Glimepiride

Description

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

Glimepiride appears as a white to yellowish-white, crystalline, odorless to practically odorless powder, which is practically insoluble in water. Each tablet formulation includes glimepiride along with several inactive ingredients: lactose monohydrate, polysorbate 80, sodium starch glycolate, povidone, microcrystalline cellulose, and magnesium stearate. Additionally, the 1 mg tablet formulation contains Ferric Oxide Red, while the 2 mg tablet formulation includes Ferric Oxide Yellow.

Uses and Indications

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

Limitations of use include the fact 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 glycemic control. 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.

Warnings and Precautions

Patients using glimepiride tablets should be closely monitored for several critical warnings and precautions to ensure safe and effective treatment.

Hypoglycemia Severe hypoglycemia may occur, necessitating careful patient selection, appropriate dosing, and 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 Postmarketing surveillance has reported hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, glimepiride tablets should be discontinued immediately. Healthcare professionals should assess for other potential causes of the reaction and consider alternative diabetes treatments.

Hemolytic Anemia Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency may experience hemolytic anemia. In such cases, it is advisable to consider a non-sulfonylurea alternative to glimepiride.

Cardiovascular Risks There is a potential increased risk of cardiovascular mortality associated with sulfonylureas. Healthcare providers should inform patients about the risks, benefits, and available treatment alternatives.

Macrovascular Outcomes Currently, there are no clinical studies that provide conclusive evidence of macrovascular risk reduction with glimepiride tablets or any other antidiabetic medications. This should be communicated to patients as part of their treatment plan.

In summary, healthcare professionals must remain vigilant regarding these warnings and ensure that patients are adequately informed and monitored throughout their treatment with glimepiride tablets.

Side Effects

Common adverse reactions observed in patients include hypoglycemia, headache, nausea, and dizziness.

Serious adverse reactions may occur, with hypoglycemia being a notable concern, as it can be severe. Proper patient selection, dosing, and instructions are essential, particularly for at-risk populations such as the elderly and those with renal impairment, as well as when glimepiride is used in conjunction with other anti-diabetic medications.

Hypersensitivity reactions have been reported in the postmarketing setting, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, glimepiride tablets should be promptly discontinued, and alternative diabetes treatments should be considered after assessing for other potential causes of the reaction.

Hemolytic anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, and a non-sulfonylurea alternative should be considered in such cases. Additionally, there is a potential increased risk of cardiovascular mortality associated with sulfonylureas, necessitating that patients are informed of the risks, benefits, and available treatment alternatives. It is important to note that no clinical studies have established conclusive evidence of macrovascular risk reduction with glimepiride tablets or any other antidiabetic drug.

Other important considerations include hypersensitivity to glimepiride or any of its ingredients, as well as hypersensitivity to sulfonamide derivatives. Overdosage of glimepiride, similar to other sulfonylureas, can lead to severe hypoglycemia. Mild hypoglycemic episodes can be managed with oral glucose, while severe reactions, which may involve coma, seizure, or neurological impairment, require immediate medical intervention with glucagon or intravenous glucose. Continuous observation and additional carbohydrate intake may be necessary, as hypoglycemia can recur after apparent clinical recovery.

In pediatric patients, the profile of adverse reactions associated with glimepiride is similar to that observed in adults. Hypoglycemic events, defined by blood glucose values below 36 mg/dL, were documented 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.

For geriatric patients, greater sensitivity to glimepiride cannot be ruled out, and caution is advised when initiating or increasing the dose in this population.

Pregnant women with gestational diabetes treated with sulfonylureas may have neonates at increased risk for complications, including neonatal intensive care admission, respiratory distress, hypoglycemia, birth injury, and being large for gestational age. Prolonged severe hypoglycemia lasting 4 to 10 days has been reported in neonates born to mothers who received a sulfonylurea at the time of delivery.

Drug Interactions

Certain medications may influence glucose metabolism, necessitating careful management of glimepiride tablets. Close monitoring of blood glucose levels is advised, particularly when glimepiride is used in conjunction with other agents.

Pharmacodynamic Interactions

• Miconazole: The concomitant use of glimepiride tablets and oral miconazole has been associated with a risk of severe hypoglycemia. Patients should be monitored closely for signs of hypoglycemia and dosage adjustments may be required.

Pharmacokinetic Interactions

• Cytochrome P450 2C9 Inhibitors and Inducers: Medications that inhibit or induce cytochrome P450 2C9 can significantly alter glimepiride plasma concentrations, potentially impacting glycemic control. It is recommended that patients' blood glucose levels be monitored more frequently when initiating or discontinuing such agents.

