GLIMEPIRIDE
DESCRIPTION:
AMARYL(R) (glimepiride tablets) is an oral blood- glucose-lowering drug of the
sulfonylurea class. Glimepiride is a white to yellowish-white, crystalline,
odorless to practically odorless powder formulated into tablets of 1-mg, 2-mg,
and 4-mg strengths for oral administration. AMARYL(R) tablets contain the active
ingredient glimepiride and the following inactive ingredients: lactose
(hydrous), sodium starch glycolate, povidone, microcrystalline cellulose, and
magnesium stearate.
Chemically, glimepiride is identified as 1-((p- (2-(3-ethyl-4-methyl-2-oxo-3-
pyrroline- 1-carboxamido) ethyl)phenyl)sulfonyl)-3-(trans-4-
methylcyclohexyl)urea.
Molecular Formula: C24H34N4O5S
Molecular Weight: 490.62
Glimepiride is practically insoluble in water.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
The primary mechanism of action of glimepiride in lowering blood glucose appears
to be dependent on stimulating the release of insulin from functioning
pancreatic beta cells. In addition, extra pancreatic effects may also play a role
in the activity of sulfonylureas such as glimepiride. This is supported by both
preclinical and clinical studies demonstrating that glimepiride administration
can lead to increased sensitivity of peripheral tissues to insulin. These
findings are consistent with the results of a long-term, randomized, placebo-
controlled trial in which AMARYL(R) therapy improved postprandial insulin/C-
peptide responses and overall glycemic control without producing clinically
meaningful increases in fasting insulin/C-peptide levels. However, as with other
sulfonylureas, the mechanism by which glimepiride lowers blood glucose during
long-term administration has not been clearly established.
PHARMACODYNAMICS
A mild glucose-lowering effect first appeared following single oral doses as low
as 0.5-0.6 mg in healthy subjects. The time required to reach the maximum effect
(i.e., minimum blood glucose level (Tmin)) was about 2 to 3 hours. In
noninsulin-dependent (Type II) diabetes mellitus (NIDDM) patients, both fasting
and 2-hour postprandial glucose levels were significantly lower with glimepiride
(1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing.
The glucose-lowering effect in all active treatment groups was maintained over
24 hours.
In larger dose-ranging studies, blood glucose and HbA1c were found to respond in
a dose-dependent manner over the range of 1 to 4 mg/day of AMARYL(R). Some
patients, particularly those with higher fasting plasma glucose (FPG) levels,
may benefit from doses of AMARYL(R) up to 8 mg once daily. No difference in
response was found when AMARYL(R) was administered once or twice daily.
In two 14-week, placebo-controlled studies in 720 subjects, the average net
reduction in HbA1c for AMARYL(R) patients treated with 8 mg once daily was 2.0%
in absolute units compared with placebo- treated patients. In a long-term,
randomized, placebo-controlled study of NIDDM patients unresponsive to dietary
management, AMARYL(R) therapy improved postprandial insulin/C-peptide responses,
and 75% of patients achieved and maintained control of blood glucose and HbA1c.
Efficacy results were not affected by age, gender, weight, or race.
long-term extension trials with previously- treated patients, no meaningful
deterioration in mean fasting blood glucose (FBG) or HbA1c levels was seen after
2 1/2 years of AMARYL(R) therapy.
Combination therapy with AMARYL(R) and insulin (70% NPH/30% regular) was
compared to placebo/insulin in secondary failure patients whose body weight was
>130% of their ideal body weight. Initially, 5-10 units of insulin were
administered with the main evening meal and titrated upward weekly to achieve
predefined FPG values. Both groups in this double-blind study achieved similar
reductions in FPG levels but the AMARYL(R)/insulin therapy group used
approximately 38% less insulin.
AMARYL(R) therapy is effective in controlling blood glucose without deleterious
changes in the plasma lipoprotein profiles of patients treated for NIDDM.
PHARMACOKINETICS
ABSORPTION. After oral administration, glimepiride is completely (100%) absorbed
from the GI tract. Studies with single oral doses in normal subjects and with
multiple oral doses in patients with NIDDM have shown significant absorption of
glimepiride within 1 hour after administration and peak drug levels (Cmax) at 2
to 3 hours. When glimepiride was given with meals, the mean Tmax (time to reach
Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under the
curve) were slightly decreased (8% and 9%, respectively).
DISTRIBUTION. After intravenous (IV) dosing in normal subjects, the volume of
distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was
47.8 mL/min. Protein binding was greater than 99.5%.
