Glimepiride

Description

Glimepiride tablets USP are oral sulfonylureas 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. Glimepiride appears as a white to almost white powder, which is soluble in dimethyl formamide, sparingly soluble in methylene chloride, and practically insoluble in water.

The structural formula is provided in the accompanying documentation. 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. Additionally, glimepiride 1 mg tablets contain 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 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 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 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 may occur and can be severe. Healthcare professionals should 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 anaphylaxis, angioedema, and Stevens-Johnson Syndrome. In the event of such reactions, glimepiride should be promptly discontinued. Healthcare providers must assess for alternative causes, implement appropriate monitoring and treatment, and consider initiating alternative diabetes management strategies.

Hemolytic anemia may develop in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In these cases, it is advisable to consider a non-sulfonylurea alternative to avoid potential complications.

There is a potential increased risk of cardiovascular mortality associated with the use of sulfonylureas. It is essential for healthcare professionals to inform patients about the risks, benefits, and available treatment alternatives.

Currently, there are no clinical studies that provide conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic medication. Therefore, healthcare providers should remain vigilant regarding the macrovascular outcomes in patients treated with this medication.

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. Hypersensitivity reactions have been reported in postmarketing experiences, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome. In such cases, it is essential to discontinue glimepiride immediately, assess for alternative causes, and provide appropriate monitoring and treatment, along with initiating 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, 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 can lead to severe hypoglycemia, which constitutes a medical emergency requiring immediate intervention. Mild hypoglycemic episodes may be managed with oral glucose, while severe reactions, which may involve coma, seizure, or neurological impairment, require treatment 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. 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, greater sensitivity to glimepiride cannot be ruled out, and caution is advised when initiating or increasing the dose of glimepiride in this population.

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 dosage adjustments based on the clinical response.

• 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 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 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 1 mg single dose of glimepiride has been evaluated in a study involving 30 patients aged 10 to 17 years with type 2 diabetes.

In a single-blind, 24-week trial assessing the safety and efficacy of glimepiride, 272 patients aged 8 to 17 years with type 2 diabetes were randomized. Treatment was initiated at a dose of 1 mg, with titration to 2, 4, or 8 mg (mean last dose of 4 mg) by Week 12. Notably, hypoglycemic events, defined as blood glucose values <36 mg/dL, were documented 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

Pregnant patients should be aware that glimepiride is classified as Pregnancy Category C. There are no adequate and well-controlled studies of glimepiride in pregnant women. Animal studies have shown no increase in congenital anomalies; however, 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 appears to be associated with doses that induce maternal hypoglycemia, which is believed to be directly related to the pharmacologic action of glimepiride. Similar effects have been noted with other sulfonylureas.

Glimepiride should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. It is important to note that abnormal blood glucose levels during pregnancy are linked to 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, 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 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 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 to 54 mg/kg body weight/day, which is about 35 times the maximum recommended human 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.

Regarding fertility, 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. Additionally, no effects on fertility were observed in male and female rats administered glimepiride at 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 reported voluntarily or through surveillance programs. Hypersensitivity reactions, including rash, pruritus, and urticaria, have been documented. Additionally, cases of hepatotoxicity, characterized by elevated liver enzymes and liver failure, have been reported. Instances of hemolytic anemia have been noted in patients with glucose-6-phosphate dehydrogenase deficiency. Reports have also included cases of pancreatitis. Furthermore, there have been rare occurrences of severe cutaneous adverse reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

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 outline the conditions that may predispose patients to hypoglycemia, ensuring they understand the factors that could increase their risk.

It is important 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 regarding any plans for pregnancy, current pregnancy status, or 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 accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), adhering to the guidelines set forth by the United States Pharmacopeia (USP) for Controlled Room Temperature. Proper storage conditions are essential to maintain the integrity and efficacy 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 International Laboratories, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)