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Glimepiride

Pronunciation

Pronunciation

(GLYE me pye ride)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Amaryl: 1 mg [scored]

Amaryl: 2 mg, 4 mg [scored; contains fd&c blue #2 aluminum lake]

Generic: 1 mg, 2 mg, 4 mg

Brand Names: U.S.

  • Amaryl

Pharmacologic Category

  • Antidiabetic Agent, Sulfonylurea

Pharmacology

Stimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sites

Absorption

100%; delayed when given with food

Distribution

Vd: 8.8 L

Metabolism

Hepatic oxidation via CYP2C9 to M1 metabolite (~33% activity of parent compound); further oxidative metabolism to inactive M2 metabolite

Excretion

Urine (60%, 80% to 90% as M1 and M2 metabolites); feces (40%, 70% as M1 and M2 metabolites)

Onset of Action

Peak effect: Blood glucose reductions: 2-3 hours

Time to Peak

2-3 hours

Duration of Action

24 hours

Half-Life Elimination

5-9 hours

Protein Binding

>99.5%

Special Populations: Renal Function Impairment

As renal function declines, glimepiride serum levels decrease and metabolite (M1 and M2) AUC and half-lives increase.

Special Populations: Elderly

Mean AUC was about 13% lower. Mean weight-adjusted clearance was about 11% higher.

Use: Labeled Indications

Type 2 diabetes mellitus: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Contraindications

Hypersensitivity to glimepiride, any component of the formulation, or sulfonamides; diabetic ketoacidosis (with or without coma)

Note: Although the FDA approved product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See “Warnings/Precautions” for more detail.

Documentation of allergenic cross-reactivity for drugs in this class is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in U.S. labeling): Pregnancy; breast-feeding; type 1 diabetes; severe renal or hepatic impairment

Dosing: Adult

Type 2 diabetes: Oral: Initial: 1-2 mg once daily, administered with breakfast or the first main meal; based on response, may increase dose by 1-2 mg every 1-2 weeks up to maximum of 8 mg once daily. If inadequate response to maximal dose, combination therapy with other agents (eg, metformin, insulin) may be considered. Combination therapy is individualized based on glycemic response.

Conversion from therapy with long half-life agents: Observe patient carefully for 1-2 weeks when converting from a longer half-life agent (eg, chlorpropamide) to glimepiride due to overlapping hypoglycemic effects.

Dosing: Geriatric

Type 2 diabetes: Oral: Initial: 1 mg once daily; dose titration and maintenance dosing should be conservative to avoid hypoglycemia.

Dosing: Renal Impairment

U.S. labeling: Initial: 1 mg once daily; titrate carefully based on fasting blood glucose levels

Canadian labeling:

Mild-to-moderate impairment: Initial: 1 mg once daily; titrate carefully based on fasting blood glucose levels

Severe impairment: Use is contraindicated

Dosing: Hepatic Impairment

U.S. labeling: No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Canadian labeling:

Mild-to-moderate impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Severe impairment: Use is contraindicated.

Administration

Administer once daily with breakfast or first main meal of the day. Patients that are NPO or require decreased caloric intake may need doses held to avoid hypoglycemia.

Dietary Considerations

Take with breakfast or the first main meal of the day. Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Storage

Store at 25°C (77°F); excursions permitted between 20°C and 25°C (68°F and 77°F)

Drug Interactions

Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Alcohol (Ethyl): Sulfonylureas may enhance the adverse/toxic effect of Alcohol (Ethyl). A flushing reaction may occur. Monitor therapy

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Antidiabetic Agents (Thiazolidinedione): May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification

Beta-Blockers: May enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Carbocisteine: Sulfonylureas may enhance the adverse/toxic effect of Carbocisteine. Specifically, sulfonylureas may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates. Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

Chloramphenicol: May decrease the metabolism of Sulfonylureas. Monitor therapy

Cimetidine: May increase the serum concentration of Sulfonylureas. Monitor therapy

Colesevelam: May decrease the serum concentration of Glimepiride. Management: Administer glimepiride at least 4 hours prior to colesevelam. Consider therapy modification

Cyclic Antidepressants: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy

DPP-IV Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Fibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Fluconazole: May increase the serum concentration of Sulfonylureas. Management: Seek alternatives when possible. If used together, monitor closely for increased effects of sulfonylureas if fluconazole is initiated/dose increased, or decreased effects if fluconazole is discontinued/dose decreased. Consider therapy modification

