LAVIDA

Glimepiride tablets

USP, are an oral sulfonylurea that contains the active ingredient glimepiride USP.

Chemically, glimepiride USP 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 24 H 34 N 4 O 5 S) with a molecular weight of 490.62.

USP is a white to almost white powder, soluble in dimethyl formamide, sparingly soluble in methylene chloride, practically insoluble in water.

The structural formula is

Glimepiride tablets meets USP drug release test 2.

USP, contain the active ingredient glimepiride USP and the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate.

In addition, glimepiride 1 mg tablets contain ferric oxide red, glimepiride 2 mg tablets contain lake blend green (contains D&C yellow # 10 aluminium lake and FD&C blue #1/ brilliant blue FCF aluminium lake) and glimepiride 4 mg tablets contain lake blend blue (contains D&C yellow # 10 aluminium lake and FD&C blue # 1/ brilliant blue FCF aluminium lake).

The Glymbraid drug is used for the treatment of type II diabetes, the non-insulin-dependent type, together with a healthy diet and exercise.

The case of glympirid may increase the body's fluid retention, increase the heart failure, increase the risk of serious heart disease and exacerbate its symptoms, but the lack of treatment for diabetes may also lead to heart and other organ diseases.

Pure blood degradation, also called vatomy, is called the case of glucose deficiency, is a case of bone weakness and fragility, where the treatment may increase the risk of fractures in the bones, in which case the body may not respond to insulin treatment.

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 to 3 hours after single oral doses of glimepiride tablets.

The effects of glimepiride on

HbA 1c, fasting plasma glucose, and postprandial glucose have been assessed in clinical trials. 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.

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%.

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).

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.

When 14 C-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.

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 tablets 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.

There were no differences between males and females in the pharmacokinetics of glimepiride when adjustment was made for differences in body weight.

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 HbA 1C was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).

In a single-dose, open-label study glimepiride tablets 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.

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.

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.

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 hours·ng/mL vs. 2820 ± 1110 hours·ng/mL and 4000 ± 1320 hours·ng/mL vs. 3280 ± 1360 hours·ng/mL, respectively.

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 of each study period, a single 1 mg dose of glimepiride tablets was administered.

The glimepiride tablets 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.

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.

In a randomized, open-label, 3-way crossover study, healthy subjects received either a single 4 mg dose of glimepiride tablets 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 tablets did not significantly alter the absorption and disposition of glimepiride.

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 of each study period, a single 2 mg dose of glimepiride tablets was administered.

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.

In an open-label, two-way, crossover study, healthy subjects received 4 mg of glimepiride tablets daily for 10 days.

Single 25 mg doses of warfarin were administered 6 days before starting glimepiride and on Day 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.

Glimepiride is a drug from the sulfonyl urea group, which is used to reduce blood sugar in second type diabetes patients by stimulating the release of insulin from beta cells in the pancreas, where the second type of diabetes releases the body, but with less than the body needs, or the insulin is not working properly.

The drug starts to reduce blood sugar nearly an hour after the dose.

Do you have questions related to this subject? Ask Sina, artificial intelligence to answer all your medical questions.

The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling: Hypoglycemia Hemolytic anemia In clinical trials, the most common adverse reactions with glimepiride 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.

To report SUSPECTED ADVERSE

REACTIONS, contact Dr. Reddy’s Laboratories, Inc.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 glimepiride in the controlled clinical trials.

In these trials, approximately 1,700 patients were treated with glimepiride 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.

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 doses ranged from to 16 mg administered daily Glimepiride N=745 % Placebo N=294 % Headache 8.2 7.8 Accidental Injury Insufficient information to determine whether any of the accidental injury events were associated with hypoglycemia 5.8 3.4 Flu Syndrome 5.4 4.4 Nausea 5 3.4 Dizziness 5 2.4 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 tablets 1 mg, 4 mg, 8 mg or placebo.

