GlucoNorm®
Repaglinide
Oral Antidiabetic Agent
Novo Nordisk
http://www.novonordisk.com/
GlucoNorm Monograph PDF download here.
Pharmacology
Repaglinide is an oral blood glucose-lowering
drug used in the management of type 2 diabetes mellitus. Repaglinide is a
short-acting insulin secretagogue which lowers blood glucose levels (as
measured by HbA1C and fasting plasma glucose) and is effective in
regulating meal-related (prandial) glucose loads. Repaglinide lowers blood
glucose levels by stimulating the release of insulin from the pancreas. This
action is dependent upon functioning beta cells in the pancreatic islets.
Insulin release is glucose-dependent and diminishes at low glucose
concentrations.
Repaglinide is
chemically unrelated to oral sulphonylurea insulin secretagogues used in the
treatment of type 2 diabetes.
Repaglinide closes
ATP-dependent potassium channels in the β -cell membrane by binding at
characterizable sites. This potassium channel blockade depolarizes the β
-cell which leads to an opening of calcium channels. The resulting increased
calcium influx induces insulin secretion. The ion channel mechanism is highly
tissue selective with low affinity for heart and skeletal muscle.
Pharmacokinetics
Absorption: After oral administration,
repaglinide is rapidly and completely absorbed from the gastrointestinal tract.
After single and multiple oral doses in healthy subjects or in patients, peak
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 i.v. dosing in healthy
subjects, the volume of distribution at steady state (VSS) was approximately
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 i.v. or oral dose. The major metabolites are an
oxidized dicarboxylic acid (M2), the aromatic amine (M1)
and the acyl glucuronide (M7). The cytochrome P450 enzyme system,
specifically 3A4, has been shown to be involved in the N-dealkylation of
repaglinide to M2 and the further oxidation to M1.
Metabolites do not contribute to the glucose-lowering effect of repaglinide.
Excretion: Within 96 hours after dosing with 14C-repaglinide
as a single oral dose, approximately 90% of the radiolabel was recovered in the
feces and 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: Data indicate that
repaglinide did not accumulate in serum. Repaglinide demonstrated
pharmacokinetic linearity over the 0.5 to 4 mg dose range.
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 Table 1.
CPS:Gluconorm_t1Click here for Table 1
Table 1: GlucoNorm
Pharmacokinetic Parameters
|
Parameter
|
Patients with Type 2
Diabetesa
|
|
AUC0-24 h (ng/mL· h)
|
Mean (SD)
|
|
0.5 mg
|
68.9 (154.4)
|
|
1.0 mg
|
125.8 (129.8)
|
|
2.0 mg
|
152.4 (89.6)
|
|
4.0 mg
|
447.4 (211.3)
|
|
Cmax 0-5 h (ng/mL)
|
Mean (SD)
|
|
0.5 mg
|
9.8 (10.2)
|
|
1.0 mg
|
18.3 (9.1)
|
|
2.0 mg
|
26.0 (13.0)
|
|
4.0 mg
|
65.8 (30.1)
|
|
Tmax 0-5 h (h)
|
Means (SD range)
|
|
0.5 to 4 mg
|
1.0 to 1.4 (0.3 to
0.5)
|
|
T1/2 (h)
|
Means (Individual Range)
|
|
0.5 to 4 mg
|
1.0 to 1.4 (0.4 to
8.0)
|
|
Parameter
|
Healthy Subjects
|
|
CL based on i.v. (L/h)
|
38 (16)
|
|
Vss based on i.v. (L)
|
31 (12)
|
|
AbsBio (%)
|
56 (9)
|
a Dosed preprandially 3 times daily.
Legend:
CL=Total body clearance.
VSS=Volume of distribution at steady
state.
AbsBio=Absolute bioavailability.
Variability: The intraindividual and
interindividual variabilities (coefficient of variation) in AUC were 36% and
69%, respectively, after multiple dosing of repaglinide tablets (0.25 to 4 mg
with each meal) in patients.
Geriatrics: 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.
Gender: A comparison of pharmacokinetics in
males and females showed the AUC over the 0.5 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).
