 31 L, and the total body clearance (CL) was 38 L/hr. Protein-binding to human serum albumin was greater than 98%.
Metabolism: Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an IV or oral dose. The major metabolites are an oxidized dicarboxylic acid (M2), the aromatic amine (M1) and the acyl glucuronide (M7). The cytochrome P-450 enzyme system, specifically 3A4, has been shown to be involved in the N-dealkylation of repaglinide to M2 and the further oxidation to M1. Metabolites do not contribute to the glucose-lowering effect of repaglinide.
Excretion: Within 96 hours after dosing with 14C-repaglinide as a single oral dose, approximately 90% of the radiolabel was recovered in the feces and approximately 8% in the urine. Only 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M2) accounted for 60% of the administered dose. Less than 2% of parent drug was recovered in feces.
Variability of Exposure: Repaglinide AUC after multiple doses of 0.25 to 4 mg with each meal varies over a wide range. The intra-individual and interindividual coefficients of variation were 36% and 69%, respectively. AUC over the therapeutic dose range included 69 to 1,005 ng/mL·hr, but AUC exposure up to 5,417 ng/mL·hr was reached in dose escalation studies without apparent adverse consequences.
Special Populations: Geriatric: Healthy volunteers were treated with a regimen of 2 mg taken before each of 3 meals. There were no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and a comparably sized group of patients ≥65 years of age.
Pediatric: No studies have been performed in pediatric patients.
Gender: A comparison of pharmacokinetics in males and females showed the AUC over the 0.5 mg to 4 mg dose range to be 15% to 70% higher in females with type 2 diabetes. This difference was not reflected in the frequency of hypoglycemic episodes (male: 16%; female: 17%) or other adverse events. With respect to gender, no change in general dosage recommendation is indicated since dosage for each patient should be individualized to achieve optimal clinical response.
Race: No pharmacokinetic studies to assess the effects of race have been performed, but in a U.S. 1-year study in patients with type 2 diabetes, the blood glucose-lowering effect was comparable between Caucasians (n=297) and African-Americans (n=33). In a U.S. dose-response study, there was no apparent difference in exposure (AUC) between Caucasians (n=74) and Hispanics (n=33).
Renal Insufficiency: Initial dose adjustment does not appear to be necessary for patients with mild to moderate renal dysfunction (CrCl=40-80 mL/min). Patients with type 2 diabetes who have severe renal function impairment (CrCl=20-40 mL/min) should initiate repaglinide therapy with the 0.5 mg dose - subsequently, patients should be carefully titrated. Studies were not conducted in patients with creatinine clearances below 20 mL/min or patients with renal failure requiring hemodialysis.
Hepatic Insufficiency: Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations of both total and unbound repaglinide than healthy subjects. No difference in glucose profiles was observed across patient groups (healthy patients; patients with chronic liver disease). Patients with impaired liver function may be exposed to higher concentrations of repaglinide and its associated metabolites than would patients with normal liver function receiving usual doses. Repaglinide should be used cautiously in patients with impaired liver function. Longer intervals between dose adjustments should be utilized to allow full assessment of response.
As an adjunct to diet and exercise to lower the blood glucose in patients with type 2 diabetes mellitus (NIDDM) whose hyperglycemia cannot be controlled satisfactorily by diet and exercise alone.
Combination therapy (use with metformin or thiazolidinediones) to lower blood glucose in patients whose hyperglycemia cannot be controlled by diet and exercise plus monotherapy with any of the following agents: Metformin, sulfonylureas, repaglinide or thiazolidinediones. If glucose control has not been achieved after a suitable trial of combination therapy, consideration should be given to discontinuing these drugs and using insulin. Judgements should be based on regular clinical and laboratory evaluations.
In initiating treatment for patients with type 2 diabetes, diet and exercise should be emphasized as the primary form of treatment. Caloric restriction, weight loss and exercise are essential in an obese diabetic patient. Proper dietary management and exercise alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. In addition to regular physical activity, cardiovascular risk factors should be identified and corrective measures taken where possible.
If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral blood glucose lowering agent or insulin should be considered. Use of repaglinide must be viewed by both physician and patient as a treatment in addition to diet and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of repaglinide.
During maintenance programs, repaglinide should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgements should be based on regular clinical and laboratory evaluations.
In considering the use of repaglinide or other antidiabetic therapies, it should be recognized that blood glucose control in type 2 diabetes has not been definitely established to be effective in preventing the long-term cardiovascular complications of diabetes. However, in patients with type 1 diabetes, the Diabetes Control and Complications Trial (DCCT) demonstrated that improved glycemic control, as reflected by HbA1c and fasting glucose levels, was associated with a reduction in the diabetic complications retinopathy, neuropathy and nephropathy.
