The format of the leaflet was set by the ministry of health and its content was checked and

approved by the
ministry of health on 01/2014 and updated according to the guidelines of the Ministry of Health on 09/2017.

AMARYL 1mg, 2mg, 3mg, 4mg

Glimepiride tablets

1 INDICATIONS AND USAGE

Amaryl is indicated for non-insulin-dependent diabetes melitus (adult-onset diabetes, type II

diabetes), when diet, regular physical exercise and weight reduction alone cannot maintain
therapeutically suitable blood glucose levels.

1.1 Important Limitations of Use

AMARYL should not be used for the treatment of type 1 diabetes mellitus or diabetic
ketoacidosis, as it would not be effective in these settings.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

AMARYL should be administered with breakfast or the first main meal of the day.

The recommended starting dose of AMARYL is 1 mg or 2 mg once daily. Patients at increased

risk for hypoglycemia (e.g., the elderly or patients with renal impairment) should be started on 1
mg once daily [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5, 8.6)].

After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or
2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently
than every 1-2 weeks. A conservative titration scheme is recommended for patients at increased
risk for hypoglycemia [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5,
8.6)].

The maximum recommended dose is 8 mg once daily.

Patients being transferred to AMARYL from longer half-life sulfonylureas (e.g.,

chlorpropamide) may have overlapping drug effect for 1-2 weeks and should be appropriately
monitored for hypoglycemia.

When colesevelam is coadministered with glimepiride, maximum plasma concentration and total
exposure to glimepiride is reduced. Therefore, Amaryl should be administered at least 4 hours
prior to colesevelam.

2 DOSAGE FORMS AND STRENGTHS

AMARYL is formulated as tablets of:

 1 mg (pink, oblong tablets, biplanar with score-line on both sides, imprinted on both sides).
 2 mg (green, tablets, biplanar with score-line on both sides, imprinted on both sides).
 3mg (yellow, tablets, biplanar with score-line on both sides, imprinted on both sides).
1
 4 mg (blue, tablets, biplanar with score-line on both sides, imprinted on both sides).

Tablets for oral administration.

The tablets can be divided into two equal doses along the score line.

4 CONTRAINDICATIONS

AMARYL is contraindicated in patients with a history of a hypersensitivity reaction to:

 Glimepiride or any of the product’s ingredients [see Warnings and Precautions (5.2].

Sulfonamide derivatives: Patients who have developed an allergic reaction to sulfonamide

derivatives may develop an allergic reaction to AMARYL. Do not use AMARYL in patients
who have a history of an allergic reaction to sulfonamide derivatives.

Reported hypersensitivity reactions include cutaneous eruptions with or without pruritus as well
as more serious reactions (e.g. anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea)
[see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypoglycemia
All sulfonylureas, including AMARYL, can cause severe hypoglycemia [see Adverse Reactions
(6.1)]. The patient's ability to concentrate and react may be impaired as a result of
hypoglycemia. These impairments may present a risk in situations where these abilities are
especially important, such as driving or operating other machinery. Severe hypoglycemia can
lead to unconsciousness or convulsions and may result in temporary or permanent impairment of
brain function or death.

Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating
and increasing AMARYL doses in patients who may be predisposed to hypoglycemia (e.g., the
elderly, patients with renal impairment, patients on other anti-diabetic medications). Debilitated
or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly
susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also
more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when
alcohol is ingested.

Early warning symptoms of hypoglycemia may be different or less pronounced in patients with
autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking
medications or other sympatholytic agents. These situations may result in severe hypoglycemia
before the patient is aware of the hypoglycemia.

5.2 Hypersensitivity Reactions

There have been postmarketing reports of hypersensitivity reactions in patients treated with
AMARYL, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson
Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue AMARYL, assess
for other potential causes for the reaction, and institute alternative treatment for diabetes.

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5.3 Hemolytic Anemia
Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase
(G6PD) deficiency. Because AMARYL is a sulfonylurea, use caution in patients with G6PD
deficiency and consider the use of a non-sulfonylurea alternative. There are also postmarketing
reports of hemolytic anemia in patients receiving AMARYL who did not have known G6PD
deficiency [see Adverse Reactions (6.2)].

5.4 Increased Risk of Cardiovascular Mortality with Sulfonylureas

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

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 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.

