GLIMEPIRIDE tablet

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Active ingredient:
GLIMEPIRIDE (UNII: 6KY687524K) (GLIMEPIRIDE - UNII:6KY687524K)
Available from:
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Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Glimepiride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies ( 14.1)]. Limitations of Use Glimepiride tablets should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings. Glimepiride tablet 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 glimepiride. Do not use glimepiride in patients who have a history of an allergic reaction to sulfonamide derivatives. 8.1 Pregnancy Risk Summary Available data from a small number of published studies and postmarketing experience with glimepiride use in pregnancy over decades have not identified any drug associated risks for major birth defects,
Product summary:
Glimepiride tablets, USP are available in the following strengths and package sizes: 1 mg tablets (pink coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 1’ on one side and break line on the other) in bottles of 100 , 500 and 1,000 2 mg tablets (green coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 2’ on one side and break line on the other) in bottles of 100 , 500 and 1,000 4 mg tablets (blue coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 4’ on one side and break line on the other) in bottles of 100, 500 and 1,000 Store at 25°C (77°F); excursions permitted to 20°C to 25°C (68°F to 77°F) (see USP Controlled Room Temperature). Dispense in well-closed containers with safety closures.
Authorization status:
Abbreviated New Drug Application
Authorization number:
61919-448-30

GLIMEPIRIDE- glimepiride tablet

Direct_Rx

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GLIMEPIRIDE

Glimepiride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults

with type 2 diabetes mellitus [see Clinical Studies ( 14.1)].

Limitations of Use

Glimepiride tablets should not be used for the treatment of type 1 diabetes mellitus or diabetic

ketoacidosis, as it would not be effective in these settings.

2.1 Recommended Dosing

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

The recommended starting dose of glimepiride tablet 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

to 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 glimepiride from longer half-life sulfonylureas (e.g., chlorpropamide) may

have overlapping drug effect for 1 to 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, glimepiride should be administered at least 4 hours

prior to colesevelam.

Glimepiride tablets, USP are formulated as tablets of:

1 mg tablets (pink coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 1’ on one side

and break line on the other)

2 mg tablets (green coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 2’ on one

side and break line on the other)

4 mg tablets (blue coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 4’ on one side

and break line on the other)

Glimepiride tablet 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 glimepiride. Do not use glimepiride in patients who have a history

of an allergic reaction to sulfonamide derivatives.

5.1 Hypoglycemia

All sulfonylureas, including glimepiride, 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 glimepiride 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 glimepiride,

including serious reactions such as anaphylaxis, angioedema, and Stevens- Johnson Syndrome [ see

Adverse Reactions ( 6.2)]. If a hypersensitivity reaction is suspected, promptly discontinue glimepiride,

assess for other potential causes for the reaction, and institute alternative treatment for diabetes.

5.3 Hemolytic Anemia

Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD)

deficiency. Because glimepiride 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 glimepiride 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 and a half 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 glimepiride 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 glimepiride or any other anti-diabetic drug.

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)]

6.1 Clinical Trials Experience

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 glimepiride in the controlled clinical trials. In these trials, approximately 1,700

patients were treated with glimepiride for at least 1 year.In clinical trials, the most common adverse

reactions with glimepiride were hypoglycemia, dizziness, asthenia, headache, and nausea.

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 glimepiride-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 glimepiride-treated Patients and at a Greater

Incidence than with Placebo*

Glimepiride 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

* Glimepiride doses ranged from 1 to 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

glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 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 glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for

glimepiride 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 glimepiride or placebo daily. The dose of glimepiride was

titrated to a target fasting plasma glucose of 90 to 150 mg/dL. Final daily doses of glimepiride 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 glimepiride vs. placebo was 19.7% vs. 3.2%. All of these

events were self-treated.

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

Allergic Reactions: In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and

morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride- treated patients.

These may resolve despite continued treatment with glimepiride. 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 glimepiride,

1.9% of glimepiride-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 postapproval use of glimepiride. 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

7.1 Drugs Affecting Glucose Metabolism

A number of medications affect glucose metabolism and may require glimepiride 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 glimepiride, 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-inflammatory drugs, salicylates, sulfonamides,

chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications

are administered to a patient receiving glimepiride, monitor the patient closely for hypoglycemia. When

these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for

worsening glycemic control.

The following are examples of medications that may reduce the glucose-lowering effect of

sulfonylureas including glimepiride, 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 glimepiride, monitor the patient closely for worsening glycemic

control. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient

closely for hypoglycemia.

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

glucose-lowering effect.

Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of

glimepiride 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, absorption is not reduced when glimepiride is administered 4 hours

prior to colesevelam. Therefore, glimepiride should be administered at least 4 hours prior to

colesevelam.

8.1 Pregnancy

Risk Summary

Available data from a small number of published studies and postmarketing experience with glimepiride

use in pregnancy over decades have not identified any drug associated risks for major birth defects,

miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glimepiride) cross the

placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore,

glimepiride should be discontinued at least two weeks before expected delivery (see Clinical

Considerations). Poorly controlled diabetes in pregnancy is also associated with risks to the mother and

fetus (see Clinical Considerations). In animal studies (see Data), there were no effects on embryo-fetal

development following administration of glimepiride to pregnant rats and rabbits at oral doses

approximately 4000 times and 60 times the maximum human dose based on body surface area,

respectively. However, fetotoxicity was observed in rats and rabbits at doses 50 times and 0.1 times the

maximum human dose, respectively.

The estimated background risk of major birth defects is 6% to 10% in women with pregestational

diabetes with a HbA1c >7% and has been reported to be as high as 20% to 25% in women with a HbA1c

>10%. The estimated background risk of miscarriage for the indicated population is unknown. In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo-fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis,

preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled

diabetes increases the fetal risk for major birth defects, still birth, and macrosomia-related morbidity.

Fetal/neonatal adverse reactions

Neonates of women with gestational diabetes who are treated with sulfonylureas during pregnancy may

be at increased risk for neonatal intensive care admission and may develop respiratory distress,

hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4

to 10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of

delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for

symptoms of hypoglycemia and respiratory distress and manage accordingly.

Dose adjustments during pregnancy and the postpartum period

Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea

at the time of delivery, glimepiride should be discontinued at least two weeks before expected delivery

(see Fetal/Neonatal Adverse Reactions).

Data

Animal data

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 was observed only at doses inducing

maternal hypoglycemia and is believed to be directly related to the pharmacologic (hypoglycemic)

action of glimepiride, as has been similarly noted with other sulfonylureas.

8.2 Lactation

Risk Summary

Breastfed infants of lactating women using glimepiride should be monitored for symptoms of

hypoglycemia (see Clinical Considerations). It is not known whether glimepiride is excreted in human

milk and there are no data on the effects of glimepiride on milk production. Glimepiride is present in rat

milk [see Data]. The developmental and health benefits of breastfeeding should be considered along

with the mother's clinical need for glimepiride and any potential adverse effects on the breastfed child

from glimepiride or from the underlying maternal condition.

Clinical Considerations

Monitoring for adverse reactions

Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia,

excessive sleepiness, poor feeding, seizures).

Data

During prenatal and postnatal 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.

8.4 Pediatric Use

The pharmacokinetics, efficacy and safety of glimepiride have been evaluated in pediatric patients with

type 2 diabetes as described below. Glimepiride 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 glimepiride 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

nghr/mL), C max (102±48 ng/mL) and t 1/2 (3.1±1.7 hours) for glimepiride were comparable to

historical data from adults (AUC (0-last) 315±96 nghr/mL, C max 103±34 ng/mL and t 1/2 5.3±4.1

hours).

The safety and efficacy of glimepiride in pediatric patients was evaluated in a single-blind, 24-week

trial that randomized 272 patients (8 to 17 years of age) with type 2 diabetes to glimepiride (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. Glimepiride 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 glimepiride and metformin

was 0.2%, favoring metformin (95% confidence interval -0.3% to +0.6%).

Based on these results, the trial did not meet its primary objective of showing a similar reduction in

HbA1c with glimepiride compared to metformin.

Table 2: Change from Baseline in HbA1C and Body Weight in Pediatric Patients Taking Glimepiride or

Metformin

Intent-to-treat population using last-observation-carried-forward for missing data (Glimepiride, n=127;

metformin, n=126)

adjusted for baseline HbA 1c and Tanner Stage

Difference is Glimepiride – metformin with positive differences favoring metformin(95%CI)

Metformin Glimepiride

Treatment-Naïve Patients * N=69 N=72

HbA1C (%)

Baseline (mean) 8.2 8.3

Change from baseline (adjusted LS mean) † -1.2 -1.0

Adjusted Treatment Difference ‡ 0.2 (-0.3; 0.6)

Previously Treated Patients * N=57 N=55

HbA1C (%)

Baseline (mean)

Change from baseline (adjusted LS mean) †

-0.2 0.2

Adjusted Treatment Difference ‡ (95%CI) 0.4 (-0.4; 1.2)

Body Weight (kg) * N=126 N=129

Baseline (mean) 67.3 66.5

Change from baseline (adjusted LS mean) † 0.7 2.0

Adjusted Treatment Difference ‡ (95% CI) 1.3 (0.3; 2.3)

The profile of adverse reactions in pediatric patients treated with glimepiride 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 glimepiride 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 glimepiride, 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 Dosage and

Administration ( 2.1) and Warnings and Precautions ( 5.1)]. Use caution when initiating glimepiride and

increasing the dose of glimepiride in this patient population.