There is no fixed dosage regimen for the management of type 2 diabetes with repaglinide. The patient's blood glucose should be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure i.e, inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e, loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels are of value in monitoring the patient's longer-term response to therapy.
Short-term administration of repaglinide may be sufficient during periods of transient loss of control in patients usually well controlled on diet.
Patients not Previously Treated or whose HbA1c is <8%: Starting Dose: 0.5 mg with each meal.
Patients Previously Treated with Blood Glucose Lowering Drugs and whose HbA1c is ≥8%: Initial Dose: 1 or 2 mg with each meal preprandially.
Dose Adjustment: Dosing adjustments should be determined by blood glucose response, usually fasting blood glucose. Postprandial glucose level testing may be clinically helpful in patients whose pre-meal blood glucose levels are satisfactory but whose overall glycemic control (HbA1c) is inadequate. The preprandial dose should be doubled up to 4 mg with each meal until satisfactory blood glucose response is achieved. At least one week should elapse to assess response after each dose adjustment.
The recommended dose range is 0.5 mg to 4 mg taken with meals. Repaglinide may be dosed preprandially 2, 3, or 4 times a day in response to changes in the patient's meal pattern. The maximum recommended daily dose is 16 mg.
Patient Management: Long-term efficacy should be monitored by measurement of HbA1c levels approximately every 3 months. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia or hyperglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy including hypoglycemia. When hypoglycemia occurs in patients taking a combination of repaglinide and a thiazolidinedione or repaglinide and metformin, the dose of repaglinide should be reduced.
Patients Receiving Other Oral Hypoglycemic Agents: When repaglinide is used to replace therapy with other oral hypoglycemic agents, repaglinide may be started on the day after the final dose is given. Patients should then be observed carefully for hypoglycemia due to potential overlapping of drug effects. When transferred from longer half-life sulfonylurea agents (e.g., chlorpropamide) to repaglinide, close monitoring may be indicated for up to one week or longer.
Combination Therapy: If repaglinide monotherapy does not result in adequate glycemic control, metformin or thiazolidinedione may be added. If metformin or thiazolidinedione monotherapy does not provide adequate control, repaglinide may be added. The starting dose and dose adjustments for repaglinide combination therapy is the same as for repaglinide monotherapy. The dose of each drug should be carefully adjusted to determine the minimal dose required to achieve the desired pharmacologic effect. Failure to do so could result in an increase in the incidence of hypoglycemic episodes. Appropriate monitoring of FPG and HbA1c measurements should be used to ensure that the patient is not subjected to excessive drug exposure or increased probability of secondary drug failure.
Administration: Repaglinide doses are usually taken within 15 minutes of the meal but time may vary from immediately preceding the meal to as long as 30 minutes before meal.
In a clinical trial, patients receiving increasing doses of repaglinide up to 80 mg a day for 14 days. There were few adverse effects other than those associated with the intended effect of lowering blood glucose. Hypoglycemia did not occur when meals were given with these high doses. Hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns.
Close monitoring may continue until the physician is assured that the patient is out of danger. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery. There is no evidence that repaglinide is dialyzable using hemodialysis.
Severe hypoglycemic reactions with coma, seizure or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL.
Known hypersensitivity to repaglinide or to any of the excipients in this drug.
Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
Type 1 diabetes.
General: Hypoglycemia: All oral blood glucose lowering drugs are capable of producing hypoglycemia. Proper patient selection, dosage and instructions to the patients are important to avoid hypoglycemic episodes. Hepatic insufficiency may cause elevated repaglinide blood levels and may diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemia. Elderly, debilitated or malnourished patients and those with adrenal, pituitary, hepatic or severe renal insufficiency may be particularly susceptible to the hypoglycemic action of glucose-lowering drugs.
Hypoglycemia may be difficult to recognize in the elderly and in people taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested or when more than one glucose-lowering drug is used.
The frequency of hypoglycemia is greater in patients with type 2 diabetes who have not been previously treated with oral blood glucose lowering drugs (naive) or whose HbA1c is less than 8%. Repaglinide should be administered with meals to lessen the risk of hypoglycemia.
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of glycemic control may occur. At such times, it may be necessary to discontinue repaglinide and administer insulin. The effectiveness of any hypoglycemic drug in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when the drug is first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.
Information for Patients: Patients should be informed of the potential risks and advantages of repaglinide and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program and of regular testing of blood glucose and HbA1c. The risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development and concomitant administration of other glucose-lowering drugs should be explained to patients and responsible family members. Primary and secondary failure should also be explained.