• Colesevelam: The coadministration of colesevelam may lead to reduced absorption of glimepiride. To mitigate this interaction, glimepiride tablets should be administered at least 4 hours prior to colesevelam. Monitoring of blood glucose levels is also advisable in this scenario to ensure adequate glycemic control.

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 is not recommended for use in pediatric patients due to its adverse effects on body weight and the risk of hypoglycemia. The pharmacokinetics of a 1 mg single 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 patients aged 8 to 17 years, who were randomized to receive either glimepiride (n=135) or metformin (n=137). Glimepiride was initiated at a dose of 1 mg, with titration to 2, 4, or 8 mg (mean last dose of 4 mg) by Week 12. Notably, hypoglycemic events, defined as blood glucose values <36 mg/dL, were reported in 4% of pediatric patients treated with glimepiride.

Geriatric Use

In clinical trials involving glimepiride, 30% of the participants (1053 out of 3491 patients) were aged 65 years or older. While no overall differences in safety or effectiveness were observed between elderly 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 (n=49) and those older than 65 years (n=42). 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 more challenging to recognize in geriatric 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 elderly patients.

Pregnancy

Available data from a small number of published studies and postmarketing experience with glimepiride tablets used during pregnancy 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 date 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 in women with pre-gestational diabetes and an HbA1c greater than 7% is between 6% to 10%, and this risk can increase to as high as 20% to 25% in women with an HbA1c greater than 10%. The estimated background risk of miscarriage in 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 during pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Additionally, it elevates the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Neonates born to women with gestational diabetes who are treated with sulfonylureas during pregnancy may face an increased risk of neonatal intensive care admission and may develop respiratory distress, hypoglycemia, birth injury, and be classified as 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.

In animal studies, glimepiride did not increase the incidence of congenital anomalies; however, an increase in fetal deaths was observed in rats and rabbits at doses significantly higher than the maximum recommended human dose. This fetotoxicity was noted only at doses that induced maternal hypoglycemia and is believed to be directly related to the pharmacologic action of glimepiride.

Lactation

There are no specific statements regarding the use of this medication in lactating mothers or its effects on breastfed infants. Healthcare professionals should consider the absence of data when advising lactating mothers about the use of this medication.

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

Management of Mild Hypoglycemia In cases of mild hypoglycemia, treatment can be effectively managed with the administration of oral glucose. It is essential to monitor the patient closely to ensure that blood glucose levels return to a safe range.

Management of Severe Hypoglycemia Severe hypoglycemic reactions are classified as medical emergencies and necessitate immediate intervention. In instances where the patient presents with severe hypoglycemia accompanied by coma, seizures, or neurological impairment, treatment options include the administration of glucagon or intravenous glucose.

Post-Treatment Considerations Following initial treatment, continued observation of the patient is crucial, as hypoglycemia may recur even after apparent clinical recovery. Additional carbohydrate intake may be required to stabilize blood glucose levels and prevent further episodes.

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 benign pancreatic adenoma formation, attributed to chronic pancreatic stimulation. Notably, no adenoma formation was observed in mice at a dose of 320 ppm in complete feed, equating to 46–54 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 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, there was no observed effect of glimepiride on male mouse fertility in animals exposed to doses up to 2500 mg/kg body weight, which exceeds 1,500 times the maximum recommended human dose based on surface area. Similarly, glimepiride did not affect the fertility of male and female rats administered doses up to 4000 mg/kg body weight, approximately 4,000 times the maximum recommended human dose based on surface area.

Postmarketing Experience

No specific postmarketing experience details are available in the extracted data. As such, there are no reported adverse events or case reports to summarize.

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 patients to recognize the signs of hypoglycemia, which can include dizziness, sweating, confusion, and palpitations, and to understand the appropriate steps to take if they experience these symptoms.

Healthcare providers should emphasize that hypoglycemia can impair a patient's 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 advised to exercise caution in these scenarios and to monitor their blood glucose levels regularly.

Additionally, patients should be made aware that hypersensitivity reactions may occur with glimepiride tablets. They should be instructed to seek medical treatment immediately if they experience any signs of an allergic reaction, such as rash, itching, or difficulty breathing, and to discontinue the use of glimepiride tablets in such cases.

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°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy 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 those with autonomic neuropathy, the elderly, and individuals taking beta-adrenergic blocking medications or other sympatholytic agents. It is important for patients to be informed about the potential risks and benefits of glimepiride, as well as alternative treatment options.

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 treated with 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 Florida Pharmaceutical Products, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)