Prandin Information
Prandin () Description
Prandin () (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, S(+)2-ethoxy-4(2((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) benzoic acid, is chemically unrelated to the oral sulfonylurea insulin secretagogues.
The structural formula is as shown below:
Repaglinide is a white to off-white powder with molecular formula C H N O and a molecular weight of 452.6. Prandin () tablets contain 0.5 mg, 1 mg, or 2 mg of repaglinide. In addition each tablet contains the following inactive ingredients: calcium hydrogen phosphate (anhydrous), microcrystalline cellulose, maize starch, polacrilin potassium, povidone, glycerol (85%), magnesium stearate, meglumine, and poloxamer. The 1 mg and 2 mg tablets contain iron oxides (yellow and red, respectively) as coloring agents.
Prandin () Clinical Pharmacology
Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (ß) cells in the pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations.
Repaglinide closes ATP-dependent potassium channels in the ß-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the ß-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.
Absorption:
Distribution:
ss
Metabolism:
Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1).
Excretion:
14
Pharmacokinetic Parameters:
These data indicate that repaglinide did not accumulate in serum. Clearance of oral repaglinide did not change over the 0.5 - 4 mg dose range, indicating a linear relationship between dose and plasma drug levels.
Variability of Exposure:
Geriatric Use
Pediatric:
Gender:
Race:
Drug interaction studies performed in healthy volunteers show that Prandin () had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline, or warfarin. Co-administration of cimetidine with Prandin () did not significantly alter the absorption and disposition of repaglinide.
Additionally, the following drugs were studied in healthy volunteers with co-administration of Prandin () . Listed below are the results:
Fenofibrate:
max
Ketoconazole
Trimethoprim:
max
Drug-Drug Interactions
In another study, co-administration of 600 mg rifampin and a single dose of 4 mg Prandin () (after 6 days of once daily rifampin 600 mg) resulted in a 48% and 17% decrease in repaglinide median AUC and median C respectively. The median decreases were from 54 ng/mL*hr to 28 ng/mL*hr for AUC and from 35 ng/mL to 29 ng/mL for C. Prandin () administered by itself (after 7 days of once daily rifampin 600 mg) resulted in an 80% and 79% decrease in repaglinide median AUC and Crespectively. The decreases were from 54 ng/mL*hr to 11 ng/mL*hr for AUC and from 35 ng/mL to 7.5 ng/mL for C.
max
max
Monotherapy Trials
A four-week, double-blind, placebo-controlled dose-response trial was conducted in 138 patients with type 2 diabetes using doses ranging from 0.25 to 4 mg taken with each of three meals. Prandin () therapy resulted in dose-proportional glucose lowering over the full dose range. Plasma insulin levels increased after meals and reverted toward baseline before the next meal. Most of the fasting blood glucose-lowering effect was demonstrated within 1-2 weeks.
In a double-blind, placebo-controlled, 3-month dose titration study, Prandin () or placebo doses for each patient were increased weekly from 0.25 mg through 0.5, 1, and 2 mg, to a maximum of 4 mg, until a fasting plasma glucose (FPG) level
Another double-blind, placebo-controlled trial was carried out in 362 patients treated for 24 weeks. The efficacy of 1 and 4 mg preprandial doses was demonstrated by lowering of fasting blood glucose and by HbA at the end of the study. HbA for the Prandin () - treated groups (1 and 4 mg groups combined) at the end of the study was decreased compared to the placebo-treated group in previously naïve patients and in patients previously treated with oral hypoglycemic agents by 2.1% units and 1.7% units, respectively. In this fixed-dose trial, patients who were naïve to oral hypoglycemic agent therapy and patients in relatively good glycemic control at baseline (HbA below 8%) showed greater blood glucose-lowering including a higher frequency of hypoglycemia. Patients who were previously treated and who had baseline HbA ≥ 8% reported hypoglycemia at the same rate as patients randomized to placebo. There was no average gain in body weight when patients previously treated with oral hypoglycemic agents were switched to Prandin () . The average weight gain in patients treated with Prandin () and not previously treated with sulfonylurea drugs was 3.3%.
The dosing of Prandin () relative to meal-related insulin release was studied in three trials including 58 patients. Glycemic control was maintained during a period in which the meal and dosing pattern was varied (2, 3 or 4 meals per day; before meals x 2, 3, or 4) compared with a period of 3 regular meals and 3 doses per day (before meals x 3). It was also shown that Prandin () can be administered at the start of a meal, 15 minutes before, or 30 minutes before the meal with the same blood glucose-lowering effect.
Prandin () was compared to other insulin secretagogues in 1-year controlled trials to demonstrate comparability of efficacy and safety. Hypoglycemia was reported in 16% of 1228 Prandin () patients, 20% of 417 glyburide patients, and 19% of 81 glipizide patients. Of Prandin () -treated patients with symptomatic hypoglycemia, none developed coma or required hospitalization.
Combination Trials
Prandin () was studied in combination with metformin in 83 patients not satisfactorily controlled on exercise, diet, and metformin alone. Prandin () dosage was titrated for 4 to 8 weeks, followed by a 3-month maintenance period. Combination therapy with Prandin () and metformin resulted in significantly greater improvement in glycemic control as compared to repaglinide or metformin monotherapy. HbA was improved by 1% unit and FPG decreased by an additional 35 mg/dL. In this study where metformin dosage was kept constant, the combination therapy of Prandin () and metformin showed dose-sparing effects with respect to Prandin () . The greater efficacy response of the combination group was achieved at a lower daily repaglinide dosage than in the Prandin () monotherapy group (see Table).