Clinical
A 4-week, double-blind, placebo-controlled
dose-response trial was conducted in patients with type 2 diabetes using doses
ranging from 0.25 to 4 mg taken with each of 3 meals. Repaglinide 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 to 2 weeks.
In a double-blind,
placebo-controlled, 3-month dose titration study, repaglinide 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 <8.9 mmol/L
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
postprandial glucose (PPG) increased in patients receiving placebo and
decreased in patients treated with repaglinide. Differences between the
repaglinide- and placebo-treated groups were -3.41 mmol/L (FPG) and -5.78
mmol/L (PPG). The between-group change in HbA1C, which reflects
long-term glycemic control, was 1.7% units. See Table 2.
CPS:Gluconorm_t2Click here for Table 2
Table 2: GlucoNorm
Results of Double-blind, Placebo-controlled,
3-month Dose Titration Study
|
FPG, PPG, and HbA1c
|
|
|
FPG (mmol/L)
|
PPG (mmol/L)
|
HbA1c (%)
|
|
|
|
PL
|
R
|
PL
|
R
|
PL
|
R
|
|
|
Baseline
|
11.96
|
12.23
|
13.62
|
14.54
|
8.1
|
8.5
|
|
|
Change from Baseline (at last visit)
|
1.68
|
− 1.72a
|
3.14
|
− 2.64a
|
1.1
|
− 0.6a
|
|
a p≤ 0.05 for between-group
difference.
Legend:
PL=placebo. R=repaglinide.
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 repaglinide-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 repaglinide. The average weight gain in
patients treated with repaglinide and not previously treated with sulfonylurea
drugs was 3.3%.
The dosing of
repaglinide relative to meal-related insulin release was studied in 3 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/day; before meals x 2,
3, or 4) compared with a period of 3 regular meals and 3 doses/day (before
meals x 3). It was also shown that repaglinide 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.
Repaglinide was
compared to other insulin secretagogues in 1-year controlled trials to
demonstrate comparability of efficacy and safety. Hypoglycemia was reported in
16% of 1 228 repaglinide patients, 20% of 417 glyburide patients, and 19%
of 81 glipizide patients. Of repaglinide-treated patients with symptomatic
hypoglycemia, none developed coma or required hospitalization.
Repaglinide was studied
in combination with metformin in 83 patients not satisfactorily controlled on
exercise, diet, and metformin alone. Combination therapy with repaglinide and
metformin resulted in synergistic improvement in glycemic control compared to
repaglinide or metformin monotherapy. HbA1C was improved by 1% unit
and FPG decreased by an additional 1.94 mmol/L. See Table 3.
CPS:Gluconorm_t3Click here for Table 3
Table 3: GlucoNorm
GlucoNorm and Metformin Therapy: Mean HbA1c
and FPG Changes from Baseline after 3-month Treatment
|
|
GlucoNorm
|
Combination
|
Metformin
|
|
N
|
28
|
27
|
27
|
|
HbA1c (% units)
|
− 0.38
|
− 1.41a
|
− 0.33
|
|
FPG (mmol/L)
|
0.49
|
− 2.18a
|
− 0.25
|
a p≤ 0.05 for between-group
comparison.
Indications
As an adjunct to diet and exercise to lower the
blood glucose in patients with type 2 diabetes mellitus whose hyperglycemia
cannot be controlled satisfactorily by diet and exercise alone.
Repaglinide is also
indicated for use in combination with metformin to lower blood glucose in
patients whose hyperglycemia cannot be controlled by exercise, diet, and either
repaglinide or metformin alone. If glucose control has not been achieved after
a suitable trial of combination therapy, consideration should be given to
discontinuing these drugs and using insulin. Judgments should be based on regular
clinical and laboratory evaluations.
In initiating treatment
for type 2 diabetes, diet and exercise should be emphasized as the primary form
of treatment. Caloric restriction, weight loss and exercise are essential in
the obese diabetic patient. Proper dietary management and exercise alone may be
effective in controlling the blood glucose and symptoms of hyperglycemia. In
addition to regular physical activity, cardiovascular risk factors should be
identified and corrective measures taken where possible.
