Glimepiride

Description

Glimepiride tablets USP are an oral sulfonylurea formulation containing the active ingredient glimepiride USP. The chemical structure of glimepiride USP is defined as 1-[[p-2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethylphenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea, with a molecular formula of C24H34N4O5S and a molecular weight of 490.62.

The active ingredient appears as a white to almost white powder, exhibiting solubility in dimethyl formamide, sparing solubility in methylene chloride, and is practically insoluble in water. Glimepiride tablets comply with USP drug release test 2 standards.

Each tablet formulation includes inactive ingredients such as lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Additionally, the 1 mg tablet variant contains ferric oxide red, the 2 mg tablet variant incorporates lake blend green (comprising D&C yellow #10 aluminum lake and FD&C blue #1/brilliant blue FCF aluminum lake), and the 4 mg tablet variant features lake blend blue (also containing D&C yellow #10 aluminum lake and FD&C blue #1/brilliant blue FCF aluminum lake).

Uses and Indications

Glimepiride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of use include that glimepiride is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. There are no teratogenic or nonteratogenic effects associated with glimepiride.

Dosage and Administration

The recommended starting dose is 1 or 2 mg administered once daily. Dosing may be increased in increments of 1 or 2 mg, but such adjustments should not occur more frequently than every 1 to 2 weeks, and should be based on the patient's glycemic response. The maximum recommended dose is 8 mg once daily.

Administration should occur with breakfast or the first meal of the day to optimize absorption and efficacy. In patients who are at increased risk for hypoglycemia, such as the elderly or those with renal impairment, it is advised to initiate treatment with a starting dose of 1 mg and to titrate slowly to minimize the risk of adverse effects.

Contraindications

Use of this product is contraindicated in patients with hypersensitivity to glimepiride or any of its ingredients. Additionally, it is contraindicated in individuals with hypersensitivity to sulfonamide derivatives due to the potential for cross-reactivity and adverse reactions.

Warnings and Precautions

Patients using glimepiride should be closely monitored for several critical safety concerns.

Hypoglycemia is a significant risk associated with glimepiride, which may be severe. Healthcare professionals must ensure proper patient selection, dosing, and provide clear instructions, particularly for at-risk populations such as the elderly and those with renal impairment. Caution is also advised when glimepiride is used in conjunction with other anti-diabetic medications.

Hypersensitivity Reactions have been reported in postmarketing surveillance, including severe cases such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, glimepiride should be discontinued immediately. The healthcare provider should assess for other potential causes of the reaction and consider alternative treatments for diabetes.

Hemolytic Anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In such cases, it is advisable to consider a non-sulfonylurea alternative to mitigate this risk.

There is a Potential Increased Risk of Cardiovascular Mortality associated with the use of sulfonylureas, including glimepiride. It is essential for healthcare providers to inform patients about the risks, benefits, and available treatment alternatives.

Regarding Macrovascular Outcomes, it is important to note that there are no clinical studies that establish conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic medication.

Healthcare professionals should remain vigilant and provide comprehensive patient education regarding these warnings and precautions to ensure safe and effective use of glimepiride.

Side Effects

Patients receiving glimepiride may experience a range of adverse reactions, which can be categorized into common and serious events.

Common adverse reactions include hypoglycemia, which may be severe and necessitates careful patient selection, dosing, and instructions, particularly for at-risk populations such as the elderly and those with renal impairment, as well as when used in conjunction with other anti-diabetic medications. Other common reactions reported include headache, nausea, and dizziness.

Serious adverse reactions have been documented, including hypersensitivity reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. In the event of a suspected hypersensitivity reaction, glimepiride should be promptly discontinued, and alternative diabetes treatments should be considered after assessing for other potential causes. Hemolytic anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, and such patients should be considered for non-sulfonylurea alternatives. Additionally, there is a potential increased risk of cardiovascular mortality associated with sulfonylureas, and patients should be informed of the risks, benefits, and available treatment alternatives. It is important to note that no clinical studies have conclusively established evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug.

