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theophylline, or warfarin. Co-administration of cimetidine with PRANDIN® did combined) at the end of the study was decreased compared to the placebo- not significantly alter the absorption and disposition of repaglinide.
treated group in previously naïve patients and in patients previously treated with Additionally, the following drugs were studied in healthy volunteers with co- oral hypoglycemic agents by 2.1% units and 1.7% units, respectively. In this administration of PRANDIN®. Listed below are the results: fixed-dose trial, patients who were naïve to oral hypoglycemic agent therapy and patients in relatively good glycemic control at baseline (HbA CYP2C8 and CYP3A4 Inhibitors/Inducer
showed greater blood glucose-lowering including a higher frequency of DESCRIPTION
Gemfibrozil and Itraconazole: Co-administration of gemfibrozil (600 mg) and hypoglycemia. Patients who were previously treated and who had baseline PRANDIN® (repaglinide) is an oral blood glucose-lowering drug of the a single dose of 0.25 mg PRANDIN® (after 3 days of twice-daily 600 mg HbA1c ≥ 8% reported hypoglycemia at the same rate as patients randomized to meglitinide class used in the management of type 2 diabetes mellitus (also gemfibrozil) resulted in an 8.1-fold higher repaglinide AUC and prolonged placebo. There was no average gain in body weight when patients previously known as non-insulin dependent diabetes mellitus or NIDDM). Repaglinide, repaglinide half-life from 1.3 to 3.7 hr. Co-administration with itraconazole and treated with oral hypoglycemic agents were switched to PRANDIN®. The average S(+)2-ethoxy-4(2((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) a single dose of 0.25 mg PRANDIN® (on the third day of a regimen of 200 mg weight gain in patients treated with PRANDIN® and not previously treated with benzoic acid, is chemically unrelated to the oral sulfonylurea insulin initial dose, twice-daily 100 mg itraconazole) resulted in a 1.4-fold higher repaglinide AUC. Co-administration of both gemfibrozil and itraconazole with The dosing of PRANDIN® relative to meal-related insulin release was studied in The structural formula is as shown below: PRANDIN® resulted in a 19-fold higher repaglinide AUC and prolonged three trials including 58 patients. Glycemic control was maintained during a repaglinide half-life to 6.1 hr. Plasma repaglinide concentration at 7h increased period in which the meal and dosing pattern was varied (2, 3 or 4 meals per day; 28.6-fold with gemfibrozil co-administration and 70.4-fold with the gemfibrozil- before meals x 2, 3, or 4) compared with a period of 3 regular meals and 3 doses itraconazole combination (see CONTRAINDICATIONS, PRECAUTIONS,
Drug-Drug Interactions).
per day (before meals x 3). It was also shown that PRANDIN® can beadministered at the start of a meal, 15 minutes before, or 30 minutes before the Fenofibrate: Co-administration of 200 mg fenofibrate with a single dose of meal with the same blood glucose-lowering effect.
0.25 mg repaglinide (after 5 days of once daily fenofibrate 200 mg) resulted inunchanged AUC and C PRANDIN® was compared to other insulin secretagogues in 1-year controlled trials to demonstrate comparability of efficacy and safety. Hypoglycemia was Ketoconazole: Co-administration of 200 mg ketoconazole and a single dose of reported in 16% of 1228 PRANDIN® patients, 20% of 417 glyburide patients, 2 mg PRANDIN® (after 4 days of once daily ketoconazole 200 mg) resulted in a and 19% of 81 glipizide patients. Of PRANDIN®-treated patients with 15% and 16% increase in repaglinide AUC and Cmax, respectively. The increases symptomatic hypoglycemia, none developed coma or required hospitalization.
were from 20.2 ng/mL to 23.5 ng/mL for Cmax and from 38.9 ng/mL*hr to Combination Trials
PRANDIN® was studied in combination with metformin in 83 patients not
Trimethoprim: Co-administration of 160 mg trimethoprim and a single dose of satisfactorily controlled on exercise, diet, and metformin alone. PRANDIN® Repaglinide is a white to off-white powder with molecular formula C27H36N2O4 0.25 mg PRANDIN® (after 2 days of twice daily and one dose on the third day dosage was titrated for 4 to 8 weeks, followed by a 3-month maintenance and a molecular weight of 452.6. PRANDIN® tablets contain 0.5 mg, 1 mg, or of trimethoprim 160 mg) resulted in a 61% and 41% increase in repaglinide 2 mg of repaglinide. In addition each tablet contains the following inactive period. Combination therapy with PRANDIN® and metformin resulted in AUC and Cmax, respectively. The increase in AUC was from 5.9 ng/mL*hr to ingredients: calcium hydrogen phosphate (anhydrous), microcrystalline cellulose, significantly greater improvement in glycemic control as compared to repaglinide 9.6 ng/mL*hr and the increase in Cmax was from 4.7 ng/mL to 6.6 ng/mL.