5.5 Macrovascular Outcomes

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

6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in more detail below and elsewhere in the
labeling:

• Hypoglycemia [see Warnings and Precautions (5.1)]

• Hemolytic anemia [see Warnings and Precautions (5.3)]

In clinical trials, the most common adverse reactions with AMARYL were hypoglycemia,
dizziness, asthenia, headache, and nausea.

6.1 Clinical Trials Experience

3
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.

Approximately 2,800 patients with type 2 diabetes have been treated with AMARYL in the
controlled clinical trials. In these trials, approximately 1,700 patients were treated with
AMARYL for at least 1 year.

Table 1 summarizes adverse events, other than hypoglycemia, that were reported in 11 pooled
placebo-controlled trials, whether or not considered to be possibly or probably related to study
medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported
represent those that occurred at an incidence of ≥5% among AMARYL-treated patients and more
commonly than in patients who received placebo.

Table 1. Eleven Pooled Placebo-Controlled Trials ranging from 13

weeks to 12 months: Adverse Events (Excluding Hypoglycemia)
Occurring in ≥5% of AMARYL-treated Patients and at a Greater
Incidence than with Placebo*
AMARYL Placebo
N=745 N=294
% %
Headache 8.2 7.8
Accidental Injury† 5.8 3.4
Flu Syndrome 5.4 4.4
Nausea 5.0 3.4
Dizziness 5.0 2.4
*AMARYL doses ranged from 1-16 mg administered daily
†Insufficient information to determine whether any of the accidental injury
events were associated with hypoglycemia

Hypoglycemia:
In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration,
patients already on sulfonylurea therapy underwent a 3-week washout period then were
randomized to AMARYL 1 mg, 4 mg, 8 mg or placebo. Patients randomized to AMARYL 4 mg
or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated
[see Clinical Studies (14.1)]. The overall incidence of possible hypoglycemia (defined by the
presence of at least one symptom that the investigator believed might be related to hypoglycemia;
a concurrent glucose measurement was not required) was 4% for AMARYL 1 mg, 17% for
AMARYL 4 mg, 16% for AMARYL 8 mg and 0% for placebo. All of these events were self-
treated.

In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration,

patients received a starting dose of either 1 mg AMARYL or placebo daily. The dose of
AMARYL was titrated to a target fasting plasma glucose of 90-150 mg/dL. Final daily doses of
AMARYL were 1, 2, 3, 4, 6 or 8 mg [see Clinical Studies (14.1)]. The overall incidence of
possible hypoglycemia (as defined above for the 14-week trial) for AMARYL vs. placebo was
19.7% vs. 3.2%. All of these events were self-treated.

Weight gain: AMARYL, like all sulfonylureas, can cause weight gain [see Clinical Studies
(14.1)].

4
Allergic Reactions: In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and
morbilliform or maculopapular eruptions, occurred in less than 1% of AMARYL-treated patients.
These may resolve despite continued treatment with AMARYL. There are postmarketing reports
of more serious allergic reactions (e.g., dyspnea, hypotension, shock) [see Warnings and
Precautions (5.2)].

Laboratory Tests:
Elevated Serum Alanine Aminotransferase (ALT): In 11 pooled placebo-controlled trials of
AMARYL, 1.9% of AMARYL-treated patients and 0.8% of placebo-treated patients developed
serum ALT greater than 2 times the upper limit of the reference range.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of AMARYL.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.

 Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-

Johnson Syndrome [see Warnings and Precautions (5.2)]
 Hemolytic anemia in patients with and without G6PD deficiency [see Warnings and
Precautions (5.3)]
 Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis,
which may progress to liver failure.
 Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis.
 Leukopenia, agranulocytosis, aplastic anemia, and pancytopenia.
 Thrombocytopenia: (including severe cases with platelet count less than 10,000/µl) and
thrombocytopenic purpura.
 Hepatic porphyria reactions and disulfiram-like reactions
 Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH),
most often in patients who are on other medications or who have medical conditions
known to cause hyponatremia or increase release of antidiuretic hormone
 Dysgeusia
 Alopecia

7 DRUG INTERACTIONS

7.1 Drugs Affecting Glucose Metabolism

A number of medications affect glucose metabolism and may require AMARYL dose adjustment
and particularly close monitoring for hypoglycemia or worsening glycemic control.