If this treatment
program fails to reduce symptoms and/or blood glucose, the use of an oral blood
glucose-lowering agent or insulin should be considered. Use of repaglinide must
be viewed by both the physician and patient as a treatment in addition to diet,
and not as a substitute for diet or as a convenient mechanism for avoiding
dietary restraint. Furthermore, loss of blood glucose control on diet alone may
be transient, thus requiring only short-term administration of repaglinide.
During maintenance
programs, repaglinide should be discontinued if satisfactory lowering of blood
glucose is no longer achieved. Judgments should be based on regular clinical
and laboratory evaluations.
Contraindications
In patients with known hypersensitivity to the
drug or any of its components. In patients with diabetic ketoacidosis, with or
without coma; this condition should be treated with insulin. In patients with
Type 1 diabetes.
In patients who are
using gemfibrozil (see Precautions, Drug Interactions).
Warnings
The administration of insulin secretagogues in
general has been reported to be associated with increased cardiovascular
mortality as compared to treatment with diet alone or diet plus insulin. In
controlled clinical trials comparing repaglinide with glyburide and other
sulfonylureas, there was no excess mortality with repaglinide use. The overall
incidence of serious cardiovascular events including death was 4.2 per 100
patients years.
Precautions
General
Repaglinide is effective as a prandial glucose
regulator and should be taken before meals (2, 3 or 4 times a day
preprandially). Therefore, if a meal is missed or delayed, the dose of
repaglinide should be skipped or delayed as appropriate.
Hypoglycemia
All oral blood glucose-lowering drugs are
capable of inducing hypoglycemia. Proper patient selection, dosage, and
instructions to the patient are important to avoid hypoglycemic episodes.
Hepatic insufficiency may cause elevated repaglinide levels in the blood and
may also diminish gluconeogenic capacity, both of which increase the risk of
serious hypoglycemic reactions.
Elderly, debilitated or
malnourished patients, and those with adrenal, pituitary or hepatic
insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering
drugs.
Hypoglycemia may be
difficult to recognize in the elderly, and in people who are taking β
-adrenergic blocking drugs.
Hypoglycemia is more
likely to occur when caloric intake is deficient or when meals are skipped.
Given the preprandial dosing regimen, patients taking repaglinide can adjust
dosing according to their changing meal patterns, thereby reducing the risk of
hypoglycemia when meals are missed.
Hypoglycemia is also
more likely to occur after strenuous or prolonged exercise, when alcohol is
ingested, or when more than one glucose-lowering drug is used.
Cardiovascular
In clinical trials, the incidence of serious
cardiovascular treatment emergent adverse events was higher for repaglinide
than for glyburide but lower than that for glipizide. This observed difference
was not statistically significant when adjustments for baseline differences in
prior medical history and predisposing conditions were made. In part,
differences in baseline ECG, cardiovascular medical history and baseline
cholesterol may have contributed to the difference in rates. When comparing
repaglinide to the sulfonylurea drugs as a whole, no statistically significant
differences were found either for serious cardiovascular events or for all
cardiovascular events. Dose analyses revealed no increase in cardiovascular
risk with increasing doses of repaglinide.
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 control of blood glucose may occur. At such times, it may be necessary
to temporarily discontinue repaglinide and administer insulin.
Geriatrics
No special dose titration is necessary in
elderly patients. In repaglinide clinical studies of 24 weeks or greater
duration, 415 patients were over 65 years of age. In 1-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 repaglinide and comparator
drugs. There was no increase in frequency or severity of hypoglycemia in older
subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients, but greater sensitivity of
some older individuals to repaglinide therapy cannot be ruled out.
Children
No studies of repaglinide have been performed in
pediatric patients.
Pregnancy
The safety of repaglinide in pregnant women has
not been established. Repaglinide was not teratogenic in rats and rabbits at
doses 40 times (rats) and approximately 0.8 times (rabbit) the maximum
recommended human dose (on a mg/m2 basis) throughout pregnancy.
However, in some studies in rats, offspring of dams exposed to high levels of
repaglinide during the last trimester of pregnancy and during lactation
developed 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 the maximum recommended human dose (on a mg/m2
basis) throughout pregnancy or at higher doses given during the first 2
trimesters of pregnancy.
Although animal
reproduction studies are not always predictive of human response, repaglinide
is not recommended for use during pregnancy.