maize starch, polacrilin potassium, povidone, glycerol (85%), magnesium or metformin monotherapy. HbA1c was improved by 1% unit and FPG decreased Cyclosporine: Co-administration of 100 mg cyclosporine with a single dose of stearate, meglumine, and poloxamer. The 1 mg and 2 mg tablets contain iron by an additional 35 mg/dL. In this study where metformin dosage was kept 0.25 mg repaglinide (after two 100 mg doses of cyclosporine twelve hours oxides (yellow and red, respectively) as coloring agents.
constant, the combination therapy of PRANDIN® and metformin showed dose- apart) increased the repaglinide (0.25 mg) Cmax 1.8-fold and the AUC 2.5-fold sparing effects with respect to PRANDIN®. The greater efficacy response of the CLINICAL PHARMACOLOGY
in an interaction study with healthy volunteers (see PRECAUTIONS, Drug-
combination group was achieved at a lower daily repaglinide dosage than in the Drug Interactions).
Mechanism of Action
PRANDIN® monotherapy group (see Table).
Repaglinide lowers blood glucose levels by stimulating the release of insulin Rifampin: Co-administration of 600 mg rifampin and a single dose of 4 mg PRANDIN® and Metformin Therapy: Mean Changes from Baseline in
from the pancreas. This action is dependent upon functioning beta (ß) cells in the PRANDIN® (after 6 days of once daily rifampin 600 mg) resulted in a 32% and Glycemic Parameters and Weight After 4 to 5 Months of Treatment1
pancreatic islets. Insulin release is glucose-dependent and diminishes at low 26% decrease in repaglinide AUC and Cmax, respectively. The decreases were from 40.4 ng/mL to 29.7 ng/mL for Cmax and from 56.8 ng/mL*hr to PRANDIN®
Combination
Metformin
Repaglinide closes ATP-dependent potassium channels in the ß-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes In another study, co-administration of 600 mg rifampin and a single dose of the ß-cell, which leads to an opening of calcium channels. The resulting increased 4 mg PRANDIN® (after 6 days of once daily rifampin 600 mg) resulted in a 48% calcium influx induces insulin secretion. The ion channel mechanism is highly and 17% decrease in repaglinide median AUC and median Cmax respectively. The tissue selective with low affinity for heart and skeletal muscle.
median decreases were from 54 ng/mL*hr to 28 ng/mL*hr for AUC and from Pharmacokinetics
max. PRANDIN® administered by itself (after 7 days of once daily rifampin 600 mg) resulted in an 80% and 79% decrease in Absorption: After oral administration, repaglinide is rapidly and completely repaglinide median AUC and Cmax respectively. The decreases were from absorbed from the gastrointestinal tract. After single and multiple oral doses in 54 ng/mL*hr to 11 ng/mL*hr for AUC and from 35 ng/mL to 7.5 ng/mL for Cmax.
healthy subjects or in patients, peak plasma drug levels (Cmax) occur within Levonorgestrel & Ethinyl Estradiol: Co-administration of a combination tablet max). Repaglinide is rapidly eliminated from the blood stream with a *: p < 0.05, for pairwise comparisons with PRANDIN® and metformin.
half-life of approximately 1 hour. The mean absolute bioavailability is 56%. When of 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol administered once daily #: p < 0.05, for pairwise comparison with metformin.
repaglinide was given with food, the mean T for 21 days with 2 mg PRANDIN® administered three times daily (days 1-4) and a single dose on Day 5 resulted in 20% increases in repaglinide, levonorgestrel, max and AUC (area under the time/plasma concentration curve) were decreased A combination therapy regimen of PRANDIN® and pioglitazone was compared and ethinyl estradiol Cmax.The increase in repaglinide Cmax was from 40.5 ng/mL to monotherapy with either agent alone in a 24-week trial that enrolled 246 to 47.4 ng/mL. Ethinyl estradiol AUC parameters were increased by 20%, while Distribution: After intravenous (IV) dosing in healthy subjects, the volume patients previously treated with sulfonylurea or metformin monotherapy (HbA repaglinide and levonorgestrel AUC values remained unchanged.