METABOLISM. Glimepiride is completely metabolized by oxidative biotransformation
after either an IV or oral dose. The major metabolites are the cyclohexyl
hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450
II C9 has been shown to be involved in the biotransformation of glimepiride to
M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but
not M2, possesses about 1/3 of the pharmacological activity as compared to its
parent in an animal model; however, whether the glucose-lowering effect of M1 is
clinically meaningful is not clear.
EXCRETION. When 14C-glimepiride was given orally, approximately 60% of the total
radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2
accounted for 80-90% of that recovered in the urine. Approximately 40% of the
total radioactivity was recovered in feces and M1 and M2 (predominant) accounted
for about 70% of that recovered in feces. No parent drug was recovered from
urine or feces. After IV dosing in patients, no significant biliary excretion of
glimepiride or its M1 metabolite has been observed.
PHARMACOKINETIC PARAMETERS. The pharmacokinetic parameters of glimepiride
obtained from a single- dose, crossover, dose-proportionality (1, 2, 4, and 8
mg) study in normal subjects and from a single- and multiple-dose, parallel,
dose- proportionality (4 and 8 mg) study in patients with NIDDM are summarized
below.
VOLUNTEERS PATIENTS WITH NIDDM
Single Dose Multiple Dose
Single Dose (Day 1) (Day 10)
MEAN SD MEAN SD MEAN SD
Cmax (ng/mL)
1 mg 103 34 (12) ---- ----
2 mg 177 44 (12) ---- ----
4 mg 308 69 (12) 352 222 (12) 309 134 (12)
8 mg 557 152 (12) 591 232 (14) 578 265 (11)
Tmax (h) 2.4 0.8 (48) 2.5 1.2 (26) 2.8 2.2 (23)
CL/f (mL/min) 52.1 16.0 (48) 48.5 29.3 (26) 52.7 40.3 (23)
Vd/f (L) 21.8 13.9 (48) 19.8 12.7 (26) 37.1 18.2 (23)
T1/2 (h) 5.3 4.1 (48) 5.0 2.5 (26) 9.2 3.6 (23)
------------------------------------------------------------------------------------------------------------------------------------------------
() = No. of subjects
CL/f = Total body clearance after oral dosing
Vd/f = Volume of distribution calculated after oral dosing
These data indicate that glimepiride did not accumulate in serum, and the
pharmacokinetics of glimepiride were not different in healthy volunteers and in
NIDDM patients. Oral clearance of glimepiride did not change over the 1-8-mg
dose range, indicating linear pharmacokinetics.
VARIABILITY. In normal healthy volunteers, the intra-individual variabilities of
Cmax, AUC, and CL/f for glimepiride were 23%, 17%, and 15%, respectively, and
the inter-individual variabilities were 25%, 29%, and 24%, respectively.
SPECIAL POPULATIONS
GERIATRIC. Comparison of glimepiride pharmacokinetics in NIDDM patients = 65
years and those > 65 years was performed in a study using a dosing regimen of 6
mg daily. There were no significant differences in glimepiride pharmacokinetics
between the two age groups. The mean AUC at steady state for the older patients
was about 13% lower than that for the younger patients; the mean weight-adjusted
clearance for the older patients was about 11% higher than that for the younger
patients.
PEDIATRIC. No studies were performed in pediatric patients.
GENDER. There were no differences between males and females in the
pharmacokinetics of glimepiride when adjustment was made for differences in body
weight.
RACE. No pharmacokinetic studies to assess the effects of race have been
performed, but in placebo-controlled studies of AMARYL(R) in patients with
NIDDM, the antihyperglycemic effect was comparable in whites (n=536), blacks
(n=63), and Hispanics (n=63).
RENAL INSUFFICIENCY. A single-dose, open-label study was conducted in 15
patients with renal impairment. AMARYL(R) (3 mg) was administered to 3 groups of
patients with different levels of mean creatinine clearance (CLcr); (Group I,
CLcr = 77.7 mL/min, n=5), (Group II, CLcr = 27.7 mL/min, n=3), and (Group III,
CLcr = 9.4 mL/min, n=7). AMARYL(R) was found to be well tolerated in all 3
groups. The results showed that glimepiride serum levels decreased as renal
function decreased. However, M1 and M2 serum levels (mean AUC values) increased
2.3 and 8.6 times from Group I to Group III. The apparent terminal half-life
(T1/2) for glimepiride did not change, while the half-lives for M1 and M2
increased as renal function decreased. Mean urinary excretion of M1 plus M2 as
percent of dose, however, decreased (44.4%, 21.9%, and 9.3% for Groups I to
III).
