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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
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
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
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
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
PRANDIN® was studied in combination with metformin in 83 patients not
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
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
in an interaction study with healthy volunteers (see PRECAUTIONS
combination group was achieved at a lower daily repaglinide dosage than in the
Mechanism of Action
PRANDIN® monotherapy group (see Table).
Repaglinide lowers blood glucose levels by stimulating the release of insulin
Co-administration of 600 mg rifampin and a single dose of 4 mg
® 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
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
max. PRANDIN® administered by itself (after 7 days
of once daily rifampin 600 mg) resulted in an 80% and 79% decrease in
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
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
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
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
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.
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
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
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
® + 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 –
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
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
® 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.
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
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:
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%).
Combination therapy resulted in significantly greater improvement in glycemiccontrol as compared to monotherapy (table below). The glycemic effects of the
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)
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
receiving placebo and decreased in patients treated with repaglinide. Differences
between the repaglinide- and placebo-treated groups were -61 mg/dL (FPG) and
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.
pharmacokinetics between the group of patients <65 years of age and a
comparably sized group of patients ≥65 years of age (See PRECAUTIONS
® vs. Placebo Treatment: Mean FPG, PPG, and HbA1c
Changes from baseline after 3 months of treatment:
Change in Weight (kg)
No studies have been performed in pediatric patients.
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
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
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:
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
Changes in blood glucose levels may result in blurred vision and visual
disturbances, especially at the initiation of treatment with hypoglycemic agents.
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.
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.
, Cardiovascular Events
Offspring of rat dams exposed to repaglinide at 15
When corrected for dropout rates of the treatment groups, the percentage of
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
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
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
) could be induced in control pups nursed by treated dams,
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
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
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,
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
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%
of glyburide patients, and 19% of glipizide patients.
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)*
glycemic control. Postprandial glucose level testing may be clinically helpful in
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
whose overall glycemic control (HbA1c) is inadequate. The preprandial dose
data indicate that PRANDIN® is metabolized by cytochrome P450
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
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
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
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
occurs in patients taking a combination of PRANDIN® and a thiazolidinedione or
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.
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
Patients should then be observed carefully for hypoglycemia due to potential
overlapping of drug effects. When transferred from longer half-life sulfonylurea
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
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
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
**: See trial description in CLINICAL PHARMACOLOGY
, Clinical Trials
pharmacologic effect. Failure to do so could result in an increase in the incidence
, and CONTRAINDICATIONS
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
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
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
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.
® is a registered trademark of Novo Nordisk A/S.
Repaglinide was non-genotoxic in a battery of in vivo
and in vitro
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.
A CEREBROVASCULARIS KÓRÁLLAPOTOK MÁSODLAGOS MEGELÔZÉSEAmásodlagos megelôzés célja az újabb stroke-ese- thrombocytaaggregáció-gátló szer rekurrens stroke ese-mény elkerülése a stroke-ot (tranziens ischaemiásattakot) átvészelt betegeknél. Az újabb eseményvalószínûsége nagyobb, mint korábban gondolták: abetegek 5%-a az elsô néhány napon belül, és mintegy10%-uk a
In vitro models for the determination of drug mode of action IBAM GbR Dr. Rainer Knörle & Dr. Peter SchnierleFerdinand-Porsche-Str. 5, 79211 Denzlingen Our service offering includes several models for the identification of the molecular targets of a drug and of its off-target effects It has been shown that melanin a pigment found in the skin and other parts of the body has an ability