Glimepiride

Description

Glimepiride tablets USP are an oral sulfonylurea formulation containing the active ingredient glimepiride USP. The chemical structure of glimepiride USP is identified 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.

The compound appears as a white to yellowish-white, crystalline, odorless to practically odorless powder, which is practically insoluble in water. Glimepiride tablets meet the USP drug release test 2 standards.

Each tablet formulation includes the active ingredient glimepiride USP along with the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Specific tablet strengths contain additional colorants: glimepiride 1 mg tablets include ferric oxide red; glimepiride 2 mg tablets contain a lake blend green (comprising D&C yellow #10 aluminum lake and FD&C blue #1/brilliant blue FCF aluminum lake); and glimepiride 4 mg tablets contain a lake blend blue (also comprising D&C yellow #10 aluminum lake and FD&C blue #1/brilliant blue FCF aluminum lake).

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. There are no teratogenic or nonteratogenic effects associated with this medication.

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 absorption and efficacy. 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 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

Common adverse reactions observed in patients include hypoglycemia, which may be severe, necessitating 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 include hypersensitivity reactions, with postmarketing reports indicating occurrences of 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. 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, 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. Severe hypoglycemia can result from an overdose of glimepiride tablets, similar to other sulfonylureas. Mild hypoglycemic episodes may be managed with oral glucose, while severe reactions represent medical emergencies requiring immediate intervention. Severe hypoglycemia that leads to coma, seizure, or neurological impairment may necessitate treatment with glucagon or intravenous glucose, with continued observation and additional carbohydrate intake recommended due to the possibility of recurrence.

In pediatric patients, the profile of adverse reactions associated with glimepiride was found to be 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.

In geriatric patients, caution is advised when initiating or increasing the dose of glimepiride, as this population may exhibit greater sensitivity and a higher likelihood of renal impairment. Furthermore, hypoglycemia may be more challenging to recognize in elderly patients.

Drug Interactions

Certain medications may influence glucose metabolism, necessitating careful management of glimepiride dosage and vigilant monitoring of blood glucose levels.

Pharmacodynamic Interactions

• Miconazole: The concomitant use of glimepiride and oral miconazole can lead to severe hypoglycemia. Close monitoring of blood glucose is advised 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 recommended to monitor blood glucose levels closely and adjust the glimepiride dosage as necessary.

• Colesevelam: The coadministration of colesevelam may decrease the absorption of glimepiride. To mitigate this interaction, glimepiride should be administered at least 4 hours prior to colesevelam. Monitoring of blood glucose levels is also recommended in this scenario 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 tablets are not recommended for use in pediatric patients due to concerns regarding 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 pediatric patients aged 8 to 17 years, who were randomized to receive either glimepiride (n=135) or metformin (n=137). Glimepiride treatment 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. These findings underscore the need for caution when considering glimepiride for pediatric patients.

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. Therefore, caution is advised when initiating therapy with glimepiride or when increasing the dosage in this population. Regular monitoring of blood glucose levels and patient response is recommended to mitigate the risk of adverse effects.

Pregnancy

There are no adequate and well-controlled studies of glimepiride in pregnant women; therefore, it is classified as Pregnancy Category C. 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, specifically 50 times the dose in rats and 0.1 times in rabbits, 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, a finding that has also been 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. Healthcare professionals should carefully consider these factors when prescribing glimepiride to pregnant patients.

Lactation

It is not known whether glimepiride tablets are 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 nursing or discontinue glimepiride therapy, weighing the importance of the medication to the mother against the potential risks to the breastfed 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 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 tablets, similar to other sulfonylureas, can lead to severe hypoglycemia. Healthcare professionals should be vigilant in recognizing the symptoms associated with this condition.

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 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 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.

Furthermore, glimepiride did not adversely affect male mouse fertility in animals exposed to 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 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

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

Serious hypersensitivity reactions have been documented, including cases of anaphylaxis and angioedema. Reports of hepatotoxicity have also been received, with instances of cholestatic jaundice and hepatitis noted. Furthermore, postmarketing reports have included cases of acute renal failure, particularly in patients with pre-existing renal impairment.

Patient Counseling

Healthcare providers should inform patients about the critical importance of adhering to dietary instructions, maintaining a regular exercise program, and consistently testing their blood glucose levels. Emphasizing these aspects can significantly enhance the management of their condition.

Patients should be made aware of the potential side effects associated with glimepiride, particularly the risks of hypoglycemia and weight gain. It is essential to explain the symptoms of hypoglycemia, such as dizziness, sweating, and confusion, and to discuss appropriate treatment options, including the consumption of fast-acting carbohydrates. Additionally, healthcare providers should highlight the conditions that may predispose patients to hypoglycemia, ensuring they understand the factors that could increase their risk.

It is crucial to 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.

Furthermore, patients with diabetes should be advised to communicate with 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 20°-25°C (68°-77°F), 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, as early warning symptoms may vary or be less pronounced in individuals with autonomic neuropathy, the elderly, and those taking beta-adrenergic blocking medications 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. Additionally, there have been reports of hemolytic anemia in patients receiving 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 Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)