Glimepiride

Description

Glimepiride tablets USP are an oral sulfonylurea formulation containing the active ingredient glimepiride USP. The chemical structure of glimepiride USP 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 molecular formula of C24H34N4O5S and a molecular weight of 490.62.

The active ingredient appears as a white to almost white powder, exhibiting solubility in dimethyl formamide, sparing solubility in methylene chloride, and is practically insoluble in water. Glimepiride tablets meet the USP drug release test 2 standards.

Each tablet formulation includes inactive ingredients such as lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Additionally, the 1 mg glimepiride tablets contain ferric oxide red, the 2 mg tablets contain a lake blend green (comprising D&C yellow #10 aluminum lake and FD&C blue #1/brilliant blue FCF aluminum lake), and the 4 mg tablets contain a lake blend blue (also comprising D&C yellow #10 aluminum lake and FD&C blue #1/brilliant blue FCF aluminum lake).

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.

Important 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 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 absorption and efficacy. For patients at increased risk for hypoglycemia, such as the elderly or those with renal impairment, a starting dose of 1 mg is advised, with careful and gradual titration.

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. It is essential to assess for other potential causes of the reaction and to initiate alternative diabetes treatment as necessary.

Hemolytic Anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In such cases, consideration should be given to using a non-sulfonylurea alternative to mitigate this risk.

There is a Potential Increased Risk of Cardiovascular Mortality associated with sulfonylureas, including glimepiride. Healthcare providers should inform patients about the risks, benefits, and available treatment alternatives to ensure informed decision-making.

Regarding Macrovascular Outcomes, it is important to note that there are no clinical studies that establish conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic medication.

In summary, careful patient selection, monitoring, and education are paramount in the safe use of glimepiride to mitigate these risks effectively.

Side Effects

Patients may experience a range of adverse reactions while using glimepiride. Common adverse reactions include hypoglycemia, headache, nausea, and dizziness.

Serious adverse reactions associated with glimepiride include severe hypoglycemia, which 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. 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. Additionally, hemolytic anemia may occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, and a non-sulfonylurea alternative should be considered in such cases.

There is a potential increased risk of cardiovascular mortality associated with sulfonylureas, and patients should be 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 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. 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, as determined by the investigator based on observed signs and symptoms.

Lactating women using glimepiride should monitor breastfed infants for symptoms of hypoglycemia. 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. Newborns should be observed for symptoms of hypoglycemia and respiratory distress, with appropriate management initiated as necessary.

Drug Interactions

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

Pharmacodynamic Interactions

• Miconazole: The concomitant use of glimepiride and oral miconazole may lead to severe hypoglycemia. Close monitoring of blood glucose levels is recommended when these agents are used together.

Pharmacokinetic Interactions

• Cytochrome P450 2C9 Inhibitors and Inducers: Agents that inhibit or induce cytochrome P450 2C9 may alter the plasma concentrations of glimepiride, potentially impacting glycemic control. It is advisable to monitor blood glucose levels closely and consider dosage adjustments as necessary.

• Colesevelam: The coadministration of colesevelam may reduce the absorption of glimepiride. To mitigate this interaction, glimepiride should be administered at least 4 hours prior to colesevelam.

In summary, healthcare professionals should remain vigilant regarding these interactions and adjust glimepiride dosing and monitoring protocols accordingly to ensure optimal glycemic control.

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. Additionally, the safety and efficacy of glimepiride were evaluated in a single-blind, 24-week trial that randomized 272 patients aged 8 to 17 years with type 2 diabetes to receive either glimepiride or metformin. In this study, 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. Notably, 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. Therefore, caution is advised when initiating therapy with glimepiride or when increasing the dosage in this population. Regular monitoring of blood glucose levels and patient response is recommended to mitigate the risk of adverse effects.

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.

It is recommended that glimepiride tablets 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 pregestational 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

Breastfed infants of lactating mothers using glimepiride tablets should be monitored for symptoms of hypoglycemia. It is currently unknown whether glimepiride is excreted in human milk, and there are no data available regarding its effects on milk production. However, glimepiride has been detected in rat milk, and during prenatal and postnatal studies in rats, significant concentrations of glimepiride were found in both breast milk and the serum of the pups.

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. Monitoring for signs of hypoglycemia in breastfed infants is essential, with symptoms including jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, and seizures. Additionally, 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 glimepiride.

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 tablets, similar to other sulfonylureas, can lead to severe hypoglycemia. Healthcare professionals should be vigilant in recognizing the symptoms associated with this condition.

In cases of mild hypoglycemia, treatment can be effectively managed with oral glucose. However, severe hypoglycemic reactions are classified as medical emergencies and necessitate immediate intervention. For patients experiencing severe hypoglycemia accompanied by coma, seizures, or neurological impairment, administration of glucagon or intravenous glucose is recommended.

It is crucial to ensure continued observation of the patient following initial treatment, as hypoglycemia may recur even after apparent clinical recovery. Additional carbohydrate intake may be required to prevent further episodes.

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 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 evaluations, and the mouse micronucleus test. Furthermore, glimepiride did not adversely affect male mouse fertility in animals exposed to doses up to 2,500 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 4,000 mg/kg body weight, approximately 4,000 times the maximum recommended human dose based on surface area.

Postmarketing Experience

No postmarketing experience details are available in the provided data.

Patient Counseling

Patients should be informed about the symptoms and treatment of hypoglycemia, as well as the conditions that may predispose them to this condition. It is essential for healthcare providers to explain how to recognize the signs of hypoglycemia and the appropriate steps to take if these symptoms occur.

Healthcare providers should also advise patients that hypoglycemia may impair their ability to concentrate and react. This impairment can pose a significant risk in situations where alertness is crucial, such as driving or operating machinery. Patients should be made aware of these risks and encouraged to take necessary precautions.

Additionally, patients should be informed about the possibility of hypersensitivity reactions associated with glimepiride. They should be advised to seek immediate medical attention if they experience any signs of a hypersensitivity reaction and to discontinue the use of glimepiride if such a reaction occurs.

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°-25°C (68°-77°F), 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 recognizing and managing hypoglycemia, as early warning symptoms may vary or be less pronounced in individuals with autonomic neuropathy, the elderly, and those 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 G6PD deficiency.

FDA Insert (PDF)

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

View full prescribing information (PDF)