PRANDIN®

(repaglinide) Tablets (0.5, 1, and 2 mg)

Rx only

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:

CH3 O

H3C O OH

N O
H

N CH3

Repaglinide is a white to off-white powder with molecular formula C27 H36 N2 O4 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.

CLINICAL PHARMACOLOGY
Mechanism of Action
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.

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
blood stream 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/h. Protein binding and
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 2C8 and 3A4, have 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.

Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion
transporting protein OATP1B1).

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.

Pharmacokinetic Parameters: The pharmacokinetic parameters of repaglinide obtained from a

single-dose, crossover study in healthy subjects and from a multiple-dose, parallel, dose-
proportionality (0.5, 1, 2 and 4 mg) study in patients with type 2 diabetes are summarized in the
following table:
 Parameter Patients with type 2
diabetesa
Dose AUC0-24 hr Mean ±SD
(ng/mL*hr):
0.5 mg 68.9 ± 154.4
1 mg 125.8 ± 129.8
2 mg 152.4 ± 89.6
4 mg 447.4 ± 211.3
Dose Cmax0-5 hr Mean ±SD
(ng/mL):
0.5 mg 9.8 ± 10.2
1 mg 18.3 ± 9.1
2 mg 26.0 ± 13.0
4 mg 65.8 ± 30.1
Dose Tmax0-5 hr Means (SD)
0.5 - 4 mg 1.0 - 1.4 (0.3 - 0.5) hr
Dose T½ Means (Ind Range)
0.5 - 4 mg 1.0 - 1.4 (0.4 - 8.0) hr
Parameter Healthy Subjects
CL based on i.v. 38 ± 16 L/hr
Vss based on i.v. 31 ± 12 L
AbsBio 56 ± 9%
a: dosed preprandially with three meals
CL = total body clearance
Vss = volume of distribution at steady state
AbsBio = absolute bioavailability

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: Repaglinide AUC after multiple doses of 0.25 to 4 mg with each meal
varies over a wide range. The intra-individual and inter-individual coefficients of variation were
36% and 69%, respectively. AUC over the therapeutic dose range included 69 to 1005
ng/mL*hr, but AUC exposure up to 5417 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. (See
PRECAUTIONS, Geriatric Use)
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).

Drug-Drug Interactions:
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:

CYP2C8 and CYP3A4 Inhibitors/Inducer

Gemfibrozil and Itraconazole: Co-administration of gemfibrozil (600 mg) and a single dose of
0.25 mg PRANDIN (after 3 days of twice-daily 600 mg gemfibrozil) resulted in an 8.1-fold
higher repaglinide AUC and prolonged repaglinide half-life from 1.3 to 3.7 hr. Co­
administration with itraconazole and a single dose of 0.25 mg PRANDIN (on the third day of a
regimen of 200 mg initial dose, twice-daily 100 mg itraconazole) resulted in a 1.4-fold higher
repaglinide AUC. Co-administration of both gemfibrozil and itraconazole with PRANDIN
resulted in a 19-fold higher repaglinide AUC and prolonged repaglinide half-life to 6.1 hr.
Plasma repaglinide concentration at 7 h increased 28.6-fold with gemfibrozil co-administration
and 70.4-fold with the gemfibrozil-itraconazole combination (see CONTRAINDICATIONS,
PRECAUTIONS, Drug-Drug Interactions).

Fenofibrate: Co-administration of 200 mg fenofibrate with a single dose of 0.25 mg repaglinide

(after 5 days of once daily fenofibrate 200 mg) resulted in unchanged AUC and Cmax values for
both drugs.

Ketoconazole: Co-administration of 200 mg ketoconazole and a single dose of 2 mg PRANDIN

(after 4 days of once daily ketoconazole 200 mg) resulted in a 15% and 16% increase in
repaglinide AUC and Cmax, respectively. The increases were from 20.2 ng/mL to 23.5 ng/mL for
Cmax and from 38.9 ng/mL*hr to 44.9 ng/mL*hr for AUC.
Trimethoprim: Co-administration of 160 mg trimethoprim and a single dose of 0.25 mg
PRANDIN (after 2 days of twice daily and one dose on the third day of trimethoprim 160 mg)
resulted in a 61% and 41% increase in repaglinide AUC and Cmax, respectively. The increase in
AUC was from 5.9 ng/mL*hr to 9.6 ng/mL*hr and the increase in Cmax was from 4.7 ng/mL to
6.6 ng/mL.