Lactation
In rat reproduction studies, measurable levels
of repaglinide were detected in the breast milk of the dams and lowered blood
glucose levels were observed in the pups. It is not known whether repaglinide
is excreted in human milk. Because the potential for hypoglycemia in nursing
infants may exist, and because of the effects on nursing animals, a decision
should be made as to whether repaglinide should be discontinued in nursing
mothers, or if mothers should discontinue nursing, taking into account the
importance of the drug to the mother. If repaglinide is discontinued and if
diet alone is inadequate for controlling blood glucose, insulin therapy should
be considered.
Patients with Special Diseases and Conditions
Renal Dysfunction: Typically, repaglinide does
not require initial dose adjustment in patients with reduced kidney function.
However, subsequent increases in repaglinide should be made carefully in
patients with type 2 diabetes who have renal function impairment or renal
failure requiring hemodialysis.
Single-dose and
steady-state pharmacokinetics of repaglinide have been evaluated in patients
with various degrees of renal impairment. Repaglinide was found to be well
tolerated in all groups. Measures of AUC and Cmax after multiple
dosing of 2 mg repaglinide were found to be higher in three groups of patients
with reduced renal function (AUCmild/moderate impairment: 90.8
ng/mL·h to AUC severe impairment137.7 ng/mL·h vs AUChealthy:
29.1 ng/mL·h; Cmax, mild/moderate impairment: 46.7 ng/mL to Cmax,
severe impairment: 44.0 ng/mL vs Cmax, healthy: 20.6 ng/mL).
Repaglinide AUC is only weakly correlated to creatinine clearance.
Hepatic Dysfunction: Repaglinide should be used
cautiously in patients with impaired liver function. Longer intervals between
dose adjustments should be utilized to allow full assessment of response. A
single-dose, open-label study was conducted in 12 healthy subjects and 12
patients with chronic liver disease (CLD) classified by 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·h; AUCCLD
patients: 368.9 ng/mL·h; 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 the same doses.
Drug Interactions
Gemfibrozil and Itraconazole: A drug interaction
study in healthy volunteers showed that co-administration of gemfibrozil, an
inhibitor of CYP2C8, increased the repaglinide AUC 8.1 - fold and Cmax 2.4 -
fold. The elimination half life (t1/2) was prolonged from 1.3 to 3.7 hours and
the plasma repaglinide concentration at 7 hours was increased 28.6 - fold by
gemfibrozil. Gemfibrozil considerable enhanced and prolonged the blood
glucose-lowering effect of repaglinide. In post-market experience, there have
been rare spontaneous reports of serious hypoglycemic episodes in patients
co-administered repaglinide and gemfibrozil. The concomitant use of gemfibrozil
and repaglinide is contraindicated.
Co-administration of iraconazole
an inhibitor of CYP3A4, increased the repaglinide AUC 1.4 - fold in healthy
volunteers. Co-administration of both itraconazole and gemfibrozil with
repaglinide produced a more pronounced effect: the AUC for repaglinide was
increased by 19.4 - fold, t1/2 was increased from 1.3 to 6.1 hours and the
plasma repaglinide concentration at 7 hours was increased 70.4 - fold.
In vitro data indicate
that repaglinide metabolism potentially may be inhibited by antifungal agents
like ketoconazole and miconazole, and antibacterial agents like erythromycin.
Other drugs including rifampin, barbiturates and carbamazepine induce the
cytochrome P450 enzyme system 3A4 and thereby may increase repaglinide
metabolism. No systemically acquired data are available on increased or
decreased plasma levels with 3A4 inhibitors or inducers.
Drug interaction
studies performed in healthy volunteers show that repaglinide had no clinically
relevant effect on the pharmacokinetic properties of digoxin
(0.25 mg daily) or theophylline (300 mg b.i.d.) or warfarin
(individually dosed). Thus, no dosage adjustment is required for digoxin,
theophylline, or warfarin on coadministration of repaglinide. Coadministration
of cimetidine (400 mg b.i.d.) with multiple dosing of repaglinide (2 mg ac
x 3) did not significantly alter the absorption and disposition of repaglinide.