A combination therapy regimen of Prandin () and pioglitazone was compared to monotherapy with either agent alone in a 24-week trial that enrolled 246 patients previously treated with sulfonylurea or metformin monotherapy (HbA > 7.0%). Numbers of patients treated were: Prandin () (N = 61), pioglitazone (N = 62), combination (N = 123). Prandin () dosage was titrated during the first 12 weeks, followed by a 12-week maintenance period. Combination therapy resulted in significantly greater improvement in glycemic control as compared to monotherapy (figure below). The changes from baseline for completers in FPG (mg/dL) and HbA (%), respectively were: -39.8 and -0.1 for Prandin () , -35.3 and -0.1 for pioglitazone and -92.4 and -1.9 for the combination. In this study where pioglitazone dosage was kept constant, the combination therapy group showed dose-sparing effects with respect to Prandin () (see figure legend). The greater efficacy response of the combination group was achieved at a lower daily repaglinide dosage than in the Prandin () monotherapy group. Mean weight increases associated with combination, Prandin () and pioglitazone therapy were 5.5 kg, 0.3 kg, and 2.0 kg respectively.
HbA Values from Prandin () / Pioglitazone Combination Study
HbA values by study week for patients who completed study (combination, N = 101; Prandin () , N = 35, pioglitazone, N = 26).
Subjects with FPG above 270 mg/dL were withdrawn from the study.
Pioglitazone dose: fixed at 30 mg/day; Prandin () median final dose: 6 mg/day for combination and 10 mg/day for monotherapy.
A combination therapy regimen of Prandin () and rosiglitazone was compared to monotherapy with either agent alone in a 24-week trial that enrolled 252 patients previously treated with sulfonylurea or metformin (HbA > 7.0%). Combination therapy resulted in significantly greater improvement in glycemic control as compared to monotherapy (table below). The glycemic effects of the combination therapy were dose-sparing with respect to both total daily Prandin () dosage and total daily rosiglitazone dosage (see table legend). A greater efficacy response of the combination therapy group was achieved with half the median daily dose of Prandin () and rosiglitazone, as compared to the respective monotherapy groups. Mean weight change associated with combination therapy was greater than that of Prandin () monotherapy.
Prandin () Indications And Usage
Prandin () is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Prandin () Contraindications
Prandin () is contraindicated in patients with:
Prandin () Precautions
Prandin () is not indicated for use in combination with NPH-insulin (See ).
Macrovascular Outcomes:
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Prandin () or any other anti-diabetic drug.
Hypoglycemia:
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 (naïve) or whose HbAis less than 8%. Prandin () should be administered with meals to lessen the risk of hypoglycemia.
Loss of Control of Blood Glucose:
Information for Patients
Patients should be informed of the potential risks and advantages of Prandin () 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 HbA. The risks 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.
Laboratory Tests
Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels with a goal of decreasing these 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 (HbA) is inadequate.
Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Drugs that inhibit OATP1B1 (e.g. cyclosporine) may likewise have the potential to increase plasma concentrations of repaglinide. See section, .
Gemfibrozil significantly increased Prandin () exposure. Therefore, patients should not take Prandin () with gemfibrozil. See section, , and .
The hypoglycemic action of oral blood glucose-lowering agents may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, cyclosporine, 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.
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/m 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 humans 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/m basis.
Repaglinide was non-genotoxic in a battery of and studies: Bacterial mutagenesis (Ames test), forward cell mutation assay in V79 cells (HGPRT), chromosomal aberration assay in human lymphocytes, unscheduled and replicating DNA synthesis in rat liver, and mouse and rat micronucleus tests.
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/m basis.
Pregnancy category C
Teratogenic Effects
2
Because recent information suggests 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
Prandin () Adverse Reactions
Hypoglycemia: See and sections.
Prandin () has been administered to 2931 individuals during clinical trials. Approximately 1500 of these individuals with type 2 diabetes have been treated for at least 3 months, 1000 for at least 6 months, and 800 for at least 1 year. The majority of these individuals (1228) received Prandin () 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 Prandin () patients were discontinued due to adverse events, as were 14% of SU patients. The most common adverse events leading to withdrawal were hyperglycemia, hypoglycemia, and related symptoms (see ). Mild or moderate hypoglycemia occurred in 16% of Prandin () patients, 20% of glyburide patients, and 19% of glipizide patients.
The table below lists common adverse events for Prandin () patients compared to both placebo (in trials 12 to 24 weeks duration) and to glyburide and glipizide in one year trials. The adverse event profile of Prandin () was generally comparable to that for sulfonylurea drugs (SU).
Prandin () Overdosage
In a clinical trial, patients received increasing doses of Prandin () 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.
Prandin () Dosage And Administration
There is no fixed dosage regimen for the management of type 2 diabetes with Prandin () .
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 Prandin () may be sufficient during periods of transient loss of control in patients usually well controlled on diet.
Prandin () 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.
Prandin () How Supplied
Prandin () (repaglinide) tablets are supplied as unscored, biconvex tablets available in 0.5 mg (white), 1 mg (yellow) and 2 mg (peach) strengths. Tablets are embossed with the Novo Nordisk (Apis) bull symbol and colored to indicate strength.
Do not store above 25° C (77° F).
Protect from moisture. Keep bottles tightly closed.
Dispense in tight containers with safety closures.
Manufactured in Germany for
Novo Nordisk Inc.
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
© 2003-2010 Novo Nordisk A/S
All rights reserved.
Date of Issue: March 19, 2010
Version: 10
Prandin () 1 mg tablets are available from Cardinal Health in unit dose
packages of 100 tablets.
1 mg, unit dose package of 100 tablets, NDC 55154-4575-4
Cardinal Health
Zanesville OH 43701
IU40284600710
Prandin ()
Prandin ()
Prandin ()