In clinical trials, hypoglycemic events, defined by blood glucose values less than 36 mg/dL, were observed in 4% of pediatric patients treated with glimepiride, compared to 1% in those treated with metformin. Severe hypoglycemic episodes were reported in one patient from each treatment group, with severity assessed by the investigator based on observed signs and symptoms.

Patients should also be aware of the potential for severe hypoglycemia in cases of overdosage, which can occur with glimepiride and other sulfonylureas. Mild hypoglycemic episodes can typically be managed with oral glucose, while severe reactions represent medical emergencies requiring immediate intervention. Severe hypoglycemia may lead to coma, seizure, or neurological impairment, necessitating treatment with glucagon or intravenous glucose, along with continued observation and additional carbohydrate intake, as hypoglycemia may recur after initial recovery.

Drug Interactions

Certain medications may influence glucose metabolism, necessitating careful dose adjustments and monitoring for glimepiride tablets.

Pharmacodynamic Interactions Miconazole has been identified to cause severe hypoglycemia when used concurrently with glimepiride. Therefore, it is crucial to monitor blood glucose levels closely in patients receiving both medications.

Pharmacokinetic Interactions Interactions involving cytochrome P450 2C9 can significantly impact glycemic control. Both inhibitors and inducers of this enzyme may alter the plasma concentrations of glimepiride, which could necessitate dosage adjustments based on the patient's glycemic response.

Additionally, the coadministration of colesevelam may lead to a reduction in the absorption of glimepiride. To mitigate this interaction, glimepiride should be administered at least 4 hours prior to colesevelam. This timing is essential to ensure optimal therapeutic efficacy of glimepiride.

Packaging & NDC

The table below lists all NDC Code configurations of Glimepiride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Glimepiride tablets are not recommended for use in pediatric patients due to concerns regarding adverse effects on body weight and the risk of hypoglycemia. The pharmacokinetics of a single 1 mg dose of glimepiride was assessed in a study involving 30 patients aged 10 to 17 years with type 2 diabetes.

In a single-blind, 24-week trial, the safety and efficacy of glimepiride were evaluated in 272 pediatric patients aged 8 to 17 years, who were randomized to receive either glimepiride or metformin. Glimepiride was initiated at a dose of 1 mg, with titration to 2, 4, or 8 mg (mean final dose of 4 mg) by Week 12.

Hypoglycemic events, defined by blood glucose values of less than 36 mg/dL, were reported in 4% of pediatric patients treated with glimepiride, compared to 1% in those receiving metformin. Additionally, one patient in each treatment group experienced a severe hypoglycemic episode, as determined by the investigator based on observed signs and symptoms.

Geriatric Use

In clinical trials involving glimepiride, 30% of the 3,491 participants were elderly patients aged 65 years and older. While no overall differences in safety or effectiveness were observed between these geriatric patients and their younger counterparts, it is important to note that greater sensitivity to the medication may be present in some older individuals.

Pharmacokinetic studies have shown no significant differences in the metabolism of glimepiride between patients with type 2 diabetes aged 65 years or younger and those older than 65 years. However, glimepiride is primarily excreted by the kidneys, and elderly patients are more likely to experience renal impairment, which may necessitate careful monitoring and potential dose adjustments.

Additionally, hypoglycemia can be particularly challenging to recognize in elderly patients, increasing the risk of adverse effects. Therefore, it is recommended to exercise caution when initiating therapy with glimepiride or when increasing the dosage in this population. Regular monitoring for signs of hypoglycemia and renal function is advised to ensure the safe use of glimepiride in geriatric patients.

Pregnancy

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 the expected delivery to mitigate these risks.

Poorly controlled diabetes in pregnancy poses significant risks to both the mother and fetus. The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes and an HbA1c >7%, escalating to as high as 20% to 25% in those with an HbA1c >10%. The estimated background risk of miscarriage for this population remains 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.

Poorly controlled diabetes increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Additionally, it heightens the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Neonates of women with gestational diabetes 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. Therefore, it is essential to observe newborns for symptoms of hypoglycemia and respiratory distress and manage them accordingly.

In animal studies, there was no increase in congenital anomalies; however, 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.

Lactation

There is no specific information available regarding the use of glimepiride in lactating mothers or its effects on breast milk. The potential for excretion of glimepiride in breast milk has not been established. Therefore, caution should be exercised when administering glimepiride to nursing mothers.