A multiple-dose titration study was also conducted in 16 NIDDM patients with
renal impairment using doses ranging from 1-8 mg daily for 3 months. The results
were consistent with those observed after single doses. All patients with a CLcr
less than 22 mL/min had adequate control of their glucose levels with a dosage
regimen of only 1 mg daily. The results from this study suggested that a
starting dose of 1 mg AMARYL(R) may be given to NIDDM patients with kidney
disease, and the dose may be titrated based on fasting blood glucose levels.
HEPATIC INSUFFICIENCY. No studies were performed in patients with hepatic
insufficiency.
OTHER POPULATIONS. There were no important differences in glimepiride metabolism
in subjects identified as phenotypically different drug- metabolizers by their
metabolism of sparteine.
The pharmacokinetics of glimepiride in morbidly obese patients were similar to
those in the normal weight group, except for a lower Cmax and AUC. However,
since neither Cmax nor AUC values were normalized for body surface area, the
lower values of Cmax and AUC for the obese patients were likely the result of
their excess weight and not due to a difference in the kinetics of glimepiride.
DRUG INTERACTIONS. The hypoglycemic action of sulfonylureas may be potentiated
by certain drugs, including nonsteroidal anti-inflammatory drugs and other drugs
that are highly protein bound, such as salicylates, sulfonamides,
chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta
adrenergic blocking agents. When these drugs are administered to a patient
receiving AMARYL(R), the patient should be observed closely for hypoglycemia.
When these drugs are withdrawn from a patient receiving AMARYL(R), the patient
should be observed closely for loss of glycemic control.
Certain drugs tend to produce hyperglycemia and may lead to loss of control.
These drugs include the thiazides and other diuretics, corticosteroids,
phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin,
nicotinic acid, sympathomimetics, and isoniazid. When these drugs are
administered to a patient receiving AMARYL(R), the patient should be closely
observed for loss of control. When these drugs are withdrawn from a patient
receiving AMARYL(R), the patient should be observed closely for hypoglycemia.
Coadministration of aspirin (1 g tid) and AMARYL(R) led to a 34% decrease in the
mean glimepiride AUC and, therefore, a 34% increase in the mean CL/f. The mean
Cmax had a decrease of 4%. Blood glucose and serum C-peptide concentrations were
unaffected and no hypoglycemic symptoms were reported. Pooled data from clinical
trials showed no evidence of clinically significant adverse interactions with
uncontrolled concurrent administration of aspirin and other salicylates.
Coadministration of either cimetidine (800 mg once daily) or ranitidine (150 mg
bid) with a single 4-mg oral dose of AMARYL(R) did not significantly alter the
absorption and disposition of glimepiride, and no differences were seen in
hypoglycemic symptomatology. Pooled data from clinical trials showed no evidence
of clinically significant adverse interactions with uncontrolled concurrent
administration of H2-receptor antagonists.
Concomitant administration of propranolol (40 mg tid) and AMARYL(R)
significantly increased Cmax, AUC, and T1/2 of glimepiride by 23%, 22%, and 15%,
respectively, and it decreased CL/f by 18%. The recovery of M1 and M2 from
urine, however, did not change. The pharmacodynamic responses to glimepiride
were nearly identical in normal subjects receiving propranolol and placebo.
Pooled data from clinical trials in patients with NIDDM showed no evidence of
clinically significant adverse interactions with uncontrolled concurrent
administration of beta- blockers. However, if beta-blockers are used, caution
should be exercised and patients should be warned about the potential for
hypoglycemia.
Concomitant administration of AMARYL(R) (4 mg once daily) did not alter the
pharmacokinetic characteristics of R- and S-warfarin enantiomers following
administration of a single dose (25 mg) of racemic warfarin to healthy subjects.
No changes were observed in warfarin plasma protein binding. AMARYL(R) treatment
did result in a slight, but statistically significant, decrease in the
pharmacodynamic response to warfarin. The reductions in mean area under the
prothrombin time (PT) curve and maximum PT values during AMARYL(R) treatment
were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically
important.
