Glimepiride

Description

Glimepiride tablets, USP are an oral sulfonylurea that contains the active ingredient glimepiride. Chemically, glimepiride is identified as 1-[[p-2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethylphenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea (C24H34N4O5S) with a molecular weight of 490.62. Glimepiride USP appears as a white or almost white powder and is practically insoluble in water. The tablets contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Additionally, the 1 mg strength contains ferric oxide red, the 2 mg strength contains ferric oxide yellow and FD&C blue No. 2, and the 4 mg strength contains FD&C blue No. 2.

Uses and Indications

Glimepiride is 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 mg or 2 mg administered once daily. Dosing may be increased in increments of 1 mg 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 1 mg starting dose and to titrate slowly to minimize the risk of adverse effects.

Contraindications

Use of this product is contraindicated in patients with a known hypersensitivity to glimepiride or any of its ingredients. Additionally, individuals with a hypersensitivity to sulfonamide derivatives should not use this product due to the potential for cross-reactivity.

Warnings and Precautions

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 individuals with renal impairment. Caution is also advised when glimepiride is used in conjunction with other anti-diabetic medications (5.1).

Hypersensitivity reactions have been reported in postmarketing surveillance, including anaphylaxis, angioedema, and Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, glimepiride should be discontinued immediately. Healthcare providers should assess for other potential causes of the reaction and consider alternative treatments for diabetes (5.2).

Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency may experience hemolytic anemia when treated with glimepiride. In such cases, it is advisable to consider a non-sulfonylurea alternative to mitigate this risk (5.3).

There is a potential increased risk of cardiovascular mortality associated with the use of sulfonylureas, including glimepiride. Healthcare professionals should inform patients about the risks, benefits, and available treatment alternatives (5.4). Additionally, it is important to note that there are no clinical studies that conclusively establish macrovascular risk reduction with glimepiride or any other anti-diabetic medication (5.5).

In summary, careful monitoring and patient education are essential to ensure the safe use of glimepiride, particularly regarding the risks of hypoglycemia and hypersensitivity reactions.

Side Effects

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

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. Hemolytic anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, and a non-sulfonylurea alternative should be contemplated in such cases. 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.

Additional adverse reactions 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, which constitutes a medical emergency requiring immediate treatment. Mild hypoglycemic episodes can be managed with oral glucose, while severe reactions may necessitate glucagon or intravenous glucose. Continuous observation and additional carbohydrate intake may be required, as hypoglycemia can recur after apparent clinical recovery.

In pediatric patients, the profile of adverse reactions appears 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. Notably, one patient in each treatment group experienced a severe hypoglycemic episode, as determined by the investigator based on observed signs and symptoms.

Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, it is recommended that glimepiride be discontinued at least two weeks prior to the expected delivery date. Neonates of women with gestational diabetes treated with sulfonylureas may face an increased risk of 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 such neonates, particularly with agents that have a prolonged half-life. Therefore, it is essential to observe newborns for symptoms of hypoglycemia and respiratory distress and manage them accordingly.

Drug Interactions

Severe hypoglycemia may occur when glimepiride is used concurrently with miconazole. It is advisable to monitor blood glucose levels closely in patients receiving this combination.

In terms of pharmacokinetic interactions, inhibitors and inducers of cytochrome P450 2C9 can significantly impact glycemic control by altering the plasma concentrations of glimepiride. Clinicians should consider adjusting the dosage of glimepiride based on the patient's response and glycemic control when such agents are introduced or discontinued.

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. Monitoring of glycemic levels is recommended to ensure adequate control during this combination therapy.

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 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 patients aged 8 to 17 years with type 2 diabetes. Treatment was initiated with 1 mg of glimepiride, which was subsequently titrated to doses of 2, 4, or 8 mg, with a mean final 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 receiving 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 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.

It is recommended that glimepiride be discontinued at least two weeks before the expected delivery date to mitigate risks associated with neonatal hypoglycemia. 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 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 of women with gestational diabetes treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may experience 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 crucial to observe newborns for symptoms of hypoglycemia and respiratory distress and manage them accordingly.

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 sections or statements regarding nursing mothers or lactation in the provided drug insert text. Therefore, the effects of this medication on lactating mothers and breastfed infants are not established. Healthcare professionals should consider the absence of data when advising lactating mothers on 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 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 can lead to severe hypoglycemia, necessitating prompt medical intervention. Healthcare professionals should be vigilant in recognizing the signs and symptoms of hypoglycemia, as the severity of the condition can vary significantly among patients.

In cases of mild hypoglycemia, treatment typically involves the administration of oral glucose. However, for patients experiencing severe hypoglycemic reactions, the use of glucagon or intravenous glucose may be required to restore normal blood glucose levels. It is crucial to monitor the patient closely following treatment, as hypoglycemia can recur even after an initial clinical recovery. Continued observation and the provision of additional carbohydrate intake may be necessary to ensure patient safety.

Particular attention should be given to at-risk populations, including the elderly and individuals with renal impairment, as these groups are more susceptible to severe hypoglycemic episodes. Regular monitoring and appropriate management strategies should be implemented to mitigate the risks associated with glimepiride overdosage in these patients.

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 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 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 assessments, 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. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Healthcare providers should explain to patients the symptoms and treatment of hypoglycemia, as well as the conditions that may predispose them to this condition. It is important for patients to understand 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.

Providers should inform patients that hypersensitivity reactions may occur with glimepiride. Patients should be advised to seek medical treatment and discontinue glimepiride if they experience any such reactions.

For females of reproductive potential, it is essential to advise them to inform their prescriber of any known or suspected pregnancy. Additionally, breastfeeding women taking glimepiride should be counseled to monitor their breastfed infants for signs of hypoglycemia, which may include jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, and seizures.

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° to 25°C (68° 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, particularly when initiating or increasing doses of glimepiride. Caution is advised for patients predisposed to hypoglycemia, including the elderly, those with renal impairment, and individuals on other anti-diabetic medications. Debilitated or malnourished patients, as well as those with adrenal, pituitary, or hepatic impairments, are especially vulnerable to the hypoglycemic effects of glucose-lowering agents. Additionally, early warning symptoms of hypoglycemia may be atypical or less pronounced in patients with autonomic neuropathy, the elderly, and those taking beta-adrenergic blockers 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. There have also been instances of hemolytic anemia in patients treated with glimepiride who did not have a known G6 PD deficiency.

FDA Insert (PDF)

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

View full prescribing information (PDF)