> 7.0%). Numbers of patients treated were: PRANDIN® (N = 61), pioglitazone ss) was 31 L, and the total body clearance (CL) was 38 L/h. Protein binding and binding to human serum albumin was Simvastatin: Co-administration of 20 mg simvastatin and a single dose of 2 mg (N = 62), combination (N = 123). PRANDIN® dosage was titrated during the first PRANDIN® (after 4 days of once daily simvastatin 20 mg and three times daily 12 weeks, followed by a 12-week maintenance period. Combination therapy PRANDIN® 2 mg) resulted in a 26% increase in repaglinide C resulted in significantly greater improvement in glycemic control as compared to Metabolism: Repaglinide is completely metabolized by oxidative biotrans- 23.6 ng/mL to 29.7 ng/mL. AUC was unchanged.
monotherapy (figure below). The changes from baseline for completers in FPG formation and direct conjugation with glucuronic acid after either an IV or oral dose. The major metabolites are an oxidized dicarboxylic acid (M2), the aromatic Nifedipine: Co-administration of 10 mg nifedipine with a single dose of 2 mg 1c (%), 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 amine (M1), and the acyl glucuronide (M7). The cytochrome P-450 enzyme PRANDIN® (after 4 days of three times daily nifedipine 10 mg and three times where pioglitazone dosage was kept constant, the combination therapy group system, specifically 2C8 and 3A4, have been shown to be involved in the N- daily PRANDIN® 2 mg) resulted in unchanged AUC and Cmax values for both showed dose-sparing effects with respect to PRANDIN® (see figure legend).
dealkylation of repaglinide to M2 and the further oxidation to M1. Metabolites The greater efficacy response of the combination group was achieved at a lower do not contribute to the glucose-lowering effect of repaglinide.
Clarithromycin: Co-administration of 250 mg clarithromycin and a single dose daily repaglinide dosage than in the PRANDIN® monotherapy group. Mean Repaglinide appears to be a substrate for active hepatic uptake transporter of 0.25 mg PRANDIN® (after 4 days of twice daily clarithromycin 250 mg) weight increases associated with combination, PRANDIN® and pioglitazone (organic anion transporting protein OATP1B1).
resulted in a 40% and 67% increase in repaglinide AUC and Cmax, respectively.
therapy were 5.5 kg, 0.3 kg, and 2.0 kg respectively.
The increase in AUC was from 5.3 ng/mL*hr to 7.5 ng/mL*hr and the increase 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 max was from 4.4 ng/mL to 7.3 ng/mL.
1c Values from PRANDIN®/Pioglitazone Combination Study
approximately 8% in the urine. Only 0.1% of the dose is cleared in the urine as Renal Insufficiency: Single-dose and steady-state pharmacokinetics of
parent compound. The major metabolite (M2) accounted for 60% of the repaglinide were compared between patients with type 2 diabetes and normal Prandin®
Prandin® + Pioglitazone
Pioglitazone
administered dose. Less than 2% of parent drug was recovered in feces.
renal function (CrCl > 80 mL/min), mild to moderate renal function impairment (CrCl = 40 – 80 mL/min), and severe renal function impairment (CrCl = 20 – Pharmacokinetic Parameters: The pharmacokinetic parameters of repaglinide obtained from a single-dose, crossover study in healthy subjects and from a max of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 multiple-dose, parallel, dose-proportionality (0.5, 1, 2 and 4 mg) study in ng/mL*hr vs 57.2 ng/mL*hr and 37.5 ng/mL vs 37.7 ng/mL, respectively.) patients with type 2 diabetes are summarized in the following table: Patients with severely reduced renal function had elevated mean AUC and Parameter
Patients with type 2 diabetesa
Cmax values (98.0 ng/mL*hr and 50.7 ng/mL, respectively), but this study showed only a weak correlation between repaglinide levels and creatinine clearance. Initial dose adjustment does not appear to be necessary for patients with mild to moderate renal dysfunction. However, patients with type 2
diabetes who have severe renal function impairment should initiate
PRANDIN® 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
Change -1.5
failure requiring hemodialysis.
Hepatic Insufficiency: A single-dose, open-label study was conducted in 12
healthy subjects and 12 patients with chronic liver disease (CLD) classified by Child-Pugh scale and caffeine clearance. Patients with moderate to severe impairment of liver function had higher and more prolonged serum Treatment Week
concentrations of both total and unbound repaglinide than healthy subjects healthy: 91.6 ng/mL*hr; AUCCLD patients: 368.9 ng/mL*hr; Cmax, healthy: 46.7 1c values by study week for patients who completed study (combination, N = 101; PRANDIN®, N = 35, pioglitazone, N = 26).
max, CLD patients: 105.4 ng/mL). AUC was statistically correlated with caffeine clearance. No difference in glucose profiles was observed across patient Subjects with FPG above 270 mg/dL were withdrawn from the study.
groups. Patients with impaired liver function may be exposed to higher Pioglitazone dose: fixed at 30 mg/day; PRANDIN® median final dose: Parameter
Healthy Subjects
concentrations of repaglinide and its associated metabolites than would patients 6 mg/day for combination and 10 mg/day for monotherapy.
with normal liver function receiving usual doses. Therefore, PRANDIN®
should be used cautiously in patients with impaired liver function.
A combination therapy regimen of PRANDIN® and rosiglitazone was compared Longer intervals between dose adjustments should be utilized to
to monotherapy with either agent alone in a 24-week trial that enrolled allow full assessment of response.
