Gliperide

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Gliperide uses


1 INDICATIONS AND USAGE

Gliperide tablets USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies ].

Gliperide is a sulfonylurea indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus ( 1.1).

Important Limitations of Use:

1.1 Important Limitations of Use

Gliperide tablets USP 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

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

The recommended starting dose of Gliperide tablets 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 Gliperide tablets 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 Gliperide, maximum plasma concentration and total exposure to Gliperide is reduced. Therefore, Gliperide tablets should be administered at least 4 hours prior to colesevelam.

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3 DOSAGE FORMS AND STRENGTHS

Gliperide is formulated as tablets of:


Tablets (scored): 1 mg, 2 mg, 3 mg, 4 mg, 6 mg and 8 mg ( 3)

4 CONTRAINDICATIONS

Gliperide tablets are contraindicated in patients with a history of a hypersensitivity reaction to:


Sulfonamide derivatives: Patients who have developed an allergic reaction to sulfonamide derivatives may develop an allergic reaction to Gliperide. Do not use Gliperide 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) ].

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5 WARNINGS AND PRECAUTIONS

5.1 Hypoglycemia

All sulfonylureas, including Gliperide, 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 Gliperide 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 Gliperide, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue Gliperide, 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 deficiency. Because Gliperide 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 Gliperide 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 to 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 Gliperide 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 Gliperide or any other anti-diabetic drug.

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6 ADVERSE REACTIONS

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


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

Common adverse reactions in clinical trials (≥5% and more common than with placebo) include hypoglycemia, headache, nausea, and dizziness


( 6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 Gliperide in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with Gliperide 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 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 *


Gliperide N=745 %

Placebo N=294 %

Headache

8.2

7.8

Accidental Injury

5.8

3.4

Flu Syndrome

5.4

4.4

Nausea

5

3.4

Dizziness

5

2.4

* Gliperide 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 Gliperide 1 mg, 4 mg, 8 mg or placebo. Patients randomized to Gliperide 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated . 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 Gliperide 1 mg, 17% for Gliperide 4 mg, 16% for Gliperide 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 Gliperide or placebo daily. The dose of Gliperide was titrated to a target fasting plasma glucose of 90 to 150 mg/dL. Final daily doses of Gliperide were 1, 2, 3, 4, 6 or 8 mg . The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for Gliperide vs. placebo was 19.7% vs. 3.2%. All of these events were self-treated.

Weight gain: Gliperide, 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 Gliperide. 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 Gliperide, 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 post-approval use of Gliperide. 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.

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7 DRUG INTERACTIONS

7.1 Drugs Affecting Glucose Metabolism

A number of medications affect glucose metabolism and may require Gliperide 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 Gliperide, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H 2 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 Gliperide, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving Gliperide, monitor the patient closely for worsening glycemic control.

The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including Gliperide, 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 Gliperide, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving Gliperide, 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 Gliperide 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 Gliperide and inhibitors and inducers (e.g., rifampin) of cytochrome P450 2C9. Fluconazole may inhibit the metabolism of Gliperide, causing increased plasma concentrations of Gliperide which may lead to hypoglycemia. Rifampin may induce the metabolism of Gliperide, causing decreased plasma concentrations of Gliperide which may lead to worsening glycemic control.

7.4 Concomitant Administration of Colesevelam

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Gliperide 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 Gliperide 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 Gliperide and has been similarly noted with other sulfonylureas. Gliperide 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 Gliperide is excreted in human milk. During pre- and post-natal studies in rats, significant concentrations of Gliperide were present in breast milk and the serum of the pups. Offspring of rats exposed to high levels of Gliperide 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 Gliperide. 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 Gliperide, taking into account the importance of Gliperide to the mother.