The responses of serum glucose, insulin, C- peptide, and plasma glucagon to 2 mg
AMARYL(R) were unaffected by coadministration of ramipril (an ACE inhibitor) 5
mg once daily in normal subjects. No hypoglycemic symptoms were reported. Pooled
data from clinical trials in patients with NIDDM showed no evidence of
clinically significant adverse interactions with uncontrolled concurrent
administration of ACE inhibitors.
A potential interaction between oral miconazole and oral hypoglycemic agents
leading to severe hypoglycemia has been reported. Whether this interaction also
occurs with the intravenous, topical, or vaginal preparations of miconazole is
not known. Potential interactions of glimepiride with other drugs metabolized by
cytochrome P450 II C9 also include phenytoin, diclofenac, ibuprofen, naproxen,
and mefenamic acid.
Although no specific interaction studies were performed, pooled data from
clinical trials showed no evidence of clinically significant adverse
interactions with uncontrolled concurrent administration of calcium-channel
blockers, estrogens, fibrates, NSAIDS, HMG CoA reductase inhibitors,
sulfonamides, or thyroid hormone.
INDICATIONS AND USAGE:
AMARYL(R) is indicated as an adjunct to diet and exercise to lower the blood
glucose in patients with noninsulin-dependent (Type II) diabetes mellitus
(NIDDM) whose hyperglycemia cannot be controlled by diet and exercise alone.
AMARYL(R) is also indicated for use in combination with insulin to lower blood
glucose in patients whose hyperglycemia cannot be controlled by diet and
exercise in conjunction with an oral hypoglycemic agent. Combined use of
glimepiride and insulin may increase the potential for hypoglycemia.
In initiating treatment for noninsulin-dependent 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 sulfonylurea or insulin should be considered. Use of AMARYL(R) must
be viewed by both the physician and patient as a treatment in addition to diet
and exercise and not as a substitute for diet and exercise or as a convenient
mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose
control on diet and exercise alone may be transient, thus requiring only short-
term administration of AMARYL(R).
During maintenance programs, AMARYL(R) monotherapy should be discontinued if
satisfactory lowering of blood glucose is no longer achieved. Judgments should
be based on regular clinical and laboratory evaluations. Secondary failures to
AMARYL(R) monotherapy can be treated with AMARYL(R)-insulin combination therapy.
In considering the use of AMARYL(R) in asymptomatic patients, it should be
recognized that blood glucose control in NIDDM has not definitely been
established to be effective in preventing the long-term cardiovascular and
neural complications of diabetes. However, the Diabetes Control and
Complications Trial (DCCT) demonstrated that control of HbA1c and glucose was
associated with a decrease in retinopathy, neuropathy, and nephropathy for
insulin-dependent diabetic (IDDM) patients.
CONTRAINDICATIONS:
AMARYL(R) is contraindicated in patients with
1. Known hypersensitivity to the drug.
2. Diabetic ketoacidosis, with or without coma. This condition should be
treated with insulin.
WARNINGS:
SPECIAL WARNING ON INCREASED RISK OF
CARDIOVASCULAR MORTALITY
THE ADMINISTRATION OF ORAL HYPOGLYCEMIC DRUGS HAS BEEN REPORTED TO BE ASSOCIATED
WITH INCREASED CARDIOVASCULAR MORTALITY AS COMPARED TO TREATMENT WITH DIET ALONE
OR DIET PLUS INSULIN. THIS WARNING IS BASED ON THE STUDY CONDUCTED BY THE
UNIVERSITY GROUP DIABETES PROGRAM (UGDP), A LONG- TERM, PROSPECTIVE CLINICAL
TRIAL DESIGNED TO EVALUATE THE EFFECTIVENESS OF GLUCOSE-LOWERING DRUGS IN
PREVENTING OR DELAYING VASCULAR COMPLICATIONS IN PATIENTS WITH NON-INSULIN-
DEPENDENT DIABETES. THE STUDY INVOLVED 823 PATIENTS WHO WERE RANDOMLY ASSIGNED
TO ONE OF FOUR TREATMENT GROUPS (DIABETES, 19 SUPP. 2: 747-830, 1970).