252 patients previously treated with sulfonylurea or metformin (HbA1c > 7.0%).
Clinical Trials
Combination therapy resulted in significantly greater improvement in glycemiccontrol as compared to monotherapy (table below). The glycemic effects of the Monotherapy Trials
combination therapy were dose-sparing with respect to both total daily Vss = volume of distribution at steady state A four-week, double-blind, placebo-controlled dose-response trial was conducted PRANDIN® dosage and total daily rosiglitazone dosage (see table legend).
in 138 patients with type 2 diabetes using doses ranging from 0.25 to 4 mg taken A greater efficacy response of the combination therapy group was achieved with with each of three meals. PRANDIN® therapy resulted in dose-proportional half the median daily dose of PRANDIN® and rosiglitazone, as compared to the These data indicate that repaglinide did not accumulate in serum. Clearance of glucose lowering over the full dose range. Plasma insulin levels increased after respective monotherapy groups. Mean weight change associated with oral repaglinide did not change over the 0.5 - 4 mg dose range, indicating a meals and reverted toward baseline before the next meal. Most of the fasting combination therapy was greater than that of PRANDIN® monotherapy.
linear relationship between dose and plasma drug levels.
blood glucose-lowering effect was demonstrated within 1-2 weeks.
Variability of Exposure: Repaglinide AUC after multiple doses of 0.25 to 4 mg In a double-blind, placebo-controlled, 3-month dose titration study, PRANDIN® Mean Changes from Baseline in Glycemic Parameters and Weight
with each meal varies over a wide range. The intra-individual and inter-individual or placebo doses for each patient were increased weekly from 0.25 mg through in a 24-Week PRANDIN®/Rosiglitazone Combination Study1
coefficients of variation were 36% and 69%, respectively. AUC over the 0.5, 1, and 2 mg, to a maximum of 4 mg, until a fasting plasma glucose (FPG) PRANDIN®
Combination
Rosiglitazone
therapeutic dose range included 69 to 1005 ng/mL*hr, but AUC exposure up to level <160 mg/dL was achieved or the maximum dose reached. The dose that 5417 ng/mL*hr was reached in dose escalation studies without apparent achieved the targeted control or the maximum dose was continued to end of study. FPG and 2-hour post-prandial glucose (PPG) increased in patients HbA1c (%)
Special Populations
receiving placebo and decreased in patients treated with repaglinide. Differences between the repaglinide- and placebo-treated groups were -61 mg/dL (FPG) and Geriatric: Healthy volunteers were treated with a regimen of 2 mg taken before -104 mg/dL (PPG). The between-group change in HbA each of 3 meals. There were no significant differences in repaglinide term glycemic control, was 1.7% units.
FPG (mg/dL)
pharmacokinetics between the group of patients <65 years of age and a comparably sized group of patients ≥65 years of age (See PRECAUTIONS,
PRANDIN® vs. Placebo Treatment: Mean FPG, PPG, and HbA1c
Geriatric Use).
Changes from baseline after 3 months of treatment:
Change in Weight (kg) +1.3
Pediatric: No studies have been performed in pediatric patients.
FPG (mg/dL)
PPG (mg/dL)
HbA1c (%)
Gender: A comparison of pharmacokinetics in males and females showed the *: p-value ≤ 0.001 for comparison to either monotherapy AUC over the 0.5 mg to 4 mg dose range to be 15% to 70% higher in females #: p-value < 0.001 for comparison to PRANDIN with type 2 diabetes. This difference was not reflected in the frequency of Final median doses: rosiglitazone - 4 mg/day for combination and 8 mg/day hypoglycemic episodes (male: 16%; female: 17%) or other adverse events. With for monotherapy; PRANDIN® - 6 mg/day for combination and 12 mg/day respect to gender, no change in general dosage recommendation is indicated since dosage for each patient should be individualized to achieve optimal clinicalresponse.
FPG = fasting plasma glucosePPG = post-prandial glucose INDICATIONS AND USAGE
Race: No pharmacokinetic studies to assess the effects of race have beenperformed, but in a U.S. 1-year study in patients with type 2 diabetes, the blood PRANDIN® is indicated as an adjunct to diet and exercise to improve glycemic glucose-lowering effect was comparable between Caucasians (n=297) and control in adults with type 2 diabetes mellitus.
*: p < 0.05 for between group difference African-Americans (n=33). In a U.S. dose-response study, there was no apparent CONTRAINDICATIONS
difference in exposure (AUC) between Caucasians (n=74) and Hispanics (n=33).