8.4 Pediatric Use

The pharmacokinetics, efficacy and safety of Gliperide have been evaluated in pediatric patients with type 2 diabetes as described below. Gliperide 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 Gliperide was evaluated in 30 patients with type 2 diabetes between ages 10 and 17 years. The mean (± SD) AUC (0 to last) (339±203 ng -hr/mL), C max (102±48 ng/mL) and t 1/2 (3.1±1.7 hours) for Gliperide were comparable to historical data from adults (AUC (0 to last) 315±96 ng -hr/mL, C max 103±34 ng/mL and t 1/2 5.3±4.1 hours).

The safety and efficacy of Gliperide 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 Gliperide (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. Gliperide 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 Gliperide 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 Gliperide compared to metformin.

Table 2. Change from Baseline in HbA 1C and Body Weight in Pediatric Patients Taking Gliperide or Metformin


Metformin

Gliperide

Treatment-Naïve Patients *

N=69

N=72

HbA 1C (%)


Baseline (mean)

8.2

8.3

Change from baseline (adjusted LS mean) +

-1.2

-1

Adjusted Treatment Difference ** (95%CI)

0.2 (-0.3; 0.6)


Previously Treated Patients *

N=57

N=55

HbA 1C (%)



Baseline (mean)

9

8.7

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

Adjusted Treatment Difference ** (95% CI)

1.3 (0.3; 2.3)


* 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 Gliperide – metformin with positive differences favoring metformin


The profile of adverse reactions in pediatric patients treated with Gliperide 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 Gliperide 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 Gliperide, 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 Gliperide pharmacokinetics between patients with type 2 diabetes ­ ≤65 years (n=49) and those >65 years (n=42) [see Clinical Pharmacology (12.3) ].


Gliperide 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 Gliperide and increasing the dose of Gliperide in this patient population.

8.6 Renal Impairment

To minimize the risk of hypoglycemia, the recommended starting dose of Gliperide 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 Gliperide 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 Gliperide 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 Gliperide, 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

Glimepiride tablets, USP are an oral sulfonylurea that contains the active ingredient Gliperide. Chemically, Gliperide is identified as 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea (C 24H 34N 4O 5S) with a molecular weight of 490.62. Gliperide USP is a white to almost white, crystalline, odorless to practically odorless powder and is practically insoluble in water.

The structural formula is:

Glimepiride tablets, USP contain the active ingredient Gliperide and the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate and sodium starch glycolate. In addition, Gliperide 1 mg tablets contain Ferric Oxide Red, Gliperide 2 mg tablets contain FD&C Blue #2 Indigo carmine Lake and Ferric Oxide Yellow, Gliperide 3 mg tablets contain Ferric Oxide Yellow, Gliperide 4 mg tablets contain FD&C Blue #2 Indigo carmine Lake and Gliperide 6 mg tablets contain Ferric Oxide Red.

Gliperide structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Gliperide 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 was approximately 2 to 3 hours after single oral doses of Gliperide. The effects of Gliperide on HbA 1c, fasting plasma glucose, and post-prandial glucose have been assessed in clinical trials .

12.3 Pharmacokinetics

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

Gliperide does not accumulate in serum following multiple dosing. The pharmacokinetics of Gliperide does not differ between healthy subjects and patients with type 2 diabetes. Clearance of Gliperide 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 Gliperide 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: Gliperide 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 Gliperide 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 Gliperide, 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 Gliperide or its M1 metabolite was observed.

Geriatric Patients: A comparison of Gliperide pharmacokinetics in patients with type 2 diabetes ≤65 years and those >65 years was evaluated in a multiple-dose study using Gliperide 6 mg daily. There were no significant differences in Gliperide 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 Gliperide when adjustment was made for differences in body weight.

Race: No studies have been conducted to assess the effects of race on Gliperide pharmacokinetics but in placebo-controlled trials of Gliperide in patients with type 2 diabetes, the reduction in HbA 1C was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).

