Glimepiride

Description

Glimepiride tablets USP contain the active ingredient glimepiride USP. Chemically, 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 (C24H34N4O5S) with a molecular weight of 490.62. Glimepiride USP 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 tablets contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Glimepiride 1 mg tablets include ferric oxide red, while glimepiride 2 mg tablets contain lake blend green, which consists of D&C yellow # 10 aluminium lake and FD&C blue #1/brilliant blue FCF aluminium lake. Glimepiride 4 mg tablets contain lake blend blue, which also includes D&C yellow # 10 aluminium lake and FD&C blue # 1/brilliant blue FCF aluminium 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.

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 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 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

Severe hypoglycemia may occur with glimepiride, necessitating careful patient selection, appropriate dosing, and clear instructions, particularly for at-risk populations such as the elderly and individuals with renal impairment. Caution is advised when glimepiride is used in conjunction with other anti-diabetic medications, as this may further increase the risk of hypoglycemia.

Healthcare professionals should be vigilant for hypersensitivity reactions, which have been reported postmarketing and include 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.

Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency may be at risk for hemolytic anemia when treated with glimepiride. In such cases, consideration should be given to prescribing a non-sulfonylurea alternative to mitigate this risk.

It is important to inform patients about the potential increased risk of cardiovascular mortality associated with sulfonylureas, including glimepiride. Healthcare providers should discuss the risks, benefits, and available treatment alternatives with patients to ensure informed decision-making.

Currently, there are no clinical studies that provide conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic medication. Therefore, healthcare professionals should remain cautious and consider this when discussing treatment options with patients.

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 cases where a hypersensitivity reaction is suspected, 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 such patients should be considered for non-sulfonylurea alternatives. 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 include documented hypoglycemic events, with blood glucose values falling below 36 mg/dL observed 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. Patients may also experience 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 typically be managed with oral glucose, while severe reactions may necessitate glucagon or intravenous glucose administration. Continuous observation and additional carbohydrate intake may be required, as hypoglycemia can recur after apparent clinical recovery.

Drug Interactions

Severe hypoglycemia may occur when glimepiride is used concomitantly with oral 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 increased monitoring of blood glucose levels when initiating or discontinuing such agents.

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.

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 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 pediatric patients aged 8 to 17 years, who were randomized to receive either glimepiride (n=135) or metformin (n=137). Glimepiride treatment 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 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 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 tablets should be discontinued at least two weeks before the expected delivery to mitigate these risks.

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 pregestational diabetes and an HbA1c >7%, escalating to as high as 20% to 25% in those with an HbA1c >10%. The estimated background risk of miscarriage in 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. Additionally, it heightens the fetal risk for 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. Prolonged severe hypoglycemia lasting 4 to 10 days has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery. Therefore, it is essential to observe newborns for symptoms of hypoglycemia and respiratory distress and manage them accordingly.

In animal studies, no increase in congenital anomalies was observed; however, an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits) the maximum recommended human dose based on body surface area. This fetotoxicity was noted only at doses that induced maternal hypoglycemia and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride.

Lactation

There is no specific information available regarding the use of glimepiride in lactating mothers. Additionally, there is no data on the potential for excretion of glimepiride in breast milk. Consequently, the effects on breastfed infants are also not established. Healthcare professionals should consider these factors when advising lactating mothers on the use of this medication.

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. Healthcare professionals should be vigilant in recognizing the symptoms of hypoglycemia, which may include confusion, sweating, tremors, and in severe cases, loss of consciousness.

For the management of mild hypoglycemia, oral glucose administration is typically sufficient to restore normal blood glucose levels. However, in instances of severe hypoglycemia, the use of glucagon or intravenous glucose may be required to rapidly elevate blood glucose levels and stabilize the patient.

It is crucial to ensure continued observation of the patient following initial treatment, as hypoglycemia can recur even after apparent clinical recovery. Additional carbohydrate intake may be necessary to prevent subsequent episodes. Healthcare providers should remain alert to the possibility of recurrent hypoglycemia and be prepared to implement further management strategies as needed.

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 recommended human 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, there was no observed effect on male mouse fertility in animals exposed to glimepiride at doses up to 2,500 mg/kg body weight, which exceeds 1,500 times the maximum recommended human dose based on surface area. Similarly, glimepiride did not impact the fertility of male and female rats administered doses up to 4,000 mg/kg body weight, approximately 4,000 times the maximum recommended human dose based on surface area.

Postmarketing Experience

Postmarketing experience has identified the following adverse reactions reported voluntarily or through surveillance programs: hypoglycemia and hypersensitivity reactions. These events have been documented in the context of routine pharmacovigilance activities.

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 about the potential for hypersensitivity reactions associated with glimepiride. Patients should be advised to seek medical treatment and discontinue glimepiride if they experience any allergic reactions.

For females of reproductive potential, it is essential to advise them to inform their prescriber if they know or suspect they are pregnant. Additionally, breastfeeding women taking glimepiride tablets should be instructed 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 dispensed in a Unit Dose Package and is intended for institutional use only. It should be stored at a temperature range of 20°-25°C (68°-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, as early warning symptoms may vary or be less pronounced in those with autonomic neuropathy, the elderly, and individuals taking beta-adrenergic blocking medications or other sympatholytic agents. It is important for patients to be 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 G6 PD deficiency.

FDA Insert (PDF)

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

View full prescribing information (PDF)