Another double-blind, placebo-controlled trial was carried out in 362 patients PRANDIN® is contraindicated in patients with: Drug-Drug Interactions
treated for 24 weeks. The efficacy of 1 and 4 mg preprandial doses was 1. Diabetic ketoacidosis, with or without coma. This condition should be treated Drug interaction studies performed in healthy volunteers show that PRANDIN® demonstrated by lowering of fasting blood glucose and by HbA1c at the end of had no clinically relevant effect on the pharmacokinetic properties of digoxin, the study. HbA1c for the PRANDIN®-treated groups (1 and 4 mg groups Pregnancy
Changes in blood glucose levels may result in blurred vision and visual disturbances, especially at the initiation of treatment with hypoglycemic agents.
Teratogenic Effects: Safety in pregnant women has not been established.
These changes are usually transient.
Repaglinide was not teratogenic in rats or rabbits at doses 40 times (rats) and Combination Therapy with Thiazolidinediones
approximately 0.8 times (rabbit) clinical exposure (on a mg/m2 basis) throughout During 24-week treatment clinical trials of PRANDIN®-rosiglitazone or pregnancy. Because animal reproduction studies are not always predictive of PRANDIN®-pioglitazone combination therapy (a total of 250 patients in 3. Co-administration of gemfibrozil.
human response, PRANDIN® should be used during pregnancy only if it is clearly combination therapy), hypoglycemia (blood glucose < 50 mg/dL) occurred in 7% 4. Known hypersensitivity to the drug or its inactive ingredients.
of combination therapy patients in comparison to 7% for PRANDIN® Because recent information suggests that abnormal blood glucose levels during monotherapy, and 2% for thiazolidinedione monotherapy.
PRECAUTIONS
pregnancy are associated with a higher incidence of congenital abnormalities, Peripheral edema was reported in 12 out of 250 PRANDIN®-thiazolidinedione many experts recommend that insulin be used during pregnancy to maintain combination therapy patients and 3 out of 124 thiazolidinedione monotherapy PRANDIN® is not indicated for use in combination with NPH-insulin (See blood glucose levels as close to normal as possible.
patients, with no cases reported in these trials for PRANDIN® monotherapy.
ADVERSE REACTIONS, Cardiovascular Events).
Nonteratogenic Effects: Offspring of rat dams exposed to repaglinide at 15 When corrected for dropout rates of the treatment groups, the percentage of Macrovascular Outcomes
times clinical exposure on a mg/m2 basis during days 17 to 22 of gestation and patients having events of peripheral edema per 24 weeks of treatment were 5% There have been no clinical studies establishing conclusive evidence of during lactation developed nonteratogenic skeletal deformities consisting of for PRANDIN®-thiazolidinedione combination therapy, and 4% for thiazo- macrovascular risk reduction with PRANDIN® or any other anti-diabetic drug.
shortening, thickening, and bending of the humerus during the postnatal period.
lidinedione monotherapy. There were reports in 2 of 250 patients (0.8%) treated This effect was not seen at doses up to 2.5 times clinical exposure (on a mg/m2 Hypoglycemia: All oral blood glucose-lowering drugs including repaglinide are
with PRANDIN®-thiazolidinedione therapy of episodes of edema with congestive basis) on days 1 to 22 of pregnancy or at higher doses given during days 1 to capable of producing hypoglycemia. Proper patient selection, dosage, and heart failure. Both patients had a prior history of coronary artery disease and 16 of pregnancy. Relevant human exposure has not occurred to date and instructions to the patients are important to avoid hypoglycemic episodes.
recovered after treatment with diuretic agents. No comparable cases in the therefore the safety of PRANDIN® administration throughout pregnancy or Hepatic insufficiency may cause elevated repaglinide blood levels and may monotherapy treatment groups were reported.
diminish gluconeogenic capacity, both of which increase the risk of serious Mean change in weight from baseline was +4.9 kg for PRANDIN®-thiazo- hypoglycemia. Elderly, debilitated, or malnourished patients, and those with Nursing Mothers
lidinedione therapy. There were no patients on PRANDIN®-thiazolidinedione adrenal, pituitary, hepatic, or severe renal insufficiency may be particularly In rat reproduction studies, measurable levels of repaglinide were detected in the combination therapy who had elevations of liver transaminases (defined as 3 susceptible to the hypoglycemic action of glucose-lowering drugs.
breast milk of the dams and lowered blood glucose levels were observed in the times the upper limit of normal levels).
pups. Cross fostering studies indicated that skeletal changes (see Non-
Hypoglycemia may be difficult to recognize in the elderly and in people taking teratogenic Effects) could be induced in control pups nursed by treated dams,
OVERDOSAGE
beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when although this occurred to a lesser degree than those pups treated in utero.
caloric intake is deficient, after severe or prolonged exercise, when alcohol is In a clinical trial, patients received increasing doses of PRANDIN® up to 80 mg Although it is not known whether repaglinide is excreted in human milk some ingested, or when more than one glucose-lowering drug is used.