The following are examples of medications that may increase the glucose-lowering effect of
sulfonylureas including AMARYL, increasing the susceptibility to and/or intensity of
hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting
enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline,
somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol,
guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide,
quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-

5
inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and
monoamine oxidase inhibitors. When these medications are administered to a patient receiving
AMARYL, monitor the patient closely for hypoglycemia. When these medications are
withdrawn from a patient receiving AMARYL, monitor the patient closely for worsening
glycemic control.

The following are examples of medications that may reduce the glucose-lowering effect of
sulfonylureas including AMARYL, leading to worsening glycemic control: danazol, glucagon,
somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and
clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics,
corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin,
nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When
these medications are administered to a patient receiving AMARYL, monitor the patient closely
for worsening glycemic control. When these medications are withdrawn from a patient receiving
AMARYL, monitor the patient closely for hypoglycemia.

Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of

AMARYL’s glucose-lowering effect.

Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of
AMARYL in an unpredictable fashion.

The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such
as beta-blockers, clonidine, guanethidine, and reserpine.

7.2 Miconazole
A potential interaction between oral miconazole and sulfonylureas leading to severe
hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms
of miconazole is not known.

7.3 Cytochrome P450 2C9 Interactions

There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers
(e.g., rifampin) of cytochrome P450 2C9. Fluconazole may inhibit the metabolism of
glimepiride, causing increased plasma concentrations of glimepiride which may lead to
hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma
concentrations of glimepiride which may lead to worsening glycemic control.

7.4 Concomitant Administration of Colesevelam

Colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride
when the two are coadministered. However, absorbtion is not reduced when glimepiride is
administered 4 hours prior to cloesevelam. Therefore, Amaryl should be administered at least 4
hours prior to colesevelam.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
6
Pregnancy Category C
There are no adequate and well-controlled studies of AMARYL in pregnant women. In animal
studies there was no increase in congenital anomalies, but an increase in fetal deaths occurred in
rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits) the maximum
recommended human dose (based on body surface area). This fetotoxicity, observed only at
doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic
(hypoglycemic) action of glimepiride and has been similarly noted with other sulfonylureas.
AMARYL should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus. Because data suggest that abnormal blood glucose during pregnancy is
associated with a higher incidence of congenital abnormalities, diabetes treatment during
pregnancy should maintain blood glucose as close to normal as possible.

Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in

neonates born to mothers receiving a sulfonylurea at the time of delivery.

8.3 Nursing Mothers

It is not known whether AMARYL is excreted in human milk. During pre- and post-natal studies
in rats, significant concentrations of glimepiride were present in breast milk and the serum of the
pups. Offspring of rats 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. These skeletal deformations were determined to be the result of
nursing from mothers exposed to glimepiride. Based on these animal data and the potential for
hypoglycemia in a nursing infant, a decision should be made whether to discontinue nursing or
discontinue AMARYL, taking into account the importance of AMARYL to the mother.

8.4 Pediatric Use

The pharmacokinetics, efficacy and safety of AMARYL have been evaluated in pediatric patients
with type 2 diabetes as described below. AMARYL is not recommended in pediatric patients
because of its adverse effects on body weight and hypoglycemia.

The pharmacokinetics of a 1 mg single dose of AMARYL was evaluated in 30 patients with type
2 diabetes (male = 7; female = 23) between ages 10 and 17 years. The mean (± SD) AUC(0-last)
(339±203 ng•hr/mL), Cmax (102±48 ng/mL) and t1/2 (3.1±1.7 hours) for glimepiride were
comparable to historical data from adults (AUC(0-last) 315±96 ng•hr/mL, Cmax 103±34 ng/mL and
t1/2 5.3±4.1 hours).

The safety and efficacy of AMARYL in pediatric patients was evaluated in a single-blind, 24-
week trial that randomized 272 patients (8-17 years of age) with type 2 diabetes to AMARYL
(n=135) or metformin (n=137). Both treatment-naïve patients (those treated with only diet and
exercise for at least 2 weeks prior to randomization) and previously treated patients (those
previously treated or currently treated with other oral antidiabetic medications for at least 3
months) were eligible to participate. Patients who were receiving oral antidiabetic agents at the
time of study entry discontinued these medications before randomization without a washout
period. AMARYL was initiated at 1 mg, and then titrated up to 2, 4 or 8 mg (mean last dose 4
mg) through Week 12, targeting a self-monitored fasting fingerstick blood glucose < 126 mg/dL.
Metformin was initiated at 500 mg twice daily and titrated at Week 12 up to 1000 mg twice daily
(mean last dose 1365 mg).
After 24 weeks, the overall mean treatment difference in HbA1c between AMARYL and
metformin was 0.2%, favoring metformin (95% confidence interval -0.3% to +0.6%). Based on
7
these results, the trial did not meet its primary objective of showing a similar reduction in HbA1c
with AMARYL compared to metformin.