UGDP REPORTED THAT PATIENTS TREATED FOR 5 TO 8 YEARS WITH DIET PLUS A FIXED DOSE
OF TOLBUTAMIDE (1.5 GRAMS PER DAY) HAD A RATE OF CARDIOVASCULAR MORTALITY
APPROXIMATELY 2 1/2 TIMES THAT OF PATIENTS TREATED WITH DIET ALONE. A
SIGNIFICANT INCREASE IN TOTAL MORTALITY WAS NOT OBSERVED, BUT THE USE OF
TOLBUTAMIDE WAS DISCONTINUED BASED ON THE INCREASE IN CARDIOVASCULAR MORTALITY,
THUS LIMITING THE OPPORTUNITY FOR THE STUDY TO SHOW AN INCREASE IN OVERALL
MORTALITY. DESPITE CONTROVERSY REGARDING THE INTERPRETATION OF THESE RESULTS,
THE FINDINGS OF THE UGDP STUDY PROVIDE AN ADEQUATE BASIS FOR THIS WARNING. THE
PATIENT SHOULD BE INFORMED OF THE POTENTIAL RISKS AND ADVANTAGES OF AMARYL(R)
(GLIMEPIRIDE TABLETS) AND OF ALTERNATIVE MODES OF THERAPY.
ALTHOUGH ONLY ONE DRUG IN THE SULFONYLUREA CLASS (TOLBUTAMIDE) WAS INCLUDED IN
THIS STUDY, IT IS PRUDENT FROM A SAFETY STANDPOINT TO CONSIDER THAT THIS WARNING
MAY ALSO APPLY TO OTHER ORAL HYPOGLYCEMIC DRUGS IN THIS CLASS, IN VIEW OF THEIR
CLOSE SIMILARITIES IN MODE OF ACTION AND CHEMICAL STRUCTURE.
PRECAUTIONS:
GENERAL
Hypoglycemia: All sulfonylurea drugs are capable of producing severe
hypoglycemia. Proper patient selection, dosage, and instructions are important
to avoid hypoglycemic episodes. Patients with impaired renal function may be
more sensitive to the glucose-lowering effect of AMARYL(R). A starting dose of 1
mg once daily followed by appropriate dose titration is recommended in those
patients. 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 beta-adrenergic blocking
drugs or other sympatholytic agents. 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.
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 may occur. At such times, it may be necessary to add insulin in
combination with AMARYL(R) or even use insulin monotherapy. The effectiveness of
any oral hypoglycemic drug, including AMARYL(R), 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 the 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 first given. Should secondary failure occur with AMARYL(R) monotherapy,
AMARYL(R)-insulin combination therapy may be instituted. Combined use of
glimepiride and insulin may increase the potential for hypoglycemia.
INFORMATION FOR PATIENTS
Patients should be informed of the potential risks and advantages of AMARYL(R)
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.
The risks of hypoglycemia, its symptoms and treatment, and conditions that
predispose to its development should be explained to patients and responsible
family members. The potential for primary and secondary failure should also be
explained.
LABORATORY TESTS
Fasting blood glucose should be monitored periodically to determine therapeutic
response. Glycosylated hemoglobin should also be monitored, usually every 3 to 6
months, to more precisely assess long-term glycemic control.
DRUG INTERACTIONS
(See ACTIONS/CLINICAL PHARMACOLOGY, DRUG INTERACTIONS.)
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
Studies in rats at doses of up to 5000 ppm in complete feed (approximately 340
times the maximum recommended human dose, based on surface area) for 30 months
showed no evidence of carcinogenesis. In mice, administration of glimepiride for
24 months resulted in an increase in benign pancreatic adenoma formation which
was dose related and is thought to be the result of chronic pancreatic
stimulation. The no-effect dose for adenoma formation in mice in this study was
320 ppm in complete feed, or 46-54 mg/kg body weight/day. This is about 35 times
the maximum human recommended dose of 8 mg once daily based on surface area.
Glimepiride was non-mutagenic in a battery of In Vitro and In Vivo mutagenicity
studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled
DNA synthesis, mouse micronucleus test).
There was no effect of glimepiride on male mouse fertility in animals exposed up
to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based
on surface area). Glimepiride had no effect on the fertility of male and female
rats administered up to 4000 mg/kg body weight (approximately 4,000 times the
maximum recommended human dose based on surface area).
PREGNANCY
TERATOGENIC EFFECTS. Pregnancy Category C. Glimepiride did not produce
teratogenic effects in rats exposed orally up to 4000 mg/kg body weight
(approximately 4,000 times the maximum recommended human dose based on surface
area) or in rabbits exposed up to 32 mg/kg body weight (approximately 60 times
the maximum recommended human dose based on surface area). Glimepiride has been
shown to be associated with intrauterine fetal death in rats when given in doses
as low as 50 times the human dose based on surface area and in rabbits when
given in doses as low as 0.1 times the human dose based on surface area. This
fetotoxicity, observed only at doses inducing maternal hypoglycemia, has been
similarly noted with other sulfonylureas, and is believed to be directly related
to the pharmacologic (hypoglycemic) action of glimepiride.