a day for 14 days. There were few adverse effects other than those associated oral agents are known to be excreted by this route. Because the potential for with the intended effect of lowering blood glucose. Hypoglycemia did not occur The frequency of hypoglycemia is greater in patients with type 2 diabetes who hypoglycemia in nursing infants may exist, and because of the effects on nursing when meals were given with these high doses. Hypoglycemic symptoms without have not been previously treated with oral blood glucose-lowering drugs (naïve) animals, a decision should be made as to whether PRANDIN® should be loss of consciousness or neurologic findings should be treated aggressively with or whose HbA1c is less than 8%. PRANDIN® should be administered with meals discontinued in nursing mothers, or if mothers should discontinue nursing. If oral glucose and adjustments in drug dosage and/or meal patterns. Close PRANDIN® is discontinued and if diet alone is inadequate for controlling blood monitoring may continue until the physician is assured that the patient is out of Loss of Control of Blood Glucose: When a patient stabilized on any diabetic
glucose, insulin therapy should be considered.
danger. Patients should be closely monitored for a minimum of 24 to 48 hours, regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of Pediatric Use
since hypoglycemia may recur after apparent clinical recovery. There is no glycemic control may occur. At such times, it may be necessary to discontinue No studies have been performed in pediatric patients.
evidence that repaglinide is dialyzable using hemodialysis.
PRANDIN® and administer insulin. The effectiveness of any hypoglycemic drug in Geriatric Use
Severe hypoglycemic reactions with coma, seizure, or other neurological lowering blood glucose to a desired level decreases in many patients over a impairment occur infrequently, but constitute medical emergencies requiring period of time, which may be due to progression of the severity of diabetes or to In repaglinide clinical studies of 24 weeks or greater duration, 415 patients were immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the diminished responsiveness to the drug. This phenomenon is known as secondary over 65 years of age. In one-year, active-controlled trials, no differences were patient should be given a rapid intravenous injection of concentrated (50%) failure, to distinguish it from primary failure in which the drug is ineffective in an seen in effectiveness or adverse events between these subjects and those lessthan 65 other than the expected age-related increase in cardiovascular events glucose solution. This should be followed by a continuous infusion of more dilute individual patient when the drug is first given. Adequate adjustment of dose and observed for PRANDIN® and comparator drugs. There was no increase in (10%) glucose solution at a rate that will maintain the blood glucose at a level adherence to diet should be assessed before classifying a patient as a secondary frequency or severity of hypoglycemia in older subjects. Other reported clinical experience has not identified differences in responses between the elderly and Information for Patients
DOSAGE AND ADMINISTRATION
younger patients, but greater sensitivity of some older individuals to PRANDIN® Patients should be informed of the potential risks and advantages of PRANDIN® There is no fixed dosage regimen for the management of type 2 diabetes and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, ADVERSE REACTIONS
The patient's blood glucose should be monitored periodically to determine the and of regular testing of blood glucose and HbA1c. The risks of hypoglycemia, its Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections.
minimum effective dose for the patient; to detect primary failure, i.e., inadequate symptoms and treatment, and conditions that predispose to its development and PRANDIN® has been administered to 2931 individuals during clinical trials.
lowering of blood glucose at the maximum recommended dose of medication; concomitant administration of other glucose-lowering drugs should be explained Approximately 1500 of these individuals with type 2 diabetes have been treated and to detect secondary failure, i.e., loss of an adequate blood glucose-lowering to patients and responsible family members. Primary and secondary failure for at least 3 months, 1000 for at least 6 months, and 800 for at least 1 year.
response after an initial period of effectiveness. Glycosylated hemoglobin levels The majority of these individuals (1228) received PRANDIN® in one of five are of value in monitoring the patient's longer term response to therapy.
Patients should be instructed to take PRANDIN® before meals (2, 3, or
1-year, active-controlled trials. The comparator drugs in these 1-year trials were Short-term administration of PRANDIN® may be sufficient during periods of 4 times a day preprandially). Doses are usually taken within 15 minutes of
oral sulfonylurea drugs (SU) including glyburide and glipizide. Over one year, transient loss of control in patients usually well controlled on diet.
the meal but time may vary from immediately preceding the meal to as long as 13% of PRANDIN® patients were discontinued due to adverse events, as were PRANDIN® doses are usual y taken within 15 minutes of the meal but time may 30 minutes before the meal. Patients who skip a meal (or add an extra
14% of SU patients. The most common adverse events leading to withdrawal vary from immediately preceding the meal to as long as 30 minutes before the meal) should be instructed to skip (or add) a dose for that meal.
were hyperglycemia, hypoglycemia, and related symptoms (see PRECAUTIONS).
Mild or moderate hypoglycemia occurred in 16% of PRANDIN® patients, 20%
Laboratory Tests
of glyburide patients, and 19% of glipizide patients.