Table 2. Change from Baseline in HbA1C and Body Weight in Pediatric Patients Taking
Amaryl or Metformin
Metformin AMARYL
Treatment-Naïve Patients* N=69 N=72
HbA1C (%)
Baseline (mean) 8.2 8.3
Change from baseline (adjusted LS -1.2 -1.0
mean) +
Adjusted Treatment Difference** 0.2 (-0.3; 0.6)
(95%CI)
Previously Treated Patients* N=57 N=55
HbA1C (%)
Baseline (mean) 9.0 8.7
Change from baseline (adjusted LS -0.2 0.2
mean) +
Adjusted Treatment Difference** 0.4 (-0.4; 1.2)
(95%CI)
Body Weight (kg)* N=126 N=129
Baseline (mean) 67.3 66.5
Change from baseline (adjusted LS 0.7 2.0
mean)+
Adjusted Treatment Difference** 1.3 (0.3; 2.3)
(95% CI)
* Intent-to-treat population using last-observation-carried-forward for missing data (AMARYL, n=127; metformin,
n=126)
+ adjusted for baseline HbA1c and Tanner Stage
** Difference is AMARYL – metformin with positive differences favoring metformin

The profile of adverse reactions in pediatric patients treated with AMARYL was similar to that
observed in adults [see Adverse Reactions (6)].

Hypoglycemic events documented by blood glucose values <36 mg/dL were observed in 4% of
pediatric patients treated with AMARYL and in 1% of pediatric patients treated with metformin.
One patient in each treatment group experienced a severe hypoglycemic episode (severity was
determined by the investigator based on observed signs and symptoms).

8.5 Geriatric Use

In clinical trials of AMARYL, 1053 of 3491 patients (30%) were >65 years of age. No overall
differences in safety or effectiveness were observed between these patients and younger patients,
but greater sensitivity of some older individuals cannot be ruled out.

There were no significant differences in glimepiride pharmacokinetics between patients with type
2 diabetes 65 years (n=49) and those >65 years (n=42) [see Clinical Pharmacology (12.3)].

Glimepiride is substantially excreted by the kidney. Elderly patients are more likely to have
renal impairment. In addition, hypoglycemia may be difficult to recognize in the elderly [see
8
Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. Use caution when
initiating AMARYL and increasing the dose of AMARYL in this patient population.

8.6 Renal Impairment

To minimize the risk of hypoglycemia, the recommended starting dose of AMARYL is 1 mg
daily for all patients with type 2 diabetes and renal impairment [see Dosage and Administration
(2.1) and Warnings and Precautions (5.1)].

A multiple-dose titration study was conducted in 16 patients with type 2 diabetes and renal
impairment using doses ranging from 1 mg to 8 mg daily for 3 months. Baseline creatinine
clearance ranged from 10-60 mL/min. The pharmacokinetics of AMARYL were evaluated in the
multiple-dose titration study and the results were consistent with those observed in patients
enrolled in a single-dose study. In both studies, the relative total clearance of AMARYL
increased when kidney function was impaired. Both studies also demonstrated that the
elimination of the two major metabolites was reduced in patients with renal impairment [see
Clinical Pharmacology (12.3)].

10 OVERDOSAGE

An overdosage of AMARYL, as with other sulfonylureas, can produce severe hypoglycemia.

Mild episodes of hypoglycemia can be treated with oral glucose. Severe hypoglycemic reactions
constitute medical emergencies requiring immediate treatment. Severe hypoglycemia with coma,
seizure, or neurological impairment can be treated with glucagon or intravenous glucose.
Continued observation and additional carbohydrate intake may be necessary because
hypoglycemia may recur after apparent clinical recovery [see Warnings and Precautions (5.1)].

11 DESCRIPTION

AMARYL is an oral sulfonylurea that contains the active ingredient glimepiride. 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 (C24H34N4O5S) with a molecular
weight of 490.62. Glimepiride is a white to yellowish-white, crystalline, odorless to practically
odorless powder and is practically insoluble in water.

