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.

This drug is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

No teratogenic or nonteratogenic effects have been reported.

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 the dose slowly.

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 components of safe glimepiride use, ensuring that patients are well-informed about their treatment and any associated risks.

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 have been documented, including hypersensitivity reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome, which have been reported in postmarketing experiences. In such cases, glimepiride should be promptly discontinued, and appropriate monitoring and treatment should be initiated, 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 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. Mild hypoglycemic episodes may be managed with oral glucose, while severe reactions represent medical emergencies requiring immediate intervention. Severe hypoglycemia that results in 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 after apparent clinical recovery.

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, 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 they may exhibit greater sensitivity and are more likely to have renal impairment, making hypoglycemia more difficult to recognize in this population.

Drug Interactions

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

Pharmacodynamic Interactions Miconazole has been identified to cause severe hypoglycemia when used concurrently with glimepiride. Close monitoring of blood glucose levels is advised in patients receiving this combination.

Pharmacokinetic Interactions Interactions involving cytochrome P450 2C9 can significantly impact glycemic control. Both inhibitors and inducers of this enzyme may alter the plasma concentrations of glimepiride, which could necessitate dosage adjustments based on clinical response and blood glucose monitoring.

Additionally, the coadministration of colesevelam may lead to reduced 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 effective glycemic control in patients receiving these medications.

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 30 patients aged 10 to 17 years with type 2 diabetes.

In a single-blind, 24-week trial involving 272 patients aged 8 to 17 years, the safety and efficacy of glimepiride were compared to metformin. Patients were randomized to receive glimepiride (n=135) or metformin (n=137), with glimepiride initiated at 1 mg and titrated to doses of 2, 4, or 8 mg (mean last 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.

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 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

There are no adequate and well-controlled studies of glimepiride in pregnant patients. The drug is classified as Pregnancy Category C, indicating that risk cannot be ruled out. 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, with rats experiencing effects at 50 times and rabbits at 0.1 times this dose based on body surface area. This fetotoxicity appears to be associated with doses that induce maternal hypoglycemia, which is consistent with findings related to 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 linked to a higher incidence of congenital abnormalities. Therefore, diabetes management 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 is excreted in human milk. However, during pre- and post-natal studies in rats, significant concentrations of glimepiride were found 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 determined to be a consequence of 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 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, in cases of severe hypoglycemic reactions, which are classified as medical emergencies, immediate intervention is required. Symptoms of severe hypoglycemia may include coma, seizures, or neurological impairment.

Emergency Treatment For severe hypoglycemia, treatment options include the administration of glucagon or intravenous glucose. These interventions 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, as hypoglycemia may recur even after apparent clinical recovery. Additional carbohydrate intake may be necessary to ensure sustained stabilization of blood glucose levels. Healthcare professionals should remain vigilant in monitoring the patient’s condition to mitigate the risk of subsequent hypoglycemic episodes.

Nonclinical Toxicology

Prolonged severe hypoglycemia (4 to 10 days) 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, chromosomal aberration, unscheduled DNA synthesis, 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 had no impact on 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 reported voluntarily or through surveillance programs. Hypersensitivity reactions, including anaphylaxis, angioedema, and various skin reactions, have been documented. Additionally, cases of hepatotoxicity have been reported, characterized by elevated liver enzymes and instances of liver failure.

Further reports include hematological events such as hemolytic anemia, thrombocytopenia, and leukopenia. Some patients have experienced severe hypoglycemia, which may necessitate hospitalization. Cardiovascular events, including myocardial infarction and stroke, have also been noted. Other adverse reactions reported consist of gastrointestinal symptoms, including nausea, vomiting, and abdominal pain.

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 any 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 alertness, 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 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 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 Liberty Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)