Starting Dose
Response to all diabetic therapies should be monitored by periodic The table below lists common adverse events for PRANDIN® patients compared For patients not previously treated or whose HbA measurements of fasting blood glucose and glycosylated hemoglobin levels with to both placebo (in trials 12 to 24 weeks duration) and to glyburide and glipizide a goal of decreasing these levels towards the normal range. During dose should be 0.5 mg with each meal. For patients previously treated with blood in one year trials. The adverse event profile of PRANDIN® was generally adjustment, fasting glucose can be used to determine the therapeutic response.
glucose-lowering drugs and whose HbA1c is ≥ 8%, the initial dose is 1 or 2 mg comparable to that for sulfonylurea drugs (SU).
Thereafter, both glucose and glycosylated hemoglobin should be monitored.
with each meal preprandially (see previous paragraph).
Glycosylated hemoglobin may be especially useful for evaluating long-term Commonly Reported Adverse Events (% of Patients)*
Dose Adjustment
glycemic control. Postprandial glucose level testing may be clinically helpful in PRANDIN®
PRANDIN®
Dosing adjustments should be determined by blood glucose response, usually patients whose pre-meal blood glucose levels are satisfactory but whose overall fasting blood glucose. Postprandial glucose levels testing may be clinically glycemic control (HbA1c) is inadequate.
helpful in patients whose pre-meal blood glucose levels are satisfactory but Drug-Drug Interactions
whose overall glycemic control (HbA1c) is inadequate. The preprandial dose In vitro data indicate that PRANDIN® is metabolized by cytochrome P450 Metabolic
should be doubled up to 4 mg with each meal until satisfactory blood glucose enzymes 2C8 and 3A4. Consequently, repaglinide metabolism may be response is achieved. At least one week should elapse to assess response after altered by drugs which influence these cytochrome P450 enzyme systems via Respiratory
induction and inhibition. Caution should therefore be used in patients who The recommended dose range is 0.5 mg to 4 mg taken with meals. PRANDIN® are on PRANDIN® and taking inhibitors and/or inducers of CYP2C8 and may be dosed preprandially 2, 3, or 4 times a day in response to changes in the CYP3A4. The effect may be very significant if both enzymes are inhibited at patient’s meal pattern. The maximum recommended daily dose is 16 mg.
the same time resulting in a substantial increase in repaglinide plasma Patient Management
concentrations. Drugs that are known to inhibit CYP3A4 include antifungal Long-term efficacy should be monitored by measurement of HbA1c levels agents like ketoconazole, itraconazole, and antibacterial agents like Gastrointestinal
approximately every 3 months. Failure to follow an appropriate dosage regimen erythromycin. Drugs that are known to inhibit CYP2C8 include agents like may precipitate hypoglycemia or hyperglycemia. Patients who do not adhere to trimethoprim, gemfibrozil and montelukast. Drugs that induce the CYP3A4 their prescribed dietary and drug regimen are more prone to exhibit and/or 2C8 enzyme systems include rifampin, barbiturates, and unsatisfactory response to therapy including hypoglycemia. When hypoglycemia carbamezapine. See CLINICAL PHARMACOLOGY section, Drug-Drug
occurs in patients taking a combination of PRANDIN® and a thiazolidinedione or Interactions.
PRANDIN® and metformin, the dose of PRANDIN® should be reduced.
Repaglinide appears to be a substrate for active hepatic uptake transporter Patients Receiving Other Oral Hypoglycemic Agents
(organic anion transporting protein OATP1B1). Drugs that inhibit OATP1B1 (e.g.
Musculoskeletal
When PRANDIN® is used to replace therapy with other oral hypoglycemic cyclosporine) may likewise have the potential to increase plasma concentrations agents, PRANDIN® may be started on the day after the final dose is given.
of repaglinide. See CLINICAL PHARMACOLOGY section, Drug-Drug
Patients should then be observed carefully for hypoglycemia due to potential Interactions.
overlapping of drug effects. When transferred from longer half-life sulfonylurea In vivo data from a study that evaluated the co-administration of a agents (e.g., chlorpropamide) to repaglinide, close monitoring may be indicated cytochrome P450 enzyme 3A4 inhibitor, clarithromycin, with PRANDIN® resulted in a clinically significant increase in repaglinide plasma levels. In Combination Therapy
addition, an increase in repaglinide plasma levels was observed in a study that evaluated the co-administration of PRANDIN® with trimethoprim, a If PRANDIN® monotherapy does not result in adequate glycemic control, cytochrome P450 enzyme 2C8 inhibitor. These increases in repaglinide plasma metformin or a thiazolidinedione may be added. If metformin or thiazolidinedione levels may necessitate a PRANDIN® dose adjustment. See CLINICAL
monotherapy does not provide adequate control, PRANDIN® may be added. The PHARMACOLOGY section, Drug-Drug Interactions.