The structural formula is:

AMARYL tablets contain the active ingredient glimepiride and the following inactive
ingredients:
Lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, plividone 25000,
magnesium stearate.
In addition, AMARYL 1 mg tablets contain Red Ferric Oxide (E172), AMARYL 2 mg tablets
contain Yellow Ferric Oxide and Indigo Carmine Aluminum Lake (E312), AMARYL 3mg
tablets contain Yellow Ferric Oxide (E172) and AMARYL 4 mg tablets contain Indigo Carmine
Aluminum Lake (E312).
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic
beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma
membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the
release of insulin.

12.2 Pharmacodynamics
In healthy subjects, the time to reach maximal effect (minimum blood glucose concentrations)
was approximately 2-3 hours after single oral doses of AMARYL. The effects of AMARYL on
HbA1c, fasting plasma glucose, and post-prandial glucose have been assessed in clinical trials
[see Clinical Studies (14)].

12.3 Pharmacokinetics
Absorption: Studies with single oral doses of glimepiride in healthy subjects and with multiple
oral doses in patients with type 2 diabetes showed peak drug concentrations (Cmax) 2 to 3 hours
post-dose. When glimepiride was given with meals, the mean Cmax and AUC (area under the
curve) were decreased by 8% and 9%, respectively.

Glimepiride does not accumulate in serum following multiple dosing. The pharmacokinetics of
glimepiride does not differ between healthy subjects and patients with type 2 diabetes. Clearance
of glimepiride after oral administration does not change over the 1 mg to 8 mg dose range,
indicating linear pharmacokinetics.

In healthy subjects, the intra- and inter-individual variabilities of glimepiride pharmacokinetic

parameters were 15-23% and 24-29%, respectively.

Distribution: After intravenous dosing in healthy 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 intravenous or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative
(M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 is involved in the
biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several
cytosolic enzymes. M2 is inactive. In animals, M1 possesses about one-third of the
pharmacological activity of glimepiride, but it is unclear whether M1 results in clinically
meaningful effects on blood glucose in humans.

Excretion: When 14C-glimepiride was given orally to 3 healthy male subjects, approximately
60% of the total radioactivity was recovered in the urine in 7 days. M1 and M2 accounted for
80-90% of the radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was
approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total
radioactivity was recovered in feces. M1 and M2 accounted for about 70% (ratio of M1 to M2
was 1:3) of the radioactivity recovered in feces. No parent drug was recovered from urine or
feces. After intravenous dosing in patients, no significant biliary excretion of glimepiride or its
M1 metabolite was observed.

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Geriatric Patients: A comparison of glimepiride pharmacokinetics in patients with type 2
diabetes ≤65 years and those >65 years was evaluated in a multiple-dose study using AMARYL
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 approximately 13%
lower than that for the younger patients; the mean weight-adjusted clearance for the older
patients was approximately 11% higher than that for the younger 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 studies have been conducted to assess the effects of race on glimepiride
pharmacokinetics but in placebo-controlled trials of AMARYL in patients with type 2 diabetes,
the reduction in HbA1C was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics
(n = 63).

Renal Impairment: A single-dose, open-label study AMARYL 3 mg was administered to patients

with mild, moderate and severe renal impairment as estimated by creatinine clearance (CLcr):
Group I consisted of 5 patients with mild renal impairment (CLcr > 50 mL/min), Group II
consisted of 3 patients with moderate renal impairment (CLcr = 20-50 mL/min) and Group III
consisted of 7 patients with severe renal impairment (CLcr < 20 mL/min). Although, glimepiride
serum concentrations decreased with decreasing renal function, Group III had a 2.3-fold higher
mean AUC for M1 and an 8.6-fold higher mean AUC for M2 compared to corresponding mean
AUCs in Group I. 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 a percentage of dose decreased from 44.4% for Group I to 21.9% for Group II and
9.3% for Group III.

Hepatic Impairment: It is unknown whether there is an effect of hepatic impairment on

AMARYL pharmacokinetics because the pharmacokinetics of AMARYL has not been
adequately evaluated in patients with hepatic impairment.