Patients should be instructed to take repaglinide before meals (2, 3 or 4 times a day preprandially). Doses are usually taken within 15 minutes of the meal but time may vary from immediately preceding the meal to as long as 30 minutes before the meal. Patients who skip a meal (or add an extra meal) should be instructed to skip (or add) a dose for that meal.
Laboratory Test: Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels with a goal of decreasing levels towards the normal range. During dose adjustment, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Glycosylated hemoglobin may be especially useful for evaluating long-term glycemic control. Postprandial glucose level testing may be clinically helpful in patients whose pre-meal blood glucose levels are satisfactory but whose overall glycemic control (HbA1c) is inadequate.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Long-term carcinogenicity studies were performed for 104 weeks at doses up to and including 120 mg/kg body weight/day (rats) and 500 mg/kg body weight/day (mice) or approximately 60 and 125 times clinical exposure, respectively, on a mg/m2 basis. No evidence of carcinogenicity was found in mice or female rats. In male rats, there was an increased incidence of benign adenomas of the thyroid and liver. The relevance of these findings to human is unclear. The no-effect doses for these observations in male rats were 30 mg/kg body weight/day for thyroid tumors and 60 mg/kg body weight/day for liver tumors, which are over 15 and 30 times, respectively, clinical exposure on a mg/m2 basis.
Repaglinide was non-genotoxic in a battery of in vivo and in vitro studies: Bacterial mutagenesis (Ames test), in vitro forward cell mutation assay in V79 cells (HGPRT), in vitro chromosomal aberration assay in human lymphocytes, unscheduled and replicating DNA synthesis in rat liver and in vivo mouse and rat micronucleus test. Fertility of male and female rats was unaffected by repaglinide administration at doses up to 80 mg/kg body weight/day (females) and 300 mg/kg body weight/day (males); over 40 times clinical exposure on a mg/m2 basis.
Use in pregnancy: Pregnancy Category C.
Teratogenic Effects: Safety in pregnant women has not been established. Repaglinide was not teratogenic in rats or rabbits at doses 40 times (rats) and approximately 0.8 times (rabbit) clinical exposure (on a mg/m2 basis) throughout pregnancy. Because animal reproduction studies are not always predictive of human response, repaglinide should be used during pregnancy only if it is clearly needed. Because recent information suggest that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Nonteratogenic Effects: Offspring of rat dams exposed to repaglinide at 15 times clinical exposure on a mg/m2 basis during days 17 to 22 of gestation and during lactation developed nonteratogenic skeletal deformities consisting of shortening, thickening and bending of the humerus during the postnatal period. This effect was not seen at doses up to 2.5 times clinical exposure (on a mg/m2 basis) on days 1 to 22 of pregnancy or at higher doses given during days 1 to 16 of pregnancy. Relevant human exposure has not occurred to date and therefore the safety of repaglinide administration throughout pregnancy or lactation cannot be established.
Use in lactation: In rat reproduction studies, measurable levels of repaglinide were detected in the breast milk of the dams and lowered blood glucose levels were observed in the pups. Cross fostering studies indicated that skeletal changes (see Nonteratogenic Effects previously stated) could be induced in control pups nursed by treated dams, although this occurred to a lesser degree than those pups treated in utero. Although it is not known whether repaglinide is excreted in human milk, some oral agents are known to be excreted by this route. Because the potential for hypoglycemia in nursing infants may exist and because of the effects on nursing animals, a decision should be made as to whether repaglinide should be discontinued in nursing mothers or if mothers should discontinued nursing. If repaglinide is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Use in children: No studies have been performed in children.
Use in the elderly: In repaglinide clinical studies of 24 weeks or greater duration, 415 patients were over 65 years of age. In one-year, active-controlled trials, no differences were seen in effectiveness or adverse events between these subject and those less than 65 other than the expected age-related increase in cardiovascular events observed for repaglinide and comparator drugs. There was no increase in frequency or severity of hypoglycemia in older subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals to repaglinide therapy cannot be ruled out.
See Overdosage and Precautions.
Repaglinide has been administered to 2,931 individuals during clinical trials. Approximately 1,500 of these individuals with type 2 diabetes have been treated for at least 3 months, 1,000 for at least 6 months, and 800 for at least 1 year. The majority of these individuals (1,228) received repaglinide in one of five 1-year, active controlled trials. The comparator drugs in these 1-year trials were oral sulfonylurea drugs (SU) including glyburide and glipizide. Over one year, 13% of repaglinide patients were discontinued due to adverse events, as were 14% of SU patients. The most common adverse reactions leading to withdrawal were hyperglycemia, hypoglycemia and related symptoms (see Precautions). Mild or moderate hypoglycemia occurred in 16% of repaglinide patients, 20% of glyburide patients and 19% of glipizide patients. Cardiovascular events also occur commonly in patients with type 2 diabetes. In one year comparator trials, the incidence of individual events was not greater than 1% except for chest pain (1.8%). The individual incidence of other cardiovascular events (hypertension, abnormal ECG, myocardial infarction, arrhythmias and palpitations) was <1% and not different for repaglinide and the comparator drugs.