Cyclosporine: Co-administration of 100 mg cyclosporine with a single dose of 0.25 mg

repaglinide (after two 100 mg doses of cyclosporine twelve hours apart) increased the
repaglinide (0.25 mg) Cmax 1.8-fold and the AUC 2.5-fold in an interaction study with healthy
volunteers (see PRECAUTIONS, Drug-Drug Interactions).

Rifampin: 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 32% and 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 38.7 ng/mL*hr for AUC.
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 Cmax 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 Cmax. 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 Cmax respectively. 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 Cmax.

Levonorgestrel & Ethinyl Estradiol: Co-administration of a combination tablet of 0.15 mg

levonorgestrel and 0.03 mg ethinyl estradiol administered once daily 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, and ethinyl estradiol Cmax. The increase in repaglinide
Cmax was from 40.5 ng/mL to 47.4 ng/mL. Ethinyl estradiol AUC parameters were increased by
20%, while repaglinide and levonorgestrel AUC values remained unchanged.

Simvastatin: Co-administration of 20 mg simvastatin and a single dose of 2 mg PRANDIN

(after 4 days of once daily simvastatin 20 mg and three times daily PRANDIN 2 mg) resulted in
a 26% increase in repaglinide Cmax from 23.6 ng/mL to 29.7 ng/mL. AUC was unchanged.

Nifedipine: Co-administration of 10 mg nifedipine with a single dose of 2 mg PRANDIN (after

4 days of three times daily nifedipine 10 mg and three times daily PRANDIN 2 mg) resulted in
unchanged AUC and Cmax values for both drugs.

Clarithromycin: Co-administration of 250 mg clarithromycin and a single dose of 0.25 mg

PRANDIN (after 4 days of twice daily clarithromycin 250 mg) resulted in a 40% and 67%
increase in repaglinide AUC and Cmax, respectively. The increase in AUC was from 5.3
ng/mL*hr to 7.5 ng/mL*hr and the increase in Cmax was from 4.4 ng/mL to 7.3 ng/mL.

Renal Insufficiency: Single-dose and steady-state pharmacokinetics of repaglinide were

compared between patients with type 2 diabetes and normal renal function (CrCl > 80 mL/min),
mild to moderate renal function impairment (CrCl = 40 – 80 mL/min), and severe renal function
impairment (CrCl = 20 – 40 mL/min). Both AUC and Cmax of repaglinide were similar in
patients with normal and mild to moderately impaired renal function (mean values 56.7
ng/mL*hr vs 57.2 ng/mL*hr and 37.5 ng/mL vs 37.7 ng/mL, respectively.) Patients with
severely reduced renal function had elevated mean AUC and 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 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 concentrations of both total and unbound repaglinide than healthy subjects
(AUChealthy: 91.6 ng/mL*hr; AUCCLD patients: 368.9 ng/mL*hr; Cmax, healthy: 46.7 ng/mL; Cmax, CLD
patients: 105.4 ng/mL). AUC was statistically correlated with caffeine clearance. No difference in
glucose profiles was observed across patient groups. 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. Therefore, PRANDIN should be used
cautiously in patients with impaired liver function. Longer intervals between dose
adjustments should be utilized to allow full assessment of response.