Obese Patients: The pharmacokinetics of glimepiride and its metabolites were measured in a
single-dose study involving 28 patients with type 2 diabetes who either had normal body weight
or were morbidly obese. While the tmax, clearance, and volume of distribution of glimepiride in
the morbidly obese patients were similar to those in the normal weight group, the morbidly obese
had lower Cmax and AUC than those of normal body weight. The mean Cmax, AUC0-24, AUC0-∞
values of glimepiride in normal vs. morbidly obese patients were 547 ± 218 ng/mL vs. 410 ± 124
ng/mL, 3210 ± 1030 hours·ng/mL vs. 2820 ± 1110 hours·ng/mL and 4000 ± 1320 hours·ng/mL
vs. 3280 ± 1360 hours·ng/mL, respectively.

Drug Interactions:

Aspirin: In a randomized, double-blind, two-period, crossover study, healthy subjects were given
either placebo or aspirin 1 gram three times daily for a total treatment period of 5 days. On Day
4 of each study period, a single 1 mg dose of AMARYL was administered. The AMARYL doses

11
were separated by a 14-day washout period. Co-administration of aspirin and AMARYL resulted
in a 34% decrease in the mean glimepiride AUC and a 4% decrease in the mean glimepiride Cmax.

Colesevelam: Concomitant administration of colesevelam and glimepiride resulted in reductions

in glimepiride AUC0-∞ and Cmax of 18% and 8%, respectively. When glimepiride was
administered 4 hours prior to colesevelam, there was no significant change in glimepiride AUC0-
∞
or Cmax, -6% and 3%, respectively [see Dosage and Administration (2.1) and Drug Interactions
(7.4)].

Cimetidine and Ranitidine: In a randomized, open-label, 3-way crossover study, healthy subjects
received either a single 4 mg dose of AMARYL alone, AMARYL with ranitidine (150 mg twice
daily for 4 days; AMARYL was administered on Day 3), or AMARYL with cimetidine (800 mg
daily for 4 days; AMARYL was administered on Day 3). Co-administration of cimetidine or
ranitidine with a single 4 mg oral dose of AMARYL did not significantly alter the absorption and
disposition of glimepiride.

Propranolol: In a randomized, double-blind, two-period, crossover study, healthy subjects were

given either placebo or propranolol 40 mg three times daily for a total treatment period of 5 days.
On Day 4 or each study period, a single 2 mg dose of AMARYL was administered. The
AMARYL doses were separated by a 14-day washout period. Concomitant administration of
propranolol and AMARYL significantly increased glimepiride Cmax, AUC, and T 1/2 by 23%,
22%, and 15%, respectively, and decreased glimepiride CL/f by 18%. The recovery of M1 and
M2 from urine was not changed.

Warfarin: In an open-label, two-way, crossover study, healthy subjects received 4 mg of

AMARYL daily for 10 days. Single 25 mg doses of warfarin were administered 6 days before
starting AMARYL and on Day 4 of AMARYL administration. The concomitant administration
of AMARYL did not alter the pharmacokinetics of R- and S-warfarin enantiomers. No changes
were observed in warfarin plasma protein binding. AMARYL resulted in a 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 treatment
were 3.3% and 9.9%, respectively, and are unlikely to be clinically relevant.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies in rats at doses of up to 5000 parts per million (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 that was dose-related and was
thought to be the result of chronic pancreatic stimulation. No adenoma formation in mice was
observed at a dose of 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, and mouse
micronucleus test).

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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).

14 CLINICAL STUDIES

14.1 Monotherapy
A total of 304 patients with type 2 diabetes already treated with sulfonylurea therapy participated
in a 14-week, multicenter, randomized, double-blind, placebo-controlled trial evaluating the
safety and efficacy of AMARYL monotherapy. Patients discontinued their sulfonylurea therapy
then entered a 3-week placebo washout period followed by randomization into 1 of 4 treatment
groups: placebo (n=74), AMARYL 1 mg (n=78), AMARYL 4 mg (n=76) and AMARYL 8 mg
(n=76). All patients randomized to AMARYL started 1 mg daily. Patients randomized to
AMARYL 4 mg or 8 mg had blinded, forced titration of the AMARYL dose at weekly intervals,
first to 4 mg and then to 8 mg, as long as the dose was tolerated, until the randomized dose was
reached. Patients randomized to the 4 mg dose reached the assigned dose at Week 2. Patients
randomized to the 8 mg dose reached the assigned dose at Week 3. Once the randomized dose
level was reached, patients were to be maintained at that dose until Week 14. Approximately
66% of the placebo-treated patients completed the trial compared to 81% of patients treated with
glimepiride 1 mg and 92% of patients treated with glimepiride 4 mg or 8 mg. Compared to
placebo, treatment with AMARYL 1 mg, 4 mg and 8 mg daily provided statistically significant
improvements in HbA1C compared to placebo (Table 3).