The incidence of serious cardiovascular adverse reactions added together, including ischemia, was slightly higher for repaglinide (4%) than for sulfonylurea drugs (3%) in controlled comparator clinical trials. In 1-year controlled trials, repaglinide treatment was not associated with excess mortality rates compared to rates observed with other oral hypoglycemic agent therapies.
Infrequent Adverse Events (<1% of Patients):
Less common adverse clinical or laboratory events observed in clinical trials included elevated liver enzymes, thrombocytopenia, leucopenia and anaphylactoid reactions (one patient).
Combination Therapy with Thiazolidinediones:
During 24-week treatment clinical trials of repaglinide-rosiglitazone or repaglinide-pioglitazone combination therapy (a total of 250 patients in combination therapy), hypoglycemia (blood glucose <50 mg/dL) occurred in 7% of combination therapy patients in comparison to 7% for repaglinide monotherapy, and 2% for thiazolidinedione monotherapy.
Peripheral edema was reported in 12 out of 250 repaglinide-thiazolidinedione combination therapy patients and 3 out of 124 thiazolidinedione monotherapy patients, with no cases reported in these trials for repaglinide monotherapy. When corrected for dropout rates of the treatment groups, the percentage of patients having events of peripheral edema per 24 weeks of treatment were 5% for repaglinide-thiazolidinedione combination therapy and 4% for thiazolidinedione monotherapy. There were reports in 2 of 250 patients (0.8%) treated with repaglinide-thiazolidinedione therapy of episodes of edema with congestive heart failure. Both patients had a prior history of coronary artery disease and recovered after treatment with diuretic agents. No comparable cases in the monotherapy treatment groups were reported.
Mean change in weight from baseline was +4.9 kg for repaglinide-thiazolidinedione therapy. There were no patients on repaglinide-thiazolidinedione combination therapy who had elevations of liver transaminases (defined as 3 times the upper limit of normal levels). Although no causal relationship has been established, post-marketing experience includes reports of the following rare adverse events: Alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson syndrome and severe hepatic dysfunction.
Drug interaction studies performed in healthy volunteers showed that repaglinide had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline or warfarin. Co-administration of cimetidine with repaglinide did not significantly alter the absorption and disposition of repaglinide.
In vitro data indicate that repaglinide metabolism may be inhibited by antifungal agents like ketoconazole and miconazole and antibacterial agents like erythromycin (cytochrome P-450 enzyme system 3A4 inhibitors). Drugs that induce the cytochrome P-450 enzyme system 3A4 may increase repaglinide metabolism, such drugs include rifampin, barbiturates and carbamazepine.
In vivo data from a study that evaluated the co-administration of a cytochrome P-450 enzyme inhibitor, clarithromycin, with repaglinide resulted in a clinically significant increase in repaglinide plasma levels. This increase in repaglinide plasma levels may necessitate a repaglinide dose adjustment.
In vivo data from a study that evaluated the co-administration of gemfibrozil with repaglinide in healthy subjects resulted in a significant increase in repaglinide blood levels. Patients taking repaglinide should not start taking gemfibrozil; patients taking gemfibrozil should not start taking repaglinide. Concomitant use may result in enhanced and prolonged blood-glucose lowering effects of repaglinide. Caution should be exercised in patients already on repaglinide and gemfibrozil - blood glucose levels should be monitored and repaglinide dose adjustment may be needed. Rare post marketing events of serious hypoglycemia have been reported in patients taking repaglinide and gemfibrozil together. Gemfibrozil and itraconazole had a synergistic metabolic inhibitory effect on repaglinide. Therefore, patients taking repaglinide and gemfibrozil should not take itraconazole.
The hypoglycemic action of oral blood-glucose lowering agents may be potentiated by certain drugs including non-steroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving oral blood-glucose lowering agents, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving oral blood-glucose lowering agents, the patient should be observed closely for loss of glycemic control.
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When these drugs are administered to a patient receiving oral blood glucose-lowering agents, the patient should be observed for loss of glycemic control. When these drugs are withdrawn from a patient receiving oral blood glucose lowering agents, the patient should be observed closely for hypoglycemia.
STORE AT TEMPERATURE BELOW 30°C. PROTECT FROM LIGHT.
A10BX02 - repaglinide ; Belongs to the class of other blood glucose lowering drugs excluding insulins. Used in the treatment of diabetes.