There are no adequate and well-controlled studies in pregnant women. On the
basis of results from animal studies, AMARYL(R) should not be used during
pregnancy. 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 glucose levels as close to normal as possible.
NONTERATOGENIC EFFECTS. In some studies in rats, offspring of dams exposed to
high levels of glimepiride during pregnancy and lactation developed skeletal
deformities consisting of shortening, thickening, and bending of the humerus
during the postnatal period. Significant concentrations of glimepiride were
observed in the serum and breast milk of the dams as well as in the serum of the
pups. These skeletal deformations were determined to be the result of nursing
from mothers exposed to glimepiride.
Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born
to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-
lives. Patients who are planning a pregnancy should consult their physician, and
it is recommended that they change over to insulin for the entire course of
pregnancy and lactation.
NURSING MOTHERS
In rat reproduction studies, significant concentrations of glimepiride were
observed in the serum and breast milk of the dams, as well as in the serum of
the pups. Although it is not known whether AMARYL(R) is excreted in human milk,
other sulfonylureas are excreted in human milk. Because the potential for
hypoglycemia in nursing infants may exist, and because of the effects on nursing
animals, AMARYL(R) should be discontinued in nursing mothers. If AMARYL(R) is
discontinued, and if diet and exercise alone are inadequate for controlling
blood glucose, insulin therapy should be considered. (See above PREGNANCY,
NONTERATOGENIC EFFECTS.)
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established.
DRUG INTERACTIONS:
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs,
including nonsteroidal anti-inflammatory drugs and other drugs that are highly
protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins,
probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents.
When these drugs are administered to a patient receiving AMARYL(R), the patient
should be observed closely for hypoglycemia. When these drugs are withdrawn from
a patient receiving AMARYL(R), the patient should be observed closely for loss
of glycemic control.
Certain drugs tend to produce hyperglycemia and may lead to loss of control.
These drugs include the thiazides and other diuretics, corticosteroids,
phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin,
nicotinic acid, sympathomimetics, and isoniazid. When these drugs are
administered to a patient receiving AMARYL(R), the patient should be closely
observed for loss of control. When these drugs are withdrawn from a patient
receiving AMARYL(R), the patient should be observed closely for hypoglycemia.
Coadministration of aspirin (1 g tid) and AMARYL(R) led to a 34% decrease in the
mean glimepiride AUC and, therefore, a 34% increase in the mean CL/f. The mean
Cmax had a decrease of 4%. Blood glucose and serum C-peptide concentrations were
unaffected and no hypoglycemic symptoms were reported. Pooled data from clinical
trials showed no evidence of clinically significant adverse interactions with
uncontrolled concurrent administration of aspirin and other salicylates.
Coadministration of either cimetidine (800 mg once daily) or ranitidine (150 mg
bid) with a single 4-mg oral dose of AMARYL(R) did not significantly alter the
absorption and disposition of glimepiride, and no differences were seen in
hypoglycemic symptomatology. Pooled data from clinical trials showed no evidence
of clinically significant adverse interactions with uncontrolled concurrent
administration of H2-receptor antagonists.
Concomitant administration of propranolol (40 mg tid) and AMARYL(R)
significantly increased Cmax, AUC, and T1/2 of glimepiride by 23%, 22%, and 15%,
respectively, and it decreased CL/f by 18%. The recovery of M1 and M2 from
urine, however, did not change. The pharmacodynamic responses to glimepiride
were nearly identical in normal subjects receiving propranolol and placebo.
Pooled data from clinical trials in patients with NIDDM showed no evidence of
clinically significant adverse interactions with uncontrolled concurrent
administration of beta- blockers. However, if beta-blockers are used, caution
should be exercised and patients should be warned about the potential for
hypoglycemia.
Concomitant administration of AMARYL(R) (4 mg once daily) did not alter the
pharmacokinetic characteristics of R- and S-warfarin enantiomers following
administration of a single dose (25 mg) of racemic warfarin to healthy subjects.
No changes were observed in warfarin plasma protein binding. AMARYL(R) treatment
did result in a slight, but statistically significant, decrease in the
pharmacodynamic response to warfarin. The reductions in mean area under the
prothrombin time (PT) curve and maximum PT values during AMARYL(R) treatment
were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically
important.
