Glimepiride

Description

Glimepiride tablets, USP are an oral sulfonylurea that contains the active ingredient glimepiride. Chemically, glimepiride is identified as 1-[[p-2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethylphenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea (C24H34N4O5S) with a molecular weight of 490.62. Glimepiride USP is a white or almost white powder and is practically insoluble in water.

Glimepiride tablets, USP contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Additionally, the 1 mg strength contains ferric oxide red, the 2 mg strength contains ferric oxide yellow and FD&C blue No. 2, and the 4 mg strength contains FD&C blue No. 2.

Uses and Indications

Glimepiride is 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 mg or 2 mg administered once daily. Dosing may be increased in increments of 1 mg 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 1 mg starting dose 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 components. Additionally, individuals with a hypersensitivity to sulfonamide derivatives should not use this product due to the potential for cross-reactivity.

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 manifest as severe episodes. Healthcare professionals must ensure appropriate patient selection, dosing, and comprehensive 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, as this may exacerbate the risk of hypoglycemic events.

Hypersensitivity reactions have been reported in postmarketing surveillance, including severe cases such as anaphylaxis, angioedema, and Stevens-Johnson syndrome. Should any hypersensitivity reaction be suspected, it is imperative to discontinue glimepiride immediately, evaluate for alternative causes, and initiate appropriate diabetes management.

Hemolytic anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In such cases, consideration should be given to prescribing 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 associated risks, benefits, and available treatment alternatives.

Lastly, while glimepiride is an effective anti-diabetic agent, there is currently no clinical evidence demonstrating a reduction in macrovascular outcomes with its use or that of 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 these risks to ensure patient safety and optimal therapeutic outcomes.

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, as it can be severe. It is essential to ensure proper patient selection, dosing, and instructions, particularly for at-risk populations such as the elderly and those with renal impairment, as well as 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. If a hypersensitivity reaction is suspected, glimepiride should be promptly discontinued, and alternative diabetes treatment should be initiated after assessing for other potential causes.

Hemolytic anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, and in such cases, a non-sulfonylurea alternative should be considered. Additionally, there is a potential increased risk of cardiovascular mortality associated with sulfonylureas, necessitating that patients are informed of the risks, benefits, and 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.

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 can be managed with oral glucose, while severe reactions require immediate medical intervention, including glucagon or intravenous glucose. Continuous observation and additional carbohydrate intake may be necessary, as hypoglycemia can recur after apparent clinical 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. Severe hypoglycemic episodes were reported in one patient from each treatment group, with severity assessed by the investigator based on observed signs and symptoms.

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

Furthermore, neonates born to women with gestational diabetes who are treated with sulfonylureas during pregnancy may face an increased risk of neonatal intensive care admission and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia lasting 4 to 10 days has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery.

Drug Interactions

Severe hypoglycemia may occur when glimepiride is used concomitantly with miconazole. It is advisable to monitor blood glucose levels closely in patients receiving this combination.

Inhibitors and inducers of cytochrome P450 2C9 can significantly impact glycemic control by altering the plasma concentrations of glimepiride. Clinicians should consider dosage adjustments and enhanced monitoring of glycemic levels when initiating or discontinuing such agents.

Coadministration of colesevelam may lead to a reduction in the absorption of glimepiride. To mitigate this interaction, glimepiride should be administered at least 4 hours prior to colesevelam.

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 with type 2 diabetes. Treatment was initiated with 1 mg of glimepiride, which was subsequently titrated to doses of 2, 4, or 8 mg, with a 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 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 particularly challenging to recognize in geriatric patients. Therefore, it is advised 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 recommended to ensure the safe use of glimepiride in elderly patients.

Pregnancy

Available data from a small number of published studies and postmarketing experience with glimepiride use in pregnancy over decades 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.

Glimepiride should be discontinued at least two weeks before the expected delivery to mitigate the risk of prolonged severe hypoglycemia in neonates, which has been reported to last from 4 to 10 days in infants born to mothers receiving a sulfonylurea at the time of delivery.

Poorly controlled diabetes in pregnancy poses significant risks to both the mother and fetus. The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes and an HbA1c >7%, escalating to as high as 20% to 25% in those with an HbA1c >10%. Additionally, the estimated background risk of miscarriage for this population remains unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Poorly controlled diabetes increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Fetal risks associated with poorly controlled diabetes include major birth defects, stillbirth, and macrosomia-related morbidity. Neonates of women with gestational diabetes 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.

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 based on body surface area.

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 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.

Overdosage

An overdosage of glimepiride can lead to severe hypoglycemia, a condition that constitutes a medical emergency and necessitates prompt intervention.

In cases of mild hypoglycemia, treatment can be effectively managed with the administration of oral glucose. However, for severe hypoglycemic episodes, more intensive measures are required, such as the administration of glucagon or intravenous glucose.

It is crucial to ensure continued observation of the patient following initial treatment, as hypoglycemia may recur even after the patient appears to have clinically recovered. Additional carbohydrate intake may be warranted to prevent the re-emergence of hypoglycemic symptoms.

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 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 on male mouse fertility in animals exposed to glimepiride at 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 specific postmarketing experience details have been reported. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Healthcare providers should explain to patients the symptoms and treatment of hypoglycemia, as well as the conditions that may predispose them to this condition. It is important for patients to understand that hypoglycemia can impair their ability to concentrate and react, which may pose risks in situations where these abilities are critical, such as driving or operating machinery.

Providers should inform patients that hypersensitivity reactions may occur with glimepiride. Patients should be advised to seek medical treatment and discontinue glimepiride if they experience any such reactions.

For females of reproductive potential, it is essential to advise them to inform their prescriber of any known or suspected pregnancy. Additionally, breastfeeding women taking glimepiride should be counseled to monitor their breastfed infants for signs of hypoglycemia, which may include jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, and seizures.

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° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

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 predisposed to hypoglycemia, including the elderly, those with renal impairment, and individuals on other anti-diabetic medications. Debilitated or malnourished patients, as well as those with adrenal, pituitary, or hepatic impairments, are especially vulnerable to the hypoglycemic effects of glucose-lowering agents. Additionally, early warning symptoms of hypoglycemia may be atypical or less pronounced in patients with autonomic neuropathy, the elderly, and those taking beta-adrenergic blockers 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. There have also been instances of hemolytic anemia in patients treated with glimepiride who did not have a known G6 PD deficiency.

FDA Insert (PDF)

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

View full prescribing information (PDF)