Glimepiride

Description

Glimepiride tablets USP 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 chemical formula of C24H34N4O5S and a molecular weight of 490.62.

Glimepiride appears as a white to yellowish-white, crystalline, odorless to practically odorless powder, which is practically insoluble in water. Each tablet formulation includes glimepiride along with several inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer, povidone, and sodium starch glycolate.

The 1 mg glimepiride tablets also contain Iron Oxide Red, while the 2 mg tablets incorporate FD&C Blue #2 Aluminum Lake and Iron Oxide Yellow. The 4 mg tablets contain FD&C Blue #2 Aluminum Lake as well.

Uses and Indications

Glimepiride is a sulfonylurea indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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 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 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 appropriate 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. If a hypersensitivity reaction is suspected, glimepiride should be discontinued immediately. A thorough assessment for other potential causes of the reaction should be conducted, and alternative diabetes treatments should be initiated as necessary.

Hemolytic Anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In such 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 glimepiride is an effective anti-diabetic agent, there is currently no clinical evidence establishing a conclusive benefit in reducing macrovascular outcomes. Healthcare professionals should remain vigilant and discuss these considerations with their patients to ensure informed decision-making regarding their diabetes management.

Side Effects

Patients receiving glimepiride may experience a range of adverse reactions, which can be categorized into common and serious events.

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 a suspected hypersensitivity reaction, glimepiride 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 contemplated in such cases. 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 medication.

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, constituting a medical emergency that requires immediate treatment. Mild hypoglycemic episodes may be managed with oral glucose, while severe cases, which may involve coma, seizure, or neurological impairment, require glucagon or intravenous glucose. Continuous observation and additional carbohydrate intake may be necessary, as hypoglycemia can recur after initial recovery.

In clinical trials, hypoglycemic events, defined by blood glucose values below 36 mg/dL, were observed 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, with severity assessed by the investigator based on observed signs and symptoms. Caution is advised when initiating or increasing the dose of glimepiride in elderly patients, as greater sensitivity in this population cannot be ruled out.

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 or metformin. 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. Notably, hypoglycemic events, defined as blood glucose values <36 mg/dL, were reported in 4% of pediatric patients treated with glimepiride.

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 of blood glucose levels and patient response is recommended to mitigate the risk of adverse effects.

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, 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 raises the risk for major birth defects, stillbirth, and macrosomia-related morbidity. The estimated background risk of major birth defects in women with pre-gestational 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 animal studies, glimepiride administration to pregnant rats and rabbits at doses approximately 4000 times and 60 times the maximum human dose (based on body surface area) did not affect embryo-fetal development. However, fetotoxicity was observed at doses 50 times (rats) and 0.1 times (rabbits) the maximum human dose, with these effects occurring only at doses that induced maternal hypoglycemia, suggesting a direct relationship to the pharmacologic action of glimepiride.

Neonates born to mothers 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 4–10 days has been reported in these neonates. Therefore, it is essential to observe newborns for symptoms of hypoglycemia and respiratory distress and manage them accordingly.

Lactation

Glimepiride 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, similar to other sulfonylureas, can lead to severe hypoglycemia, which poses significant health risks.

Symptoms and Initial Management Mild episodes of hypoglycemia can typically be managed effectively with the administration of oral glucose. However, healthcare professionals should be vigilant, as severe hypoglycemic reactions represent medical emergencies that necessitate immediate intervention.

Severe Hypoglycemia Treatment In cases of severe hypoglycemia, characterized by coma, seizures, or neurological impairment, treatment options include the administration of glucagon or intravenous glucose. These measures are critical to rapidly restore normal blood glucose levels and prevent further complications.

Post-Treatment Considerations Following initial treatment, continued observation of the patient is essential. Additional carbohydrate intake may be required, as hypoglycemia can recur even after the patient appears to have clinically recovered. Therefore, healthcare providers should ensure that patients are monitored closely for any signs of recurrent hypoglycemia.

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 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 evaluations, 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 1,500 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

No postmarketing experience details are available in the provided data.

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 emphasize that hypoglycemia can impair a patient's ability to concentrate and react, which may pose risks in situations requiring full attention, such as driving or operating machinery. Patients should be advised to exercise caution in these scenarios and to monitor their blood glucose levels regularly.

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 child-resistant closures. It should be stored at a temperature of 25°C (77°F), with permissible excursions between 20°C and 25°C (68°F to 77°F) in accordance with USP Controlled Room Temperature guidelines.

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 who may be predisposed to hypoglycemia, such as the elderly, those with renal impairment, and individuals on other anti-diabetic medications. It is important to note that early warning symptoms of hypoglycemia may be atypical or less pronounced in patients 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 treated with 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 Solco Healthcare U. S. , LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)