Clinical Trials

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 <160 mg/dL was achieved or the maximum
dose reached. The dose that 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 receiving
placebo and decreased in patients treated with repaglinide. Differences between the repaglinide-
and placebo-treated groups were -61 mg/dL (FPG) and -104 mg/dL (PPG). The between-group
change in HbA1c, which reflects long-term glycemic control, was 1.7% units.
PRANDIN vs. Placebo Treatment: Mean FPG, PPG, and HbA1c Changes from baseline
after 3 months of treatment:

FPG (mg/dL) PPG (mg/dL) HbA1c (%)

PL R PL R PL R
Baseline 215.3 220.2 245.2 261.7 8.1 8.5
Change from
Baseline 30.3 -31.0* 56.5 -47.6* 1.1 -0.6*
(at last visit)
FPG = fasting plasma glucose
PPG = post-prandial glucose
PL = placebo (N=33)
R = repaglinide (N=66)
*: p< 0.05 for between group difference

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 HbA1c at the end of the study. HbA1c 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 (HbA1c below 8%) showed greater blood glucose-lowering including a higher
frequency of hypoglycemia. Patients who were previously treated and who had baseline HbA1c
> 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. HbA1c 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).

PRANDIN and Metformin Therapy: Mean Changes from Baseline in Glycemic Parameters
and Weight after 4 to 5 Months of Treatment1
PRANDIN Combination Metformin
N 28 27 27
Median Final Dose 6 (PRANDIN)
12 1500
(mg/day) 1500 (metformin)
HbA1c (% units) -0.38 -1.41∗ -0.33
FPG (mg/dL) 8.8 -39.2 ∗ -4.5
Weight (kg) 3.0 2.4 # -0.90
1: based on intent-to-treat analysis
∗: p< 0.05, for pairwise comparisons with PRANDIN and metformin.
#: p < 0.05, for pairwise comparison with metformin.

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 (HbA1c > 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
HbA1c (%), 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.
HbA1c Values from PRANDIN / Pioglitazone Combination Study

Prandin + Pioglitazone Prandin Pioglitazone

0.5

0
Change in HbA1c (%)

-0.5

-1

-1.5

-2
0 5 10 15 20 24
Treatment Week
HbA1c 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 (HbA1c > 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.
Mean Changes from Baseline in Glycemic Parameters and Weight in a 24-Week
PRANDIN/ Rosiglitazone Combination Study1
PRANDIN Combination Rosiglitazone
N 63 127 62
HbA1c (%)
Baseline 9.3 9.1 9.0
Change by 24 weeks -0.17 -1.43 ∗ -0.56
FPG (mg/dL)
Baseline 269 257 252
Change by 24 weeks -54 -94 ∗ -67
Change in Weight (kg) +1.3 +4.5 # +3.3
1: based on intent-to-treat analysis
∗: p-value ≤ 0.001 for comparison to either monotherapy
#: p-value < 0.001 for comparison to PRANDIN
Final median doses: rosiglitazone - 4 mg/day for combination and 8 mg/day for monotherapy;
PRANDIN - 6 mg/day for combination and 12 mg/day for monotherapy

INDICATIONS AND USAGE

PRANDIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults
with type 2 diabetes mellitus.

CONTRAINDICATIONS
PRANDIN is contraindicated in patients with:
1. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
2. Type 1 diabetes.
3. Co-administration of gemfibrozil.
4. Known hypersensitivity to the drug or its inactive ingredients.

PRECAUTIONS
General: PRANDIN is not indicated for use in combination with NPH-insulin (See ADVERSE
REACTIONS, Cardiovascular Events)

Macrovascular Outcomes:
There have been no clinical studies establishing conclusive evidence of macrovascular risk
reduction with PRANDIN or any other anti-diabetic drug.

Hypoglycemia: All oral blood glucose-lowering drugs including repaglinide 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 (naïve) or whose HbA1c is less than
8%. PRANDIN 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 PRANDIN 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 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
HbA1c. 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.

Patients should be instructed to take PRANDIN 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 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 (HbA1c) is
inadequate.
Drug-Drug Interactions
In vitro data indicate that PRANDIN is metabolized by cytochrome P450 enzymes 2C8 and
3A4. Consequently, repaglinide metabolism may be altered by drugs which influence these
cytochrome P450 enzyme systems via induction and inhibition. Caution should therefore be
used in patients who are on PRANDIN and taking inhibitors and/or inducers of CYP2C8 and
CYP3A4. The effect may be very significant if both enzymes are inhibited at the same time
resulting in a substantial increase in repaglinide plasma concentrations. Drugs that are known to
inhibit CYP3A4 include antifungal agents like ketoconazole, itraconazole, and antibacterial
agents like erythromycin. Drugs that are known to inhibit CYP2C8 include agents like
trimethoprim, gemfibrozil and montelukast. Drugs that induce the CYP3A4 and/or 2C8 enzyme
systems include rifampin, barbiturates, and carbamezapine. See CLINICAL
PHARMACOLOGY section, Drug-Drug Interactions.

