Glimepiride

Description

Glimepiride Tablets are an oral sulfonylurea formulation containing the active ingredient glimepiride. The chemical structure of glimepiride 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 g/mol.

Glimepiride appears as a white to yellowish-white, crystalline, odorless to practically odorless powder, which is practically insoluble in water. In addition to glimepiride, Glimepiride Tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer, povidone, and sodium starch glycolate.

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.

Important limitations of use include that Glimepiride is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Dosage and Administration

The recommended starting dose for the medication 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 efficacy. For patients identified as being 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 present as severe in certain populations. Healthcare professionals must ensure proper patient selection, dosing, and provide clear instructions, particularly for at-risk groups 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. In the event of such reactions, glimepiride should be discontinued immediately. Healthcare providers should assess for alternative causes, implement appropriate monitoring and treatment, and consider alternative diabetes management strategies.

Hemolytic Anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In these 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. It is essential for healthcare providers to inform patients about the associated risks, benefits, and available treatment alternatives.

Lastly, while glimepiride is used for glycemic control, there is currently no clinical evidence demonstrating a reduction in macrovascular outcomes with glimepiride or any other anti-diabetic medication. This lack of conclusive evidence should be communicated to patients as part of their treatment plan.

Healthcare professionals are encouraged to remain vigilant and proactive in monitoring patients for these warnings and to engage in shared decision-making regarding treatment options.

Side Effects

Patients receiving glimepiride may experience a range of adverse reactions, 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 such reactions, glimepiride should be promptly discontinued, and appropriate monitoring and treatment should be instituted, along with alternative diabetes management. Hemolytic anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, and a non-sulfonylurea alternative should be considered in these cases. Additionally, there is a potential increased risk of cardiovascular mortality associated with sulfonylureas, and patients should be informed of the risks, benefits, and treatment alternatives. It is important to note that no clinical studies have established conclusive 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, which may involve coma, seizure, or neurological impairment, may require 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 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.

Clinical trials indicate that elderly patients are more likely to have renal impairment, and hypoglycemia may be difficult to recognize in this population. Caution is advised when initiating or increasing the dose of glimepiride in elderly patients. Furthermore, 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 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.

Drug Interactions

Certain medications can significantly influence glucose metabolism, necessitating careful management of glimepiride therapy.

Pharmacodynamic Interactions Miconazole, when used concurrently with glimepiride, may lead to severe hypoglycemia. Therefore, it is imperative to monitor blood glucose levels closely in patients receiving both medications.

Pharmacokinetic Interactions Interactions involving cytochrome P450 2C9 can impact glycemic control by modifying glimepiride plasma concentrations. Both inhibitors and inducers of this enzyme should be used with caution, as they may necessitate adjustments in glimepiride dosing.

Additionally, the coadministration of colesevelam may reduce the absorption of glimepiride. To mitigate this interaction, glimepiride should be administered at least 4 hours prior to colesevelam. Regular monitoring of blood glucose levels is recommended to ensure optimal therapeutic outcomes.

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 final dose of 4 mg) through Week 12, aiming for a self-monitored fasting fingerstick blood glucose level of less than 126 mg/dL.

Hypoglycemic events, defined as blood glucose values below 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 particularly challenging to recognize in geriatric patients, increasing the risk of adverse events. Therefore, it is advised 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 recommended to ensure the safe use of glimepiride in elderly patients.

Pregnancy

Available data from a limited number of published studies and postmarketing experience with Glimepiride during pregnancy have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal outcomes. However, it is important to note that sulfonylureas, including Glimepiride, cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore, Glimepiride 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. It is associated with an increased maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. For the fetus, poorly controlled diabetes increases the risk for major birth defects, stillbirth, and macrosomia-related morbidity. The estimated background risk of major birth defects in women with pregestational diabetes and an HbA1c >7% is 6% to 10%, escalating to as high as 20% to 25% in those with an HbA1c >10%. The 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. Neonates born to women with gestational diabetes treated with sulfonylureas during pregnancy may face an increased risk of neonatal intensive care admission and may experience respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia lasting 4–10 days has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery.

Animal studies have shown no effects on embryo-fetal development following administration of Glimepiride to pregnant rats and rabbits at oral doses approximately 4000 times and 60 times the maximum human dose based on body surface area, respectively. However, fetotoxicity was observed in these studies at doses 50 times (rats) and 0.1 times (rabbits) the maximum human dose, with this fetotoxicity believed to be directly related to the pharmacologic (hypoglycemic) action of Glimepiride, as it occurred only at doses inducing maternal hypoglycemia.

Lactation

Breastfed infants of lactating mothers using Glimepiride should be monitored for symptoms of hypoglycemia, including jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, and seizures. It is not known whether Glimepiride is excreted in human milk, and there are no data on its effects on milk production. However, Glimepiride has been detected in rat milk, and during prenatal and postnatal studies in rats, significant concentrations of Glimepiride were found in both breast milk and the serum of the pups.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for Glimepiride and any potential adverse effects on the breastfed child. Notably, offspring of rats exposed to high levels of Glimepiride during pregnancy and lactation exhibited skeletal deformities, including shortening, thickening, and bending of the humerus, attributed to nursing from mothers exposed to the drug.

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.

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 for symptoms of hypoglycemia, which may range from mild to severe.

In cases of mild hypoglycemia, treatment can be effectively managed with the administration of oral glucose. However, severe hypoglycemic reactions are classified as medical emergencies and 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 approximately 46-54 mg/kg body weight/day, which is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.

Glimepiride was evaluated 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 assessments, and the mouse micronucleus test.

In terms of reproductive toxicity, glimepiride did not adversely affect male mouse fertility when administered at doses up to 2500 mg/kg body weight, which is over 1,700 times the maximum recommended human dose based on surface area. Similarly, no effects on fertility were observed in male and female rats given 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 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 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 advise patients that hypoglycemia may impair their ability to concentrate and react, which can pose risks in situations requiring full attention, such as driving or operating machinery. Patients should be encouraged to take precautions in these scenarios to ensure their safety and the safety of others.

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

Storage and Handling

The product is supplied in well-closed containers equipped with safety closures. It should be stored at a temperature of 25ºC (77ºF), with permissible excursions between 20ºC to 25ºC (68º to 77ºF), in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)