GLP-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Metreleptin: May enhance the hypoglycemic effect of Sulfonylureas. Management: Sulfonylurea dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

Miconazole (Oral): May enhance the hypoglycemic effect of Sulfonylureas. Miconazole (Oral) may increase the serum concentration of Sulfonylureas. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C9 Substrates. Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Mitiglinide: May enhance the adverse/toxic effect of Sulfonylureas. Avoid combination

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Probenecid: May decrease the protein binding of Sulfonylureas. Probenecid may increase the serum concentration of Sulfonylureas. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

RaNITIdine: May increase the serum concentration of Sulfonylureas. Monitor therapy

RifAMPin: May decrease the serum concentration of Sulfonylureas. Management: Seek alternatives to these combinations when possible. Monitor closely for diminished therapeutic effects of sulfonylureas if rifampin is initiated/dose increased, or enhanced effects if rifampin is discontinued/dose decreased. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

SGLT2 Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Sulfonamide Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Sulfonylureas may enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Voriconazole: May increase the serum concentration of Sulfonylureas. Monitor therapy

Adverse Reactions

>10%: Endocrine & metabolic: Hypoglycemia (4% to 20%)

1% to 10%:

Central nervous system: Dizziness (2%), headache

Gastrointestinal: Nausea (5%)

Hepatic: Increased serum ALT (2%)

Respiratory: Flu-like symptoms (5%)

Miscellaneous: Accidental injury (6%)

<1% (Limited to important or life-threatening): Abnormal hepatic function tests, accommodation disturbance (early treatment), agranulocytosis, anaphylaxis, angioedema, anorexia, aplastic anemia, cholestatic jaundice, disulfiram-like reaction, epigastric fullness, hemolytic anemia, hepatic failure, hepatic porphyria, hepatitis, hypersensitivity, hypersensitivity angiitis, hyponatremia, hypotension, leukopenia, maculopapular rash, morbilliform rash, pancytopenia, porphyria cutanea tarda, shock, SIADH, skin photosensitivity, Stevens-Johnson syndrome, thrombocytopenia, weight gain

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular mortality: Product labeling states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS) have not supported an association.

• Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used. It is also more likely in elderly patients, malnourished patients and in patients with impaired renal or hepatic function; use with caution.

• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

Disease-related concerns:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Patients with G6PD deficiency may be at an increased risk of sulfonylurea-induced hemolytic anemia; however, cases have also been described in patients without G6PD deficiency during postmarketing surveillance. Use with caution and consider a nonsulfonylurea alternative in patients with G6PD deficiency.

• Hepatic function impairment: Use with caution; patients with hepatic impairment are more likely to develop hypoglycemia.

• Renal function impairment: Use with caution and reduce dosage; patients with renal impairment are more likely to develop hypoglycemia.

• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Special populations:

• CYP2C9 genotype: Systemic exposure of glimepiride is increased in patients with CYP2C9*3 allele; dose reductions may be necessary (Niemi, 2002).

• Elderly: Use with caution; elderly patients are more likely to develop hypoglycemia.

Other warnings/precautions:

• Secondary failure: Loss of efficacy may be observed following prolonged use as a result of the progression of type 2 diabetes mellitus which results in continued beta cell destruction. In patients who were previously responding to sulfonylurea therapy, consider additional factors which may be contributing to decreased efficacy (eg, inappropriate dose, nonadherence to diet and exercise regimen). If no contributing factors can be identified, consider discontinuing use of the sulfonylurea due to secondary failure of treatment. Additional antidiabetic therapy (eg, insulin) will be required.

Monitoring Parameters

Monitor for signs and symptoms of hypoglycemia (fatigue, excessive hunger, profuse sweating, numbness of extremities), fasting blood glucose, hemoglobin A1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a])

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Severe hypoglycemia lasting 4 to 10 days has been noted in infants born to mothers taking a sulfonylurea at the time of delivery.

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2015; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008). Other agents are currently recommended to treat diabetes in pregnant women (ACOG 2013; Blumer 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), arrhythmia, severe dizziness, passing out, vision changes, bruising, bleeding, angina, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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