Glimepiride

Description

Glimepiride is 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-1­carboxamido) ethylphenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea (C24H34N4O5S) with a molecular weight of 490.62. It appears as a white to yellowish-white, crystalline, odorless to practically odorless powder and is practically insoluble in water.

Glimepiride tablets, USP contain the active ingredient glimepiride along with the following inactive ingredients: lactose monohydrate, sodium starch glycolate, povidone, and magnesium stearate. The tablets are available in three strengths: 1 mg, which contains ferric oxide red; 2 mg, which contains ferric oxide yellow and FD&C blue #2 aluminum lake; and 4 mg, which contains FD&C blue #2 aluminum lake.

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: Glimepiride is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

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 guided by 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 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 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. 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 sulfonylureas, including glimepiride. It is essential for healthcare providers to inform patients about the risks, benefits, and available treatment alternatives.

Lastly, while glimepiride is used for glycemic control, there is currently no clinical evidence establishing a conclusive benefit in reducing macrovascular outcomes with glimepiride or any other anti-diabetic medication. This lack of evidence should be communicated to patients to ensure informed decision-making regarding their treatment options.

Healthcare professionals are encouraged to remain vigilant and proactive in monitoring patients for these warnings and to provide appropriate guidance and support.

Side Effects

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

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 considered 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 drug.

Additional adverse reactions and 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 treatment. Mild hypoglycemic episodes can be managed with oral glucose, while severe reactions may necessitate glucagon or intravenous glucose. Continuous observation and additional carbohydrate intake may be required, as hypoglycemia can recur after apparent clinical recovery.

In pediatric patients, the profile of adverse reactions appears similar to that observed in adults. Clinical trials indicated that 4% of pediatric patients treated with glimepiride experienced hypoglycemic events, with blood glucose values falling below 36 mg/dL, compared to 1% of 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.

Elderly patients may be at increased risk for renal impairment, and hypoglycemia may be more challenging to recognize in this population. Caution is advised when initiating or increasing the dose of glimepiride in elderly patients. Furthermore, breastfed infants of lactating women using glimepiride should be monitored for symptoms of hypoglycemia, including jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, and seizures.

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 affect 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 reduce 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, 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. 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.

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 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. Therefore, 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.

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. Fetal risks include major birth defects, stillbirth, and macrosomia-related morbidity. The estimated background risk of major birth defects in women with pregestational 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, while 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.

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 this fetotoxicity believed to be directly related to the pharmacologic action of glimepiride, as similar effects have been noted with other sulfonylureas. It is important for healthcare professionals to consider these factors when managing pregnant patients or women of childbearing potential.

Lactation

Breastfed infants of lactating mothers using glimepiride should be monitored for symptoms of hypoglycemia, including jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, and seizures. It is not known whether glimepiride is excreted in human milk, and there are no data on its effects on milk production. However, glimepiride has been detected in rat milk, with significant concentrations observed during prenatal and postnatal studies in rats.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for glimepiride and any potential adverse effects on the breastfed child. Notably, offspring of rats exposed to high levels of glimepiride during pregnancy and lactation exhibited skeletal deformities, including shortening, thickening, and bending of the humerus, attributed to nursing from mothers exposed to the drug. Therefore, careful monitoring of breastfed infants is advised.

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.

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 can lead to severe hypoglycemia, a potentially life-threatening condition that necessitates immediate medical intervention.

In cases of mild hypoglycemia, treatment can typically be managed with the administration of oral glucose. However, for severe hypoglycemic episodes, more aggressive measures are required, which may include the use of glucagon or intravenous glucose to rapidly restore blood sugar levels.

It is crucial for healthcare professionals to monitor patients closely following an overdosage event, as hypoglycemia may recur even after initial treatment appears effective. Continued observation and the provision of additional carbohydrate intake may be necessary to ensure patient safety and prevent further complications.

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 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 exceeds 1,500 times the maximum recommended human dose based on surface area. Similarly, 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

No specific postmarketing experience details have been reported. As such, there are currently no additional adverse events or rare case reports available for review.

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 of 25°C (77°F), with permissible excursions between 20°C to 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 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 Accord Healthcare Inc. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)