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Table 3. 14-week Monotherapy Trial Comparing AMARYL to Placebo in Patients Previously
Treated With Sulfonylurea Therapya

Placebo AMARYL
(N=74) 1 mg (N=78) 4 mg (N=76) 8 mg (N=76)
HbA1C (%)
n=59 n=65 n=65 n=68
Baseline (mean) 8.0 7.9 7.9 8.0
Change from Baseline 1.5 0.3 -0.3 -0.4
(adjusted meanb)
Difference from Placebo -1.2* -1.8* -1.8*
(adjusted meanb) (-1.5, -0.8) (-2.1, -1.4) (-2.2, -1.5)
95% confidence interval
Mean Baseline Weight
(kg)
n=67 n=76 n=75 n=73
Baseline (mean) 85.7 84.3 86.1 85.5
Change from Baseline -2.3 -0.2 0.5 1.0
(adjusted meanb)
Difference from Placebo 2.0* 2.8* 3.2*
b
(adjusted mean ) (1.4, 2.7) (2.1, 3.5) (2.5, 4.0)
95% confidence interval
a
Intent-to-treat population using last observation on study
b
Least squares mean adjusted for baseline value
*p<0.001

A total of 249 patients who were treatment-naïve or who had received limited treatment with
antidiabetic therapy in the past were randomized to receive 22 weeks of treatment with either
AMARYL (n=123) or placebo (n=126) in a multicenter, randomized, double-blind, placebo-
controlled, dose-titration trial. The starting dose of AMARYL was 1 mg daily and was titrated
upward or downward at 2-week intervals to a goal FPG of 90-150 mg/dL. Blood glucose levels
for both FPG and PPG were analyzed in the laboratory. Following 10 weeks of dose adjustment,
patients were maintained at their optimal dose (1, 2, 3, 4, 6 or 8 mg) for the remaining 12 weeks
of the trial. Treatment with AMARYL provided statistically significant improvements in HbA1C
and FPG compared to placebo (Table 4).

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 Table 4. 22-Week Monotherapy Trial Comparing AMARYL to Placebo in
Patients Who Were Treatment-Naïve or Who Had No Recent Treatment with
Antidiabetic Therapya
Placebo (N=126) AMARYL (N=123)
HbA1C (%) n=97 n=106
Baseline (mean) 9.1 9.3
Change from Baseline (adjusted meanb) -1.1* -2.2*
Difference from Placebo (adjusted -1.1*
meanb) (-1.5, -0.8)
95% confidence interval
Body Weight (kg)
n=122 n=119
Baseline (mean) 86.5 87.1
Change from Baseline (adjusted meanb) -0.9 1.8
Difference from Placebo (adjusted
2.7
meanb)
(1.9, 3.6)
95% confidence interval
a
Intent to treat population using last observation on study
b
Least squares mean adjusted for baseline value
*p<0.0001

16 HOW SUPPLIED/STORAGE AND HANDLING

AMARYL tablets are available in the following strengths and package sizes:
1mg, 2mg, 3mg, 4mg.

Presentation
Each pack contains 30 tablets.

Storage
Do not store above 30C.

17 PATIENT COUNSELING INFORMATION

17.1 Information for Patients

Inform patients about the importance of adherence to dietary instructions, of a regular exercise
program, and of regular testing of blood glucose.

Inform patients about the potential side effects of AMARYL including hypoglycemia and weight
gain.

Explain the symptoms and treatment of hypoglycemia as well as conditions that predispose to
hypoglycemia. Patients should be informed that the ability to concentrate and react may be
impaired as a result of hypoglycemia. This may present a risk in situations where these abilities
are especially important, such as driving or operating other machinery.

Patients with diabetes should be advised to inform their healthcare provider if they are pregnant,
contemplating pregnancy, breastfeeding, or contemplating breastfeeding.
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MANUFACTURER

Sanofi S.p.A., Italy.

LICENSE HOLDER

Sanofi Aventis Israel ltd., P.O.B 8090, Netanya 4250499.

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