*: Events ≥2% for the PRANDIN® group in the placebo-controlled studies starting dose and dose adjustments for PRANDIN® combination therapy is the same as for PRANDIN® monotherapy. The dose of each drug should be carefully Gemfibrozil significantly increased PRANDIN® exposure. Therefore, patients should adjusted to determine the minimal dose required to achieve the desired not take PRANDIN® with gemfibrozil. See CLINICAL PHARMACOLOGY section,
**: See trial description in CLINICAL PHARMACOLOGY, Clinical Trials
pharmacologic effect. Failure to do so could result in an increase in the incidence Drug-Drug Interactions, and CONTRAINDICATIONS.
Cardiovascular Events
of hypoglycemic episodes. Appropriate monitoring of FPG and HbA1c The hypoglycemic action of oral blood glucose-lowering agents may be potentiated In one-year trials comparing PRANDIN® to sulfonylurea drugs, the incidence of measurements should be used to ensure that the patient is not subjected to by certain drugs including nonsteroidal anti-inflammatory agents and other drugs angina was comparable (1.8%) for both treatments, with an incidence of chest excessive drug exposure or increased probability of secondary drug failure.
that are highly protein bound, salicylates, sulfonamides, cyclosporine, pain of 1.8% for PRANDIN® and 1.0% for sulfonylureas. The incidence of other chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta HOW SUPPLIED
selected cardiovascular events (hypertension, abnormal EKG, myocardial adrenergic blocking agents. When such drugs are administered to a patient infarction, arrhythmias, and palpitations) was ≤ 1% and not different between PRANDIN® (repaglinide) tablets are supplied as unscored, biconvex tablets receiving oral blood glucose-lowering agents, the patient should be observed available in 0.5 mg (white), 1 mg (yellow) and 2 mg (peach) strengths.
closely for hypoglycemia. When such drugs are withdrawn from a patient receiving The incidence of total serious cardiovascular adverse events, including ischemia, Tablets are embossed with the Novo Nordisk (Apis) bull symbol and oral blood glucose-lowering agents, the patient should be observed closely for loss was higher for repaglinide (4%) than for sulfonylurea drugs (3%) in controlled comparator clinical trials. In 1-year controlled trials, PRANDIN® treatment was Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic not associated with excess mortality when compared to the rates observed with control. These drugs include the thiazides and other diuretics, corticosteroids, other oral hypoglycemic agent therapies.
phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, Summary of Serious Cardiovascular Events (% of total patients
nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.
with events) in Trials Comparing PRANDIN® to Sulfonylureas
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 PRANDIN®
these drugs are withdrawn from a patient receiving oral blood glucose-lowering agents, the patient should be observed closely for hypoglycemia.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term carcinogenicity studies were performed for 104 weeks at doses up to Protect from moisture. Keep bottles tightly closed.
and including 120 mg/kg body weight/day (rats) and 500 mg/kg body Dispense in tight containers with safety closures.
weight/day (mice) or approximately 60 and 125 times clinical exposure, respectively, on a mg/m2 basis. No evidence of carcinogenicity was found in miceor female rats. In male rats, there was an increased incidence of benign Seven controlled clinical trials included PRANDIN® combination therapy with adenomas of the thyroid and liver. The relevance of these findings to humans is NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations Version: 9
unclear. The no-effect doses for these observations in male rats were 30 mg/kg (sulfonylurea plus NPH-insulin or PRANDIN® plus metformin) (n=120). There body weight/day for thyroid tumors and 60 mg/kg body weight/day for liver were six serious adverse events of myocardial ischemia in patients treated with Licensed Under US Patent No. RE 37,035.
tumors, which are over 15 and 30 times, respectively, clinical exposure on a PRANDIN® plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study.
PRANDIN® is a registered trademark of Novo Nordisk A/S. Repaglinide was non-genotoxic in a battery of in vivo and in vitro studies: Infrequent Adverse Events (<1% of Patients)
Bacterial mutagenesis (Ames test), in vitro forward cell mutation assay in V79 Less common adverse clinical or laboratory events observed in clinical trials cells (HGPRT), in vitro chromosomal aberration assay in human lymphocytes, included elevated liver enzymes, thrombocytopenia, leukopenia, and anaphy- unscheduled and replicating DNA synthesis in rat liver, and in vivo mouse and rat Although no causal relationship with repaglinide has been established, Fertility of male and female rats was unaffected by repaglinide administration at postmarketing experience includes reports of the following rare adverse events: doses up to 80 mg/kg body weight/day (females) and 300 mg/kg body alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson Syndrome, and severe weight/day (males); over 40 times clinical exposure on a mg/m2 basis.
hepatic dysfunction including jaundice and hepatitis.

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