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 g/mol. The substance appears as a white to yellowish-white, crystalline, odorless to practically odorless powder and is practically insoluble in water.

Glimepiride tablets USP contain glimepiride along with the following inactive ingredients: lactose monohydrate, polysorbate 80, sodium starch glycolate, povidone, microcrystalline cellulose, and magnesium stearate. The 1 mg tablets also contain Ferric Oxide Red, while the 2 mg tablets contain 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 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

Severe hypoglycemia may occur with glimepiride tablets, necessitating careful patient selection, appropriate dosing, and clear instructions, particularly for populations at increased risk, such as the elderly and those with renal impairment. Caution is advised when glimepiride is used in conjunction with other anti-diabetic medications, as this may further elevate the risk of hypoglycemic events.

Hypersensitivity reactions have been reported in postmarketing surveillance, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome. Should a hypersensitivity reaction be suspected, glimepiride tablets must be discontinued immediately. Healthcare professionals should evaluate the patient for alternative causes of the reaction and consider instituting a different treatment for diabetes.

Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency may be at risk for hemolytic anemia when using glimepiride. In such cases, it is advisable to consider non-sulfonylurea alternatives to mitigate this risk.

There is a potential increased risk of cardiovascular mortality associated with the use of sulfonylureas, including glimepiride. Healthcare providers should ensure that patients are informed about the risks, benefits, and available treatment alternatives.

It is important to note that there are no clinical studies demonstrating conclusive evidence of macrovascular risk reduction with glimepiride tablets or any other antidiabetic medication. Therefore, healthcare professionals should remain vigilant regarding the overall cardiovascular health of patients receiving this treatment.

Side Effects

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

Common adverse reactions include hypoglycemia, headache, nausea, and dizziness. These reactions are frequently reported among participants in clinical trials and may vary in severity.

Serious adverse reactions warrant careful consideration and monitoring. Hypoglycemia can be severe, particularly in 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 postmarketing experiences, 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.

Hemolytic anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, and a non-sulfonylurea alternative should be considered for these individuals. 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 conclusively established 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. Severe hypoglycemia can result from an overdose of glimepiride, constituting a medical emergency that requires immediate treatment. Mild hypoglycemic episodes may be managed with oral glucose, while severe cases involving coma, seizure, or neurological impairment may necessitate glucagon or intravenous glucose administration. Continuous observation and additional carbohydrate intake may be required, as hypoglycemia can recur after initial 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.

For geriatric patients, greater sensitivity to glimepiride cannot be ruled out, and caution is advised when initiating or increasing the dose in this population, as hypoglycemia may be difficult to recognize in older individuals.

During pregnancy, glimepiride tablets should be discontinued at least two weeks prior to the expected delivery date due to the risk of neonatal adverse reactions, including hypoglycemia. Neonates born to mothers treated with sulfonylureas during pregnancy may face increased risks of 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 receiving sulfonylureas at the time of delivery.

Drug Interactions

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

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 monitor for changes in glycemic control.

Coadministration of colesevelam may lead to a reduction in the absorption of glimepiride. To mitigate this interaction, glimepiride tablets should be administered at least 4 hours prior to colesevelam. Monitoring of glycemic levels is recommended to ensure adequate 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 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, 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 final dose of 4 mg) by Week 12. Hypoglycemic events, defined as blood glucose values <36 mg/dL, were reported in 4% of pediatric patients treated with glimepiride, compared to 1% in those treated with metformin.

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.

It is recommended that glimepiride tablets be discontinued at least two weeks before the expected delivery date to mitigate potential 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 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 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 essential 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

Glimepiride tablets should be discontinued at least two weeks before expected delivery due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery. Lactating mothers who have been treated with sulfonylureas during pregnancy may have neonates at increased risk for neonatal intensive care admission. These infants may also develop respiratory distress, hypoglycemia, birth injury, and may be large for gestational age.

Healthcare professionals should observe breastfed infants for symptoms of hypoglycemia and respiratory distress, managing these conditions as necessary.

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 can lead to severe hypoglycemia, necessitating immediate medical intervention. Healthcare professionals should be vigilant in recognizing the symptoms associated with hypoglycemia, which may include confusion, dizziness, sweating, and palpitations.

For mild episodes of hypoglycemia, treatment can be effectively managed with the administration of oral glucose. However, in cases of severe hypoglycemia, more aggressive measures are required, such as the administration of glucagon or intravenous glucose. It is crucial to monitor the patient closely following treatment, as hypoglycemia may recur even after an initial clinical recovery. Continued observation and additional carbohydrate intake may be necessary to ensure the patient's safety and stability.

Particular attention should be given to at-risk populations, including the elderly and individuals with renal impairment, as they are more susceptible to severe hypoglycemic events. Regular monitoring and prompt intervention in these groups are essential to mitigate the risks associated with glimepiride overdosage.

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 stimulation of the pancreas. 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 assessments, and the mouse micronucleus test. Furthermore, glimepiride did not adversely affect male mouse fertility in animals exposed to doses of up to 2500 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 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 have been reported. 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 tablets. Patients should be advised to seek medical treatment and discontinue the medication if any hypersensitivity reaction occurs.

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 tablets 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°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, 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)