The responses of serum glucose, insulin, C- peptide, and plasma glucagon to 2 mg
AMARYL(R) were unaffected by coadministration of ramipril (an ACE inhibitor) 5
mg once daily in normal subjects. No hypoglycemic symptoms were reported. Pooled
data from clinical trials in patients with NIDDM showed no evidence of
clinically significant adverse interactions with uncontrolled concurrent
administration of ACE inhibitors.
A potential interaction between oral miconazole and oral hypoglycemic agents
leading to severe hypoglycemia has been reported. Whether this interaction also
occurs with the intravenous, topical, or vaginal preparations of miconazole is
not known. Potential interactions of glimepiride with other drugs metabolized by
cytochrome P450 II C9 also include phenytoin, diclofenac, ibuprofen, naproxen,
and mefenamic acid.
Although no specific interaction studies were performed, pooled data from
clinical trials showed no evidence of clinically significant adverse
interactions with uncontrolled concurrent administration of calcium-channel
blockers, estrogens, fibrates, NSAIDS, HMG CoA reductase inhibitors,
sulfonamides, or thyroid hormone.
(See Also ACTIONS/CLINICAL PHARMACOLOGY, DRUG INTERACTIONS.)
ADVERSE REACTIONS:
The incidence of hypoglycemia with AMARYL(R), as documented by blood glucose
values <60 mg/dL, ranged from 0.9-1.7% in two large, well- controlled, 1-year
studies. (See WARNINGS and PRECAUTIONS.)
AMARYL(R) has been evaluated for safety in 2,013 patients in US controlled
trials, and in 1,551 patients in foreign controlled trials. More than 1,650 of
these patients were treated for at least 1 year.
Adverse events, other than hypoglycemia, considered to be possibly or probably
related to study drug that occurred in US placebo-controlled trials in more than
1% of patients treated with AMARYL(R) are shown below.
Adverse Events Occurring in >/=1%
AMARYL(R) Patients
AMARYL(R) PLACEBO
NO. % NO. %
Total Treated 746 100 294 100
Dizziness 13 1.7 1 0.3
Asthenia 12 1.6 3 1.0
Headache 11 1.5 4 1.4
Nausea 8 1.1 0 0.0
GASTROINTESTINAL REACTIONS
Vomiting, gastrointestinal pain, and diarrhea have been reported, but the
incidence in placebo- controlled trials was less than 1%. Isolated transaminase
elevations have been reported. Cholestatic jaundice has been reported to occur
rarely with sulfonylureas.
DERMATOLOGIC REACTIONS
Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform
or maculopapular eruptions, occur in less than 1% of treated patients. These may
be transient and may disappear despite continued use of AMARYL(R); if skin
reactions persist, the drug should be discontinued. Porphyria cutanea tarda and
photosensitivity reactions have been reported with sulfonylureas.
HEMATOLOGIC REACTIONS
Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic
anemia, and pancytopenia have been reported with sulfonylureas.
METABOLIC REACTIONS
Hepatic porphyria reactions and disulfiram-like reactions have been reported
with sulfonylureas; however, no cases have yet been reported with AMARYL(R).
Cases of hyponatremia have been reported with glimepiride and all other
sulfonylureas, most often in patients who are on other medications or have
medical conditions known to cause hyponatremia or increase release of
antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH)
secretion has been reported with certain other sulfonylureas, and it has been
suggested that these sulfonylureas may augment the peripheral (antidiuretic)
action of ADH and/or increase release of ADH.
OTHER REACTIONS
Changes in accommodation and/or blurred vision may occur with the use of
AMARYL(R). This is thought to be due to changes in blood glucose, and may be
more pronounced when treatment is initiated. This condition is also seen in
untreated diabetic patients, and may actually be reduced by treatment. In
placebo-controlled trials of AMARYL(R), the incidence of blurred vision was
placebo, 0.7%, and AMARYL(R), 0.4%.
OVERDOSAGE:
Overdosage of sulfonylureas, including AMARYL(R), can produce hypoglycemia. Mild
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 should continue until the physician is
assured that the patient is out of danger. 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 a more dilute (10%) glucose solution at a
rate that will maintain the blood glucose at a level above 100 mg/dL. Patients
should be closely monitored for a minimum of 24 to 48 hours, because
hypoglycemia may recur after apparent clinical recovery.
