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. The substance appears as a white to yellowish-white, crystalline, odorless to practically odorless powder and is practically insoluble in water. Glimepiride tablets USP include the active ingredient glimepiride along with inactive ingredients such as lactose monohydrate, polysorbate 80, sodium starch glycolate, povidone, microcrystalline cellulose, and magnesium stearate. The 1 mg tablets contain Ferric Oxide Red, while the 2 mg tablets contain Ferric Oxide Yellow.

Uses and Indications

Glimepiride tablets are indicated as an adjunct to diet and exercise for the improvement of glycemic control in adults with type 2 diabetes mellitus. This medication 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.

This medication should be administered with breakfast or the first meal of the day to optimize its 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 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, individuals with a known hypersensitivity to sulfonamide derivatives should not use this product due to the potential for cross-reactivity.

Warnings and Precautions

Patients using glimepiride tablets should be closely monitored for several critical warnings and precautions to ensure safe and effective treatment.

Hypoglycemia Severe hypoglycemia may occur, necessitating careful patient selection, appropriate dosing, and 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 Postmarketing surveillance has reported hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, glimepiride tablets should be discontinued immediately. Healthcare professionals should assess for other potential causes of the reaction and consider alternative diabetes treatments.

Hemolytic Anemia Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency may experience hemolytic anemia. In such cases, it is advisable to consider a non-sulfonylurea alternative to mitigate this risk.

Cardiovascular Considerations There is a potential increased risk of cardiovascular mortality associated with sulfonylureas. Healthcare providers should inform patients about the risks, benefits, and available treatment alternatives.

Macrovascular Outcomes Currently, there are no clinical studies that provide conclusive evidence of macrovascular risk reduction with glimepiride tablets or any other antidiabetic medications. This lack of evidence should be communicated to patients as part of their treatment plan.

In summary, healthcare professionals must remain vigilant regarding these warnings and ensure that patients are adequately informed and monitored throughout their treatment with glimepiride tablets.

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 tablets should be promptly discontinued, and alternative diabetes treatments should be considered after assessing for other potential causes. 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 tablets or any other antidiabetic drug.

In clinical trials, hypoglycemic events, defined by blood glucose values less than 36 mg/dL, were 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 should also be aware of the potential for hypersensitivity to glimepiride or any of its ingredients, as well as 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 with coma, seizure, or neurological impairment may necessitate treatment with glucagon or intravenous glucose, and continued observation along with additional carbohydrate intake may be required due to the possibility of recurrent hypoglycemia following apparent clinical recovery.

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.

In terms of pharmacokinetic interactions, inhibitors and inducers of cytochrome P450 2C9 can significantly impact glycemic control by altering the plasma concentrations of glimepiride. Clinicians should consider adjusting the dosage of glimepiride based on the patient's response and the presence of any CYP2C9-modulating agents.

Additionally, the coadministration of colesevelam may lead to reduced absorption of glimepiride. To mitigate this interaction, glimepiride tablets should be administered at least 4 hours prior to colesevelam. Monitoring of glycemic control is recommended in patients receiving both medications to ensure therapeutic effectiveness.

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 (n=135) or metformin (n=137). 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 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 tablets used 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 tablets 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. The estimated background risk of major birth defects in women with pre-gestational diabetes and an HbA1c greater than 7% is between 6% to 10%, and this risk can increase to as high as 20% to 25% in women with an HbA1c greater than 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 during pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Additionally, it elevates the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Neonates born to 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

Glimepiride tablets 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 should be aware of the potential risks associated with the use of glimepiride during the perinatal period.

Breastfed infants may be at increased risk for complications if their mothers were treated with sulfonylureas during pregnancy. These infants should be closely monitored for symptoms of hypoglycemia and respiratory distress, and appropriate management should be implemented as necessary. Additionally, neonates of women with gestational diabetes treated with sulfonylureas may face an increased risk for neonatal intensive care admission, respiratory distress, hypoglycemia, birth injury, and being large for gestational age.

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 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 condition that necessitates prompt medical intervention. Healthcare professionals should be vigilant in recognizing the symptoms associated with this adverse effect.

In cases of mild hypoglycemia, treatment can typically be managed with oral glucose administration. However, for patients experiencing severe hypoglycemic reactions, more aggressive measures are required, such as the administration of glucagon or intravenous glucose. It is crucial to monitor the patient closely, as hypoglycemia may recur even after initial treatment appears effective.

Continued observation is essential, and additional carbohydrate intake may be warranted to ensure the patient's safety and recovery. Severe hypoglycemic reactions are classified as medical emergencies, underscoring the importance of immediate and appropriate treatment to mitigate potential 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 46–54 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, 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 doses of 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 are available. 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 tablets. Patients should be advised to seek medical treatment and discontinue the use of glimepiride tablets if they experience any allergic 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 tablets 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°C to 25°C (68°F 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)