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

The dose of glimepiride tablets was titrated to a target fasting plasma glucose of to 150 mg/dL.

Final daily doses of glimepiride tablets were 1, 2, 3, 4, 6 or 8 mg.

The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride vs. placebo was 19.7% vs. 3.2%.

Weight gain

Glimepiride, like all sulfonylureas, can cause weight gain.

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) .

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 Hemolytic anemia in patients with and without G6PD deficiency 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.

An overdosage of glimepiride tablets, 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.

Glimepiride tablets are contraindicated in patients with a history of a hypersensitivity reaction to: Glimepiride or any of the product’s ingredients.

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.

Hypersensitivity to glimepiride or any of the product’s ingredients Hypersensitivity to sulfonamide derivatives.

Recommended starting dose is 1 or 2 mg once daily.

Increase in 1 or 2 mg increments no more frequently than every to 2 weeks based on glycemic response.

Maximum recommended dose is 8 mg once daily.

Administer with breakfast or first meal of the day.

Use 1 mg starting dose and titrate slowly in patients at increased risk for hypoglycemia (e.g., elderly, patients with renal impairment) . 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 tablets are 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.

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 to 2 weeks.

A conservative titration scheme is recommended for patients at increased risk for hypoglycemia.

The maximum recommended dose is 8 mg once daily.

Patients being transferred to glimepiride tablets from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 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 tablets should be administered at least 4 hours prior to colesevelam.

Glimepiride tablets

USP, are available in the following strengths and package sizes: Glimepiride tablets USP, 1 mg are peach, oval, flat beveled edged, uncoated tablets debossed “RDY” on one side and “320” separating “3” and “20” with bisect line scoring on the other side and are supplied in: Unit dose packages of 30 (5 x 6) NDC 68084-788-25 Glimepiride tablets USP, 2 mg are green, oval, flat beveled edged, uncoated tablets debossed “RDY” on one side and “321” separating “3” and “21” with bisect line scoring on the other side and are supplied in: Unit dose packages of 100 (10 x 10) NDC 68084-326-01 Glimepiride tablets USP, 4 mg are blue, oval, flat beveled edged, uncoated tablets debossed “RDY” on one side and “322” separating “3” and “22” with bisect line scoring on the other side and are supplied in: Unit dose packages of 100 (10 x 10) NDC 68084-327-01 Store at 20°-25°C (68°-77°F) .

Do not use if blister is torn or broken.

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 tablets should be discontinued at least two weeks before expected delivery.

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

In animal studies, there were no effects on embryo-fetal development following administration of glimepiride to pregnant rats and rabbits at oral doses approximately 4,000 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 HbA 1c >7% and has been reported to be as high as 20% to 25% in women with a HbA 1c >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.

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 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 tablets should be discontinued at least two weeks before expected delivery.

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.

The pharmacokinetics, efficacy and safety of glimepiride have been evaluated in pediatric patients with type 2 diabetes as described below.

Glimepiride tablets are 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 and 17 years.

The mean (± SD) AUC (0-last) (339±203 ng•hr/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 ng•hr/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 HbA 1c 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 HbA 1c with glimepiride compared to metformin.

Table 2.

Change from Baseline in

HbA 1C and Body Weight in Pediatric Patients Taking Glimepiride or Metformin Metformin Glimepiride Treatment-Naïve Patients Intent-to-treat population using last-observation-carried-forward for missing data (Glimepiride, n=127; metformin, n=126) N=69 N=72 HbA 1C (%) Baseline (mean) 8.2 8.3 Change from baseline (adjusted LS mean) adjusted for baseline HbA1c and Tanner Stage -1.2 -1 Adjusted Treatment Difference Difference is glimepiride – metformin with positive differences favoring metformin (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) The profile of adverse reactions in pediatric patients treated with glimepiride was similar to that observed in adults.

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).

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) .

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.

Use caution when initiating glimepiride and increasing the dose of glimepiride tablets in this patient population.