Renal Impairment

Patients with renal impairment may experience severe hypoglycemia. It is essential to ensure proper patient selection, dosing, and instructions, particularly in at-risk populations such as the elderly and those with reduced kidney function. Caution should be exercised when this medication is used in conjunction with other anti-diabetic medications to mitigate the risk of hypoglycemia. Regular monitoring of blood glucose levels is recommended to ensure patient safety and effective management.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

An overdosage of glimepiride tablets, similar to other sulfonylureas, can lead to significant hypoglycemia. Healthcare professionals should be vigilant in recognizing the symptoms associated with this condition.

In cases of mild hypoglycemia, treatment can be effectively managed with the administration of oral glucose. However, severe hypoglycemic reactions represent medical emergencies that necessitate immediate intervention.

For patients experiencing severe hypoglycemia accompanied by coma, seizures, or neurological impairment, treatment options include the administration of glucagon or intravenous glucose. It is crucial to monitor the patient closely following initial treatment, as hypoglycemia may recur even after apparent clinical recovery. Continued observation and the provision of additional carbohydrate intake may be required to ensure the patient's safety and stability.

Nonclinical Toxicology

Studies conducted in rats at doses of up to 5000 parts per million (ppm) in complete feed, which is approximately 340 times the maximum recommended human dose based on surface area, for a duration of 30 months, demonstrated no evidence of carcinogenesis. In contrast, administration of glimepiride in mice over a 24-month period resulted in a dose-related increase in the formation of benign pancreatic adenomas, attributed to chronic pancreatic stimulation. Notably, no adenoma formation was observed in mice at a dose of 320 ppm in complete feed, equating to 46 to 54 mg/kg body weight/day, which is at least 28 times the maximum human recommended dose of 8 mg once daily based on surface area.

Glimepiride was assessed for mutagenicity and was found to be non-mutagenic in a comprehensive array of in vitro and in vivo mutagenicity studies, including the Ames test, somatic cell mutation assays, chromosomal aberration tests, unscheduled DNA synthesis evaluations, and the mouse micronucleus test.

Furthermore, glimepiride did not adversely affect male mouse fertility in animals exposed to doses up to 2,500 mg/kg body weight, which is over 1,500 times the maximum recommended human dose based on surface area. Similarly, no effects on fertility were observed in male and female rats administered doses of up to 4,000 mg/kg body weight, approximately 4,000 times the maximum recommended human dose based on surface area.

Postmarketing Experience

No specific postmarketing experience details have been reported. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Patients should be informed about the symptoms and treatment of hypoglycemia, as well as the conditions that may predispose them to this condition. It is essential for healthcare providers to explain how to recognize the signs of hypoglycemia and the appropriate steps to take if they experience these symptoms.

Healthcare providers should also advise patients that hypoglycemia can impair their ability to concentrate and react, which may pose risks in situations where these abilities are critical, such as driving or operating machinery. Patients should be made aware of the importance of monitoring their blood sugar levels and recognizing when they may need to take action to prevent hypoglycemia.

Additionally, patients should be informed about the potential for hypersensitivity reactions associated with glimepiride. They should be advised to seek medical treatment immediately if they experience any signs of a hypersensitivity reaction and to discontinue the use of glimepiride if such a reaction occurs.

Storage and Handling

The product is supplied in well-closed containers equipped with safety closures. It should be stored at a temperature range of 20°-25°C (68°-77°F), in accordance with USP Controlled Room Temperature guidelines. Proper handling and storage conditions are essential to maintain the integrity of the product.

Additional Clinical Information

Patients should be educated on recognizing and managing hypoglycemia, as early warning symptoms may vary or be less pronounced in individuals with autonomic neuropathy, the elderly, and those taking beta-adrenergic blocking medications or other sympatholytic agents.

Postmarketing experience has revealed reports of hypersensitivity reactions associated with glimepiride, including serious conditions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. Additionally, there have been reports of hemolytic anemia in patients receiving glimepiride who did not have a known G6PD deficiency.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Glimepiride as submitted by Dr. Reddy's Laboratories Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)