Renal Impairment: A single-dose, open-label study Gliperide 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, Gliperide 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 Gliperide 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 Gliperide pharmacokinetics because the pharmacokinetics of Gliperide has not been adequately evaluated in patients with hepatic impairment.

Obese Patients: The pharmacokinetics of Gliperide 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 Gliperide 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 to 24, AUC 0 to ∞ values of Gliperide 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 Gliperide was administered. The Gliperide doses were separated by a 14-day washout period. Co-administration of aspirin and Gliperide resulted in a 34% decrease in the mean Gliperide AUC and a 4% decrease in the mean Gliperide C max.

Colesevelam: Conconmitant administration of colesevelam and Gliperide resulted in reductions in Gliperide AUC 0to∞ and C max of 18% and 8%, respectively. When Gliperide was administered 4 hours prior to colesevelam, there was no significant change in Gliperide AUC 0to∞ 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 Gliperide alone, Gliperide with ranitidine (150 mg twice daily for 4 days; Gliperide was administered on Day 3), or Gliperide with cimetidine (800 mg daily for 4 days; Gliperide was administered on Day 3). Co-administration of cimetidine or ranitidine with a single 4 mg oral dose of Gliperide did not significantly alter the absorption and disposition of Gliperide.

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 Gliperide was administered. The Gliperide doses were separated by a 14-day washout period. Concomitant administration of propranolol and Gliperide significantly increased Gliperide C max, AUC, and T 1/2 by 23%, 22%, and 15%, respectively, and decreased Gliperide 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 Gliperide daily for 10 days. Single 25 mg doses of warfarin were administered 6 days before starting Gliperide and on Day 4 of Gliperide administration. The concomitant administration of Gliperide did not alter the pharmacokinetics of R- and S-warfarin enantiomers. No changes were observed in warfarin plasma protein binding. Gliperide 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 Gliperide 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 Gliperide 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 about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.

Gliperide 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 Gliperide 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). Gliperide 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 Gliperide 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), Gliperide 1 mg (n=78), Gliperide 4 mg (n=76) and Gliperide 8 mg (n=76). All patients randomized to Gliperide started 1 mg daily. Patients randomized to Gliperide 4 mg or 8 mg had blinded, forced titration of the Gliperide 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 Gliperide 1 mg and 92% of patients treated with Gliperide 4 mg or 8 mg. Compared to placebo, treatment with Gliperide 1 mg, 4 mg and 8 mg daily provided statistically significant improvements in HbA 1C compared to placebo (Table 3).


Table 3. 14-week Monotherapy Trial Comparing Gliperide to Placebo in Patients Previously Treated With Sulfonylurea Therapy a



Placebo (N=74)


Gliperide


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


7.9


7.9


8


Change from Baseline (adjusted mean b)


1.5


0.3


-0.3


-0.4


Difference from Placebo (adjusted mean b) 95% confidence interval



-1.2 * (-1.5, -0.8)


-1.8 * (-2.1, -1.4)


1.8 * (-2.2, -1.5)


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 (adjusted mean b)


-2.3


-0.2


0.5


1


Difference from Placebo (adjusted mean b) 95% confidence interval



2 * (1.4, 2.7)


2.8 * (2.1, 3.5)


3.2 * (2.5, 4)


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 Gliperide (n=123) or placebo (n=126) in a multicenter, randomized, double-blind, placebo-controlled, dose-titration trial. The starting dose of Gliperide 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 Gliperide provided statistically significant improvements in HbA 1C and FPG compared to placebo (Table 4).