8.6 Renal Impairment

To minimize the risk of hypoglycemia, the recommended starting dose of glimepiride 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 to 60 mL/min. The pharmacokinetics of glimepiride was 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 glimepiride 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)].

An overdosage of glimepiride, 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) ]

Glimepiride 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-1carboxamido)

ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea (C 24H 34N 4O 5S) 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:

[Structure]

Glimepiride tablets, USP contain the active ingredient glimepiride and the following inactive

ingredients: lactose monohydrate, sodium starch glycolate, povidone, and magnesium stearate. In

addition, glimepiride tablets, USP 1 mg contain ferric oxide red, glimepiride tablets, USP 2 mg contain

ferric oxide yellow and FD &C blue #2 aluminum lake, and glimepiride tablets, USP 4 mg contain

FD&C blue #2 aluminum lake.

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 to 3 hours after single oral doses of glimepiride. The effects of glimepiride on

HbA1c, fasting plasma glucose, and postprandial 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 (C max) 2 to 3 hours postdose.

When glimepiride was given with meals, the mean C max 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 intraindividual and interindividual variabilities of glimepiride pharmacokinetic

parameters were 15% to 23% and 24% to 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% to 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.

Specific Populations

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 glimepiride 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 glimepiride 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:In a single-dose, open-label study glimepiride 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 to 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 (T 1/2) 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 glimepiride

pharmacokinetics because the pharmacokinetics of glimepiride 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 t max,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 C max

and AUC than those of normal body weight. The mean C max, AUC 0-24, AUC 0-∞ values of

glimepiride in normal vs. morbidly obese patients were 547 ± 218 ng/mL vs. 410 ± 124 ng/mL, 3210 ±

1030 hoursng/mL vs. 2820 ± 1110 hoursng/mL and 4000 ± 1320 hoursng/mL vs. 3280 ± 1360

hoursng/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 glimepiride was administered. The glimepiride doses were

separated by a 14-day washout period. Coadministration of aspirin and glimepiride resulted in a 34%

decrease in the mean glimepiride AUC and a 4% decrease in the mean glimepiride C max.

Colesevelam: Concomitant administration of colesevelam and glimepiride resulted in reductions in

glimepiride AUC 0-∞ and C max of 18% and 8%, respectively. When glimepiride was administered 4

hours prior to colesevelam, there was no significant change in glimepiride AUC 0-∞ or C max, -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 glimepiride alone, glimepiride with ranitidine (150 mg twice daily for 4

days; glimepiride was administered on Day 3), or glimepiride with cimetidine (800 mg daily for 4 days;

glimepiride was administered on Day 3). Co-administration of cimetidine or ranitidine with a single 4

mg oral dose of glimepiride 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

of each study period, a single 2 mg dose of glimepiride was administered. The glimepiride doses were

separated by a 14-day washout period. Concomitant administration of propranolol and glimepiride

significantly increased glimepiride C max, 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 glimepiride

daily for 10 days. Single 25 mg doses of warfarin were administered 6 days before starting glimepiride

and on Day 4 of glimepiride administration. The concomitant administration of glimepiride did not alter

the pharmacokinetics of R- and S-warfarin enantiomers. No changes were observed in warfarin plasma

protein binding. Glimepiride 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 glimepiride treatment were 3.3% and 9.9%, respectively, and are unlikely to be

clinically relevant.

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 to 54 mg/kg

body weight/day. This is at least 28 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).

There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body

weight (>1,500 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).

14.1 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 glimepiride 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),

glimepiride 1 mg (n=78), glimepiride 4 mg (n=76) and glimepiride 8 mg (n=76). All patients randomized

to glimepiride started 1 mg daily. Patients randomized to glimepiride 4 mg or 8 mg had blinded, forced

titration of the glimepiride 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 glimepiride 1 mg, 4 mg and 8 mg daily provided statistically significant

improvements in HbA1C compared to placebo (Table 3).