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, chloramphenicol, coumarins,
probenecid, MAOIs and β -adrenergic blocking agents. Therefore, when such
drugs are administered to a patient receiving oral blood glucose-lowering
agents, the patient should be observed closely for hypoglycemia. Conversely,
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 either administered or withdrawn from a patient receiving oral blood
glucose-lowering agents, the patient should again be observed for loss of
glycemic control.
Information to Be Provided to the Patient
Patients should be informed of the advantages
and potential risks of repaglinide and of alternative modes of therapy. They
should also be informed about the importance of adherence to dietary
instructions, of a regular exercise program, and of regular testing of blood
glucose and HbA1C. The 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 be
explained.
Patients should be
informed to dose repaglinide before meals (2, 3 or 4 times a day
preprandially). Doses are usually taken within 15 minutes of the meal, but time
may vary from immediately preceding the meal to as long as 30 minutes before
the meal. Patients who skip a meal (or add an extra meal) should be instructed
to skip (or add) a dose for that meal.
Patients' need for
repaglinide may change if they take other medicines. They should inform their
doctor or pharmacists, if they take any other medicines.
Patients' need for
repaglinide may also change if they drink alcohol.
Adverse Effects
Repaglinide has been administered to 2 931
individuals worldwide during clinical trials. Approximately 1 500 of these
individuals with type 2 diabetes have been treated for at least 3 months,
1 000 for at least 6 months, and 800 for at least 1 year. The majority of
these individuals (1 228) received repaglinide in one of five 1-year,
active-controlled trials. The comparator drugs in these 1-year trials were oral
sulphonylurea drugs (SU).
Repaglinide was well
tolerated in these clinical trials and analysis of adverse events shows no dose
relationship to rate of occurrence. The adverse event profiles for the
repaglinide and SU groups in these trials were generally comparable over 1
year. The rate of withdrawals due to adverse events was 13% among
repaglinide-treated patients and 14% among SU-treated patients. The most common
adverse events leading to withdrawal were hyperglycemia, hypoglycemia, and
related symptoms. Mild or moderate hypoglycemia occurred in 16% of repaglinide
patients and 20% of sulfonylurea patients.
Table 4 lists common
adverse events for repaglinide patients compared to both placebo (in trials
less than 6 months' duration) and to glyburide and glipizide in 1-year trials.
The adverse event profile of repaglinide was generally comparable to that for
sulfonylurea drugs (SU).
CPS:Gluconorm_t4Click here for Table 4
Table 4: GlucoNorm
Commonly Reported Adverse Events (% of Patients)a
|
Event
|
GlucoNorm N=352
|
Placebo N=108
|
GlucoNorm N=1 228
|
SU 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
|
|
a Events ≥ 2% for the
GlucoNorm group in the placebo-controlled studies and ≥ events in the
placebo group.
Cardiovascular events
also occur commonly in patients with type 2 diabetes. In 1-year comparator
trials, the incidence of individual events was not greater than 1% except for
chest pain (1.8%) and angina (1.8%). The overall incidence of other
cardiovascular events (hypertension, abnormal EKG, myocardial infarction,
arrhythmias, and palpitations) was ≤ 1% and not different for repaglinide
and the comparator drugs.
The incidence of
serious cardiovascular adverse events added together, including ischemia, was
slightly higher for repaglinide (4%) than for sulfonylurea drugs (3%) in
controlled comparator clinical trials. In 1-year controlled trials, repaglinide
treatment was not associated with excess mortality rates compared to rates
observed with other oral hypoglycemic agent therapies. See Table 5.
CPS:Gluconorm_t5Click here for Table 5
Table 5: GlucoNorm
Summary of Serious Cardiovascular (CV) Events (%
of total patients with events)
|
|
GlucoNorm
|
SUa
|
|
Total Exposed
|
1 228
|
498
|
|
Serious CV Events
|
4%
|
3%
|
|
Cardiac Ischemic Events
|
2%
|
2%
|
|
Deaths due to CV Events
|
0.5%
|
0.4%
|
a Glyburide and glipizide.
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 (1 patient).
Overdose
For management of a
suspected drug overdose, CPhA recommends that you contact your regional
Poison Control Centre. See the CPS Directory section for a list of
Poison Control Centres.