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 CLINICAL
PHARMACOLOGY section, Drug-Drug Interactions.

In vivo data from a study that evaluated the co-administration of a cytochrome P450 enzyme 3A4
inhibitor, clarithromycin, with PRANDIN resulted in a clinically significant increase in
repaglinide plasma levels. In addition, an increase in repaglinide plasma levels was observed in
a study that evaluated the co-administration of PRANDIN with trimethoprim, a cytochrome P­
450 enzyme 2C8 inhibitor . These increases in repaglinide plasma levels may necessitate a
PRANDIN dose adjustment. See CLINICAL PHARMACOLOGY section, Drug-Drug
Interactions.

Gemfibrozil significantly increased PRANDIN exposure. Therefore, patients should not take
PRANDIN with gemfibrozil. See CLINICAL PHARMACOLOGY section, Drug-Drug
Interactions, and CONTRAINDICATIONS.

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.
Carcinogenesis, Mutagenesis, and 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 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/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 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/m2 basis.

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, PRANDIN should be used during pregnancy only if it is
clearly needed.

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: 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
PRANDIN administration throughout pregnancy or lactation cannot be established.

Nursing Mothers
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) 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 PRANDIN should be discontinued in nursing mothers, or if mothers should discontinue
nursing. If PRANDIN is discontinued and if diet alone is inadequate for controlling blood
glucose, insulin therapy should be considered.

Pediatric Use
No studies have been performed in pediatric patients.

Geriatric Use
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 subjects and those less than 65 other than the expected age-related increase
in cardiovascular events observed for PRANDIN 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 PRANDIN therapy cannot be ruled out.

ADVERSE REACTIONS
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE 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 PRECAUTIONS). 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).
Commonly Reported Adverse Events (% of Patients)*
EVENT PRANDIN PLACEBO PRANDIN SU
N = 352 N = 108 N = 1228 N = 498

Placebo controlled studies Active controlled studies

Metabolic
Hypoglycemia 31** 7 16 20

Respiratory
URI 16 8 10 10
Sinusitis 6 2 3 4
Rhinitis 3 3 7 8
Bronchitis 2 1 6 7

Gastrointestinal
Nausea 5 5 3 2
Diarrhea 5 2 4 6
Constipation 3 2 2 3
Vomiting 3 3 2 1
Dyspepsia 2 2 4 2

Musculoskeletal
Arthralgia 6 3 3 4
Back Pain 5 4 6 7

Other
Headache 11 10 9 8
Paresthesia 3 3 2 1
Chest pain 3 1 2 1
Urinary tract infection 2 1 3 3
Tooth disorder 2 0 <1 <1
Allergy 2 0 1 <1
*: Events >2% for the PRANDIN group in the placebo-controlled studies
and > events in the placebo group
**: See trial description in CLINICAL PHARMACOLOGY, Clinical Trials

Cardiovascular Events
In one-year trials comparing PRANDIN to sulfonylurea drugs, the incidence of angina was
comparable (1.8%) for both treatments, with an incidence of chest pain of 1.8% for PRANDIN
and 1.0% for sulfonylureas. The incidence of other selected cardiovascular events (hypertension,
abnormal EKG, myocardial infarction, arrhythmias, and palpitations) was ≤ 1% and not different
between PRANDIN and the comparator drugs.

The incidence of total serious cardiovascular adverse events, including ischemia, was higher for
repaglinide (4%) than for sulfonylurea drugs (3%) in controlled comparator clinical trials. In 1­
year controlled trials, PRANDIN treatment was not associated with excess mortality when
compared to the rates observed with other oral hypoglycemic agent therapies.