Table 3: 14-week Monotherapy Trial Comparing Glimepiride to Placebo in Patients Previously Treated

With Sulfonylurea Therapy a

Placebo

(N=74) Glimepiride

1 mg (N=78) 4 mg (N=76) 8 mg (N=76)

HbA 1C (%)

n=59 n=65 n=65 n=68

Baseline (mean) 8.0 7.9 7.9 8.0

Change from Baseline

(adjusted mean b) 1.5 0.3 -0.3 -0.4

Difference from Placebo

(adjusted mean b) -1.2*

(-1.5, -0.8) -1.8*

(-2.1, -1.4) -1.8*

(-2.2, -1.5)

Mean Baseline Weight

n=67 n=76 n=75 n=73

Baseline (mean) 85.7 84.3 86.1 85.5

Change from Baseline

(adjusted mean b) -2.3 -0.2 0.5 1.0

Difference from Placebo

(adjusted mean b) 2.0*

(1.4, 2.7) 2.8*

(2.1, 3.5) 3.2*

(2.5, 4.0)

aIntent-to-treat population using last observation on study

bLeast 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 glimepiride (n=123) or

placebo (n=126) in a multicenter, randomized, double-blind, placebo-controlled, dose-titration trial. The

starting dose of glimepiride was 1 mg daily and was titrated upward or downward at 2-week intervals to

a goal FPG of 90 to 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 glimepiride provided

statistically significant improvements in HbA1C and FPG compared to placebo (Table 4).

Table 4: 22-Week Monotherapy Trial Comparing Glimepiride to Placebo in Patients Who Were

Treatment-Naïve or Who Had No Recent Treatment with Antidiabetic Therapy a

Placebo (N=126) Glimepiride (N=123)

HbA 1C (%)

n=97 n=106

Baseline (mean) 9.1 9.3

Change from Baseline (adjusted mean b) -1.1* -2.2*

Difference from Placebo (adjusted mean b)

95% confidence interval -1.1*

(-1.5, -0.8)

Body Weight (kg)

n=122 n=119

Baseline (mean) 86.5 87.1

Change from Baseline (adjusted mean b)

-0.9 1.8

Difference from Placebo (adjusted mean b)

95% confidence interval 2.7

(1.9, 3.6)

aIntent to treat population using last observation on study

b Least squares mean adjusted for baseline value

* p ≤0.0001

Glimepiride tablets, USP are available in the following strengths and package sizes:

1 mg tablets (pink coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 1’ on one side

and break line on the other) in bottles of 100 , 500 and 1,000

2 mg tablets (green coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 2’ on one

side and break line on the other) in bottles of 100 , 500 and 1,000

4 mg tablets (blue coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 4’ on one side

and break line on the other) in bottles of 100, 500 and 1,000

Store at 25°C (77°F); excursions permitted to 20°C to 25°C (68°F to 77°F) (see USP Controlled Room

Temperature).

Dispense in well-closed containers with safety closures.

Hypoglycemia

Explain the symptoms and treatment of hypoglycemia as well as conditions that predispose to

hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result of

hypoglycemia and that this may present a risk in situations where these abilities are especially important,

such as driving or operating other machinery [see Warnings and Precautions (5.1)].

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions may occur with glimepiride and that if a reaction occurs

to seek medical treatment and discontinue glimepiride [see Warnings and Precautions (5.2)].

Pregnancy

Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy

[see Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding women taking glimepiride to monitor breastfed infants for signs of hypoglycemia

(e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures) [see Use in

Specific Populations (8.2)].

Manufactured For:

Accord Healthcare, Inc.,

1009 Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Ahmedabad -380 054, India.

10 1677 2 693003

Issued February 2019

GLIMEPIRIDE

glimepiride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 19 19 -448 (NDC:16 729 -0 0 2)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

GLIMEPIRIDE (UNII: 6 KY6 8 7524K) (GLIMEPIRIDE - UNII:6 KY6 8 7524K)

GLIMEPIRIDE

2 mg

Inactive Ingredients

Ingredient Name

Stre ng th

Dire ct_Rx

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO VIDO NE (UNII: FZ9 8 9 GH9 4E)

Product Characteristics

Color

gre e n

S core

2 pieces

S hap e

OVAL

S iz e

10 mm

Flavor

Imprint Code

AHI;2

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 19 19 -448 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 8 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 18 1

0 8 /0 8 /20 19

Labeler -

Direct_Rx (079254320)

Registrant -

Direct_Rx (079254320)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dire c t_Rx

0 79 254320

re pa c k(6 19 19 -448 )

Revised: 1/2020

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