DOSAGE AND ADMINISTRATION:
There is no fixed dosage regimen for the management of diabetes mellitus with
AMARYL(R) or any other hypoglycemic agent. The patient's fasting blood glucose
and HbA1c must be measured 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 adequate blood glucose lowering response after an initial
period of effectiveness. Glycosylated hemoglobin levels should be performed to
monitor the patient's response to therapy.
Short-term administration of AMARYL(R) may be sufficient during periods of
transient loss of control in patients usually controlled well on diet and
exercise.
USUAL STARTING DOSE
The usual starting dose of AMARYL(R) as initial therapy is 1-2 mg once daily,
administered with breakfast or the first main meal. Those patients who may be
more sensitive to hypoglycemic drugs should be started at 1 mg once daily, and
should be titrated carefully. (See PRECAUTIONS Section for patients at increased
risk.)
No exact dosage relationship exists between AMARYL(R) and the other oral
hypoglycemic agents. The maximum starting dose of AMARYL(R) should be no more
than 2 mg.
Failure to follow an appropriate dosage regimen may precipitate hypoglycemia.
Patients who do not adhere to their prescribed dietary and drug regimen are more
prone to exhibit unsatisfactory response to therapy.
USUAL MAINTENANCE DOSE
The usual maintenance dose is 1 to 4 mg once daily. The maximum recommended dose
is 8 mg once daily. After reaching a dose of 2 mg, dosage increases should be
made in increments of no more than 2 mg at 1-2 week intervals based upon the
patient's blood glucose response. Long-term efficacy should be monitored by
measurement of HbA1c levels, for example, every 3 to 6 months.
AMARYL(R) -INSULIN COMBINATION THERAPY
Combination therapy with AMARYL(R) and insulin may be used in secondary failure
patients. The fasting glucose level for instituting combination therapy is in
the range of >150 mg/dL in plasma or serum depending on the patient. The
recommended AMARYL(R) dose is 8 mg once daily administered with the first main
meal. After starting with low-dose insulin, upward adjustments of insulin can be
done approximately weekly as guided by frequent measurements of fasting blood
glucose. Once stable, combination- therapy patients should monitor their
capillary blood glucose on an ongoing basis, preferably daily. Periodic
adjustments of insulin may also be necessary during maintenance as guided by
glucose and HbA1c levels.
SPECIFIC PATIENT POPULATIONS
AMARYL(R) is not recommended for use in pregnancy, nursing mothers, or children.
In elderly, debilitated, or malnourished patients, or in patients with renal or
hepatic insufficiency, the initial dosing, dose increments, and maintenance
dosage should be conservative to avoid hypoglycemic reactions (See
ACTIONS/CLINICAL PHARMACOLOGY, SPECIAL POPULATIONS and PRECAUTIONS, GENERAL).
PATIENTS RECEIVING OTHER ORAL HYPOGLYCEMIC AGENTS
As with other sulfonylurea hypoglycemic agents, no transition period is
necessary when transferring patients to AMARYL(R). Patients should be observed
carefully (1-2 weeks) for hypoglycemia when being transferred from longer half-
life sulfonylureas (e.g., chlorpropamide) to AMARYL(R) due to potential
overlapping of drug effect.
ANIMAL PHARMACOLOGY:
ANIMAL TOXICOLOGY
Reduced serum glucose values and degranulation of the pancreatic beta cells were
observed in beagle dogs exposed to 320 mg glimepiride/kg/day for 12 months
(approximately 1,000 times the recommended human dose based on surface area). No
evidence of tumor formation was observed in any organ. One female and one male
dog developed bilateral subcapsular cataracts. Non-GLP studies indicated that
glimepiride was unlikely to exacerbate cataract formation. Evaluation of the co-
cataractogenic potential of glimepiride in several diabetic and cataract rat
models was negative and there was no adverse effect of glimepiride on bovine
ocular lens metabolism in organ culture.
HUMAN OPHTHALMOLOGY DATA
Ophthalmic examinations were carried out in over 500 subjects during long-term
studies using the methodology of Taylor and West and Laties et al. No
significant differences were seen between AMARYL(R) and glyburide in the number
of subjects with clinically important changes in visual acuity, intra-ocular
tension, or in any of the five lens-related variables examined.
Ophthalmic examinations were carried out during long-term studies using the
method of Chylack et al. No significant or clinically meaningful differences
were seen between AMARYL(R) and glipizide with respect to cataract progression
by subjective LOCS II grading and objective image analysis systems, visual
acuity, intraocular pressure, and general ophthalmic examination.