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Black Box Warning
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Overview
Glimepiride is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypoglycemia, headache, nausea, and dizziness.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Type 2 Diabetes Mellitus
Glimepiride is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Important Limitations of Use
Glimepiride tablets should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.
Dosing Information
Glimepiride tablets should be administered with breakfast or the first main meal of the day.
The recommended starting dose of glimepiride tablet is 1 mg or 2 mg once daily. Patients at increased risk for hypoglycemia (e.g., the elderly or patients with renal impairment) should be started on 1 mg once daily.
After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently than every 1 to 2 weeks. A conservative titration scheme is recommended for patients at increased risk for hypoglycemia.
The maximum recommended dose is 8 mg once daily.
Patients being transferred to glimepiride from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 1 to 2 weeks and should be appropriately monitored for hypoglycemia.
When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, glimepiride should be administered at least 4 hours prior to colesevelam.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
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Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
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There is limited information regarding Off-Label Guideline-Supported Use of Glimepiride in adult patients.
Non–Guideline-Supported Use
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Dosing Information
Dosage
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There is limited information regarding Off-Label Non–Guideline-Supported Use of Glimepiride in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
Dosing Information
Dosage
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There is limited information regarding FDA-Labeled Use of Glimepiride in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Glimepiride in pediatric patients.
Non–Guideline-Supported Use
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Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Glimepiride in pediatric patients.
Contraindications
Glimepiride tablet is contraindicated in patients with a history of a hypersensitivity reaction to:
Glimepiride or any of the product’s ingredients.
Sulfonamide derivatives: Patients who have developed an allergic reaction to sulfonamide derivatives may develop an allergic reaction to glimepiride. Do not use glimepiride in patients who have a history of an allergic reaction to sulfonamide derivatives.
Reported hypersensitivity reactions include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g. anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea).
Warnings
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Hypoglycemia
All sulfonylureas, including glimepiride, can cause severe hypoglycemia. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.
Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing glimepiride doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti- diabetic medications). Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.
Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.
Hypersensitivity Reactions
There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.
Hemolytic Anemia
Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because glimepiride is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving glimepiride who did not have known G6PD deficiency.
Increased Risk of Cardiovascular Mortality with Sulfonylureas
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2-1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug.
Adverse Reactions
Clinical Trials Experience
The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling:
Hypoglycemia [see Warnings and Precautions ( 5.1) ]
Hemolytic anemia [see Warnings and Precautions ( 5.3) ]
In clinical trials, the most common adverse reactions with glimepiride were hypoglycemia, dizziness, asthenia, headache, and nausea.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Approximately 2,800 patients with type 2 diabetes have been treated with glimepiride in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with glimepiride for at least 1 year.
Table 1 summarizes adverse events, other than hypoglycemia, that were reported in 11 pooled placebo-controlled trials, whether or not considered to be possibly or probably related to study medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported represent those that occurred at an incidence of ≥5% among glimepiride-treated patients and more commonly than in patients who received placebo.
Hypoglycemia:
In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulfonylurea therapy underwent a 3-week washout period then were randomized to glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated [see Clinical Studies (14.1)]. The overall incidence of possible hypoglycemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg and 0% for placebo. All of these events were self-treated.
In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90 to 150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6 or 8 mg [see Clinical Studies (14.1)]. The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride vs. placebo was 19.7% vs. 3.2%. All of these events were self-treated.
Weight gain: glimepiride, like all sulfonylureas, can cause weight gain [see Clinical Studies (14.1)].
Allergic Reactions: In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride- treated patients. These may resolve despite continued treatment with glimepiride. There are postmarketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock) [see Warnings and Precautions (5.2)].
Laboratory Tests:
Elevated Serum Alanine Aminotransferase (ALT): In 11 pooled placebo-controlled trials of glimepiride, 1.9% of glimepiride-treated patients and 0.8% of placebo-treated patients developed serum ALT greater than 2 times the upper limit of the reference range.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of glimepiride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serious hypersensitivity reactions, including anaphylaxis, angioedema, and
Stevens-Johnson Syndrome [see Warnings and Precautions ( 5.2 )]
Hemolytic anemia in patients with and without G6PD deficiency [see Warnings and Precautions ( 5.3)]
Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure.
Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis
Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and pancytopenia
Hepatic porphyria reactions and disulfiram-like reactions
Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone
Drug Interactions
7.1 Drugs Affecting Glucose Metabolism
A number of medications affect glucose metabolism and may require glimepiride dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control.
The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications are administered to a patient receiving glimepiride, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for worsening glycemic control.
The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including glimepiride, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving glimepiride, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for hypoglycemia.
Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of glimepiride’s glucose-lowering effect.
Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of glimepiride in an unpredictable fashion.
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.
7.2 Miconazole
A potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known.
7.3 Cytochrome P450 2C9 Interactions
There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of cytochrome P450 2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may lead to worsening glycemic control.
7.4 Concomitant Administration of Colesevelam
Colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride when the two are coadministered. However, absorption is not reduced when glimepiride is administered 4 hours prior to colesevelam. Therefore, AMARYL should be administered at least 4 hours prior to colesevelam.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of glimepiride in pregnant women. In animal studies there was no increase in congenital anomalies, but 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, observed only at doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has been similarly noted with other sulfonylureas. Glimepiride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because data suggest that abnormal blood glucose during pregnancy is associated with a higher incidence of congenital abnormalities, diabetes treatment during pregnancy should maintain blood glucose as close to normal as possible.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery.
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glimepiride in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Glimepiride during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Glimepiride with respect to nursing mothers.
Pediatric Use
There is no FDA guidance on the use of Glimepiride with respect to pediatric patients.
Geriatic Use
There is no FDA guidance on the use of Glimepiride with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Glimepiride with respect to specific gender populations.
Race
There is no FDA guidance on the use of Glimepiride with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Glimepiride in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Glimepiride in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Glimepiride in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Glimepiride in patients who are immunocompromised.