Summary of Serious Cardiovascular Events (% of total patients with events)

in Trials Comparing PRANDIN to Sulfonylureas
PRANDIN SU*

Total Exposed 1228 498

Serious CV Events 4% 3%

Cardiac Ischemic Events 2% 2%

Deaths due to CV Events 0.5% 0.4%

*: glyburide and glipizide

Seven controlled clinical trials included PRANDIN combination therapy with NPH-insulin
(n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-
insulin or PRANDIN plus metformin) (n=120). There were six serious adverse events of
myocardial ischemia in patients treated with PRANDIN plus NPH-insulin from two studies, and
one event in patients using insulin formulations alone from another study.

Infrequent Adverse Events (<1% of Patients)

Less common adverse clinical or laboratory events observed in clinical trials included elevated
liver enzymes, thrombocytopenia, leukopenia, and anaphylactoid reactions.
Although no causal relationship with repaglinide has been established, postmarketing experience
includes reports of the following rare adverse events: alopecia, hemolytic anemia, pancreatitis,
Stevens-Johnson Syndrome, and severe hepatic dysfunction including jaundice and hepatitis.

Changes in blood glucose levels may result in blurred vision and visual disturbances, especially
at the initiation of treatment with hypoglycemic agents. These changes are usually transient.

Combination Therapy with Thiazolidinediones

During 24-week treatment clinical trials of PRANDIN-rosiglitazone or PRANDIN-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
PRANDIN monotherapy, and 2% for thiazolidinedione monotherapy.

Peripheral edema was reported in 12 out of 250 PRANDIN-thiazolidinedione combination

therapy patients and 3 out of 124 thiazolidinedione monotherapy patients, with no cases reported
in these trials for PRANDIN 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 PRANDIN-thiazolidinedione combination therapy, and 4% for thiazolidinedione
monotherapy. There were reports in 2 of 250 patients (0.8%) treated with PRANDIN­
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 PRANDIN-thiazolidinedione therapy.
There were no patients on PRANDIN-thiazolidinedione combination therapy who had elevations
of liver transaminases (defined as 3 times the upper limit of normal levels).

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.

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.

Starting Dose
For patients not previously treated or whose HbA1c is < 8%, the starting dose should be 0.5 mg
with each meal. For patients previously treated with blood glucose-lowering drugs and whose
HbA1c is > 8%, the initial dose is 1 or 2 mg with each meal preprandially (see previous
paragraph).
Dose Adjustment
Dosing adjustments should be determined by blood glucose response, usually fasting blood
glucose. Postprandial glucose levels 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. PRANDIN 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 PRANDIN and a thiazolidinedione or
PRANDIN and metformin, the dose of PRANDIN should be reduced.

Patients Receiving Other Oral Hypoglycemic Agents

When PRANDIN is used to replace therapy with other oral hypoglycemic agents, PRANDIN
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 PRANDIN monotherapy does not result in adequate glycemic control, metformin or a

thiazolidinedione may be added. If metformin or thiazolidinedione monotherapy does not
provide adequate control, PRANDIN may be added. The starting dose and dose adjustments for
PRANDIN combination therapy is the same as for PRANDIN 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.

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.
0.5 mg tablets Bottles of 100 NDC 00169-0081-81
(white) Bottles of 500 NDC 00169-0081-82
Bottles of 1000 NDC 00169-0081-83
1 mg tablets Bottles of 100 NDC 00169-0082-81
(yellow) Bottles of 500 NDC 00169-0082-82
Bottles of 1000 NDC 00169-0082-83
2 mg tablets Bottles of 100 NDC 00169-0084-81
(peach) Bottles of 500 NDC 00169-0084-82
Bottles of 1000 NDC 00169-0084-83

Do not store above 25° C (77° F).

Protect from moisture. Keep bottles tightly closed.
Dispense in tight containers with safety closures.

Licensed Under US Patent No. RE 37,035.

PRANDIN® is a registered trademark of Novo Nordisk A/S.

Manufactured in Germany for

Novo Nordisk Inc.
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com

© 2003-2009 Novo Nordisk A/S

All rights reserved

Date of Issue: July 14, 2008

Version: 8