Symptoms
In a clinical trial, patients received
increasing doses of repaglinide up to 80 mg a day for 14 days. There were few
adverse effects other than those associated with the intended pharmacodynamic
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 i.v. injection of glucose solution, followed by a
continuous infusion, according to standard medical practice.
Dosage
There is no fixed dosage regimen for the
management of type 2 diabetes with repaglinide. The patient's blood glucose
should be monitored periodically to determine the minimum effective dose for
the patient; to detect primary failure (inadequate lowering of blood glucose at
the maximum recommended dose of medication), and to detect secondary failure
(loss of adequate blood glucose-lowering after an initial period of
effectiveness). Glycosylated hemoglobin levels (HbA1C) are of value
in monitoring the patient's longer term response to therapy.
Short-term
administration of repaglinide may be sufficient during periods of transient
loss of control in patients usually controlled by their diet. Repaglinide doses
are usually taken within 15 minutes of the meal but time may vary from
immediately preceding the meal to as long as 30 minutes before the meal.
Initiation Dose: For patients not previously
treated or whose HbA1C is <8%, the starting dose should be 0.5
mg. 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).
Titration: Dosing adjustments should be
determined by blood glucose response, usually fasting blood glucose. The
preprandial dose should be doubled up to 4 mg until satisfactory blood glucose
response is achieved. A minimum of 1 week should elapse between titration steps
to assess response after each dose adjustment.
The recommended dose
range is 0.5 to 4.0 mg taken with meals. Repaglinide offers flexible dietary
options and may be dosed preprandially 2, 3 or 4 times a day in response to
changes in the patient's meal pattern. The recommended maximum daily dose is 16
mg.
Maintenance: Long-term efficacy should be
monitored by measurement of HbA1C levels 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.
For patients maintained
in tight glucose control, repaglinide treatment has less associated risk of
hypoglycemia when meals are missed than does treatment with agents with a
longer half-life.
Transfer From Other Therapies: When repaglinide
is used to replace therapy with other oral hypoglycemic agents, repaglinide may
be started on the day after the final dose is given. Patients should then be
observed carefully for hypoglycemia due to potential overlapping of drug
effects. When transferred from longer half-life sulfonylurea agents (e.g.,
chlorpropamide) to repaglinide, close monitoring may be indicated for up to 1
week or longer.
Combination Therapy: If repaglinide monotherapy
does not result in adequate glycemic control, metformin may be added. Or, if
metformin therapy does not provide adequate control, repaglinide may be added.
The starting dose and dose adjustments for repaglinide combination therapy is
the same as for repaglinide monotherapy. The dose of each drug should be
carefully adjusted to determine the minimal dose required to achieve the
desired pharmacologic effect. Failure to do so could result in an increase in
the incidence of hypoglycemic episodes. Appropriate monitoring of FPG and HbA1C
measurements should be used to ensure that the patient is not subjected to
excessive drug exposure or increased probability of secondary drug failure.
Supplied
0.5 mg
Each white, unscored, biconvex tablet, embossed
with the Novo Nordisk (Apis) bull symbol and colored to indicate the strength,
contains: repaglinide 0.5 mg. Nonmedicinal ingredients: dibasic calcium
phosphate (anhydrous), glycerin, magnesium stearate, maize starch, meglumine,
microcrystalline cellulose, polacrilin potassium, poloxamer and povidone.
Bottles of 100.
1 mg
Each yellow, unscored, biconvex tablet,
embossed with the Novo Nordisk (Apis) bull symbol and colored to indicate the
strength, contains: repaglinide 1 mg. Nonmedicinal ingredients: dibasic calcium
phosphate (anhydrous), glycerin, magnesium stearate, maize starch, meglumine,
microcrystalline cellulose, polacrilin potassium, poloxamer, povidone and
yellow iron oxide. Bottles of 100.
2 mg
Each peach, unscored, biconvex tablet, embossed
with the Novo Nordisk (Apis) bull symbol and colored to indicate the strength,
contains: repaglinide 2 mg. Nonmedicinal ingredients: dibasic calcium phosphate
(anhydrous), glycerin, magnesium stearate, maize starch, meglumine,
microcrystalline cellulose, polacrilin potassium, poloxamer, povidone and red
iron oxide. Bottles of 100.
Store at 15 to 25°C.
Protect from moisture.
