Glimepiride

Description

Glimepiride Tablets USP are an oral sulfonylurea formulation containing 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 comprises glimepiride along with several inactive ingredients, including lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer, povidone, and sodium starch glycolate.

Uses and Indications

Glimepiride Tablet USP is 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 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 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. In the event of such reactions, glimepiride should be promptly discontinued. Healthcare providers should assess for alternative causes, implement appropriate monitoring and treatment, and consider initiating a different diabetes management strategy.

Hemolytic Anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In these 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.

Lastly, while there is no conclusive evidence from clinical studies demonstrating macrovascular risk reduction with glimepiride or any other anti-diabetic medication, healthcare professionals should remain vigilant regarding the overall cardiovascular health of their patients.

Regular monitoring and patient education are crucial in managing these risks effectively.

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. Severe hypoglycemia can arise, particularly in at-risk populations such as the elderly and those with renal impairment, especially when glimepiride is used in conjunction with other anti-diabetic medications. It is essential to ensure proper patient selection, dosing, and instructions to mitigate this risk.

Hypersensitivity reactions have been reported in the postmarketing setting, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome. In such cases, glimepiride should be promptly discontinued, and appropriate monitoring and treatment should be instituted, along with alternative diabetes management strategies.

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 or any other anti-diabetic 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 may be managed with oral glucose, while severe reactions, which may present with 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 initial recovery.

In pediatric patients, the profile of adverse reactions associated with glimepiride is similar to that observed in adults. Clinical trials indicated that 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.

Elderly patients are more likely to experience renal impairment, and hypoglycemia may be more challenging to recognize in this population. Caution is advised when initiating or increasing the dose of glimepiride in elderly patients.

Drug Interactions

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

Pharmacodynamic Interactions

• Miconazole: The concomitant use of glimepiride and oral miconazole may lead to severe hypoglycemia. Close monitoring of blood glucose levels is recommended when these agents are used together.

Pharmacokinetic Interactions

• Cytochrome P450 2C9 Inhibitors and Inducers: Agents that inhibit or induce cytochrome P450 2C9 may alter the plasma concentrations of glimepiride, potentially impacting glycemic control. It is advisable to monitor blood glucose levels closely and consider dose adjustments of glimepiride as necessary.

• Colesevelam: 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. Monitoring of blood glucose is also recommended to ensure effective 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 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. 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 participants (1053 out of 3491 patients) were aged 65 years and 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. Therefore, caution is advised 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

There are no adequate and well-controlled studies of glimepiride in pregnant patients. Glimepiride is classified as Pregnancy Category C. In animal studies, while there was no increase in congenital anomalies, an increase in fetal deaths was observed in rats and rabbits at doses of glimepiride that were 50 times and 0.1 times the maximum recommended human dose, respectively, based on body surface area. This fetotoxicity, which occurred only at doses that induced maternal hypoglycemia, is believed to be directly related to the pharmacologic action of glimepiride and has been similarly noted with other sulfonylureas.

Glimepiride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is important to note that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities; therefore, diabetes treatment during pregnancy should aim to maintain blood glucose levels as close to normal as possible. Additionally, 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.

Lactation

It is not known whether glimepiride is excreted in human milk. However, during pre- and post-natal studies in rats, significant concentrations of glimepiride were detected in both breast milk and the serum of the pups. Offspring of rats exposed to high levels of glimepiride during pregnancy and lactation exhibited skeletal deformities, including shortening, thickening, and bending of the humerus during the postnatal period. These skeletal deformations were attributed to nursing from mothers exposed to glimepiride.

Given these animal data and the potential risk of hypoglycemia in a nursing infant, lactating mothers should carefully consider whether to discontinue breastfeeding or discontinue glimepiride therapy, weighing the importance of the medication to the mother against the potential risks to the infant.

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 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

Prolonged severe hypoglycemia has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery.

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 showed no evidence of carcinogenesis. In contrast, administration of glimepiride in mice for 24 months 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, equivalent to 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 found to be non-mutagenic in a comprehensive range 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 1,700 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

Postmarketing experience has identified several adverse reactions associated with the use of the product. These include hypoglycemia and weight gain. Additional adverse reactions reported encompass allergic skin reactions, liver enzyme elevations, hemolytic anemia, thrombocytopenia, pancreatitis, and visual disturbances.

Severe cases of hypoglycemia have been documented, with some instances necessitating hospitalization. Furthermore, reports of cardiovascular events have been noted in patients with pre-existing cardiovascular disease. Rare occurrences of hepatotoxicity have also been reported, including cases of cholestatic jaundice and hepatitis. Additionally, postmarketing reports have included instances of hypersensitivity reactions, such as anaphylaxis.

Patient Counseling

Patients should be informed about the critical importance of adhering to dietary instructions, maintaining a regular exercise program, and consistently testing their blood glucose levels. These practices are essential for effective management of their condition.

Healthcare providers should discuss the potential side effects associated with glimepiride, particularly the risks of hypoglycemia and weight gain. It is important to explain the symptoms of hypoglycemia, such as dizziness, sweating, and confusion, and to outline appropriate treatment measures, including the consumption of fast-acting carbohydrates. Additionally, patients should be made aware of conditions that may predispose them to hypoglycemia, such as irregular meal patterns or excessive physical activity.

Patients must be advised that hypoglycemia can impair their ability to concentrate and react, which poses a risk in situations requiring alertness, such as driving or operating machinery. It is crucial for patients to understand these risks and to take necessary precautions.

Furthermore, patients with diabetes should be encouraged to inform their healthcare provider if they are pregnant, contemplating pregnancy, breastfeeding, or considering breastfeeding. This information is vital for ensuring safe and effective management of their diabetes during these significant life stages.

Storage and Handling

The product is supplied in well-closed containers equipped with safety closures. It should be stored at a temperature range of 20º to 25ºC (68º to 77ºF), 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 the recognition and management of hypoglycemia while being informed about the potential risks and benefits of glimepiride, as well as alternative treatment options.

Postmarketing surveillance has identified 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 prior diagnosis of G6PD deficiency.

FDA Insert (PDF)

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

View full prescribing information (PDF)