Table 4. 22-Week Monotherapy Trial Comparing Gliperide to Placebo in Patients Who Were Treatment-Naïve or Who Had No Recent Treatment with Antidiabetic Therapy a


Placebo (N=126)

Gliperide (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)


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

Gliperide Tablets USP are available in the following strengths and package sizes:


Bottles of 100 (NDC 42571-100-01)

Bottles of 500 (NDC 42571-100-05)


Bottles of 100 (NDC 42571-101-01)

Bottles of 500 (NDC 42571-101-05)


Bottles of 100 (NDC 42571-102-01)

Bottles of 500 (NDC 42571-102-05)


Bottles of 100 (NDC 42571-103-01)

Bottles of 500 (NDC 42571-103-05)


Bottles of 100 (NDC 42571-104-01)

Bottles of 500 (NDC 42571-104-05)


Bottles of 100 (NDC 42571-105-01)

Bottles of 500 (NDC 42571-105-05)

Store at 20° to 25°C (68° to 77°F)

Dispense in well-closed containers with safety closures.

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 Gliperide 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.

Made in India


Manufactured for:

Micro Labs USA Inc.

Princeton, NJ 08540


Revised: 12/2016

Micro Labs Limited Container Labels

NDC 42571-100-01

Gliperide

TABLETS, USP

1 mg

ONCE A DAY

Rx Only

100 Tablets

NDC 42571-101-01

Gliperide

TABLETS, USP

2 mg

ONCE A DAY

Rx Only

100 Tablets


NDC 42571-102-01

Gliperide

TABLETS, USP

3 mg

ONCE A DAY

Rx Only

100 Tablets


NDC 42571-103-01

Gliperide

TABLETS, USP

4 mg

ONCE A DAY

Rx Only

100 Tablets


NDC 42571-104-01

Gliperide

TABLETS, USP

6 mg

ONCE A DAY

Rx Only

100 Tablets


NDC 42571-105-01

Gliperide

TABLETS, USP

8 mg

ONCE A DAY

Rx Only

100 Tablets

RA CHEM PHARMA LIMITED Container Labels


NDC 42571-100-01

Gliperide

TABLETS, USP

1 mg

ONCE A DAY

Rx Only

100 Tablets



NDC 42571-101-01

Gliperide

TABLETS, USP

2 mg

ONCE A DAY

Rx Only

100 Tablets

NDC 42571-103-01

Gliperide

TABLETS, USP

4 mg

ONCE A DAY

Rx Only

100 Tablets

Gliperide pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Gliperide available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Gliperide destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Gliperide Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Gliperide pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."GLIMEPIRIDE (GLIMEPIRIDE) TABLET [MICRO LABS LIMITED]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."GLIMEPIRIDE; PIOGLITAZONE HYDROCHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "glimepiride". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Gliperide?

Depending on the reaction of the Gliperide after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Gliperide not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Gliperide addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Gliperide, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Gliperide consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

One visitor reported price estimates

What is your opinion about drug cost? Did you feel the cost is apt, or did you feel it is expensive?
The report given by the sdrugs.com website users shows the following figures about several people who felt the medicine Gliperide is expensive, and the medicine is not expensive. The results are mixed. The perception of the cost of the medicine to be expensive or not depends on the brand name of the medicine, country, and place where it is sold, and the affordability of the patient. You can choose a generic drug in the place of the branded drug to save the cost. The efficiency of the medicine will not vary if it is generic or a branded one.
Visitors%
Expensive1
100.0%

Two visitors reported frequency of use

How often in a day do you take the medicine?
Are you taking the Gliperide drug as prescribed by the doctor?

Few medications can be taken Twice in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sdrugs.com website users about the frequency of taking the drug Gliperide is mentioned below.
Visitors%
Twice in a day1
50.0%
Once in a day1
50.0%

One visitor reported doses

What is the dose of Gliperide drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 1-5mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
1-5mg1
100.0%

One visitor reported time for results

What is the time duration Gliperide drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sdrugs.com website users needed > 3 month to notice the result from using Gliperide drug. The time needed to show improvement in health condition after using the medicine Gliperide need not be same for all the users. It varies based on other factors.
Visitors%
> 3 month1
100.0%

Visitor reported administration

No survey data has been collected yet

One visitor reported age

Visitors%
> 601
100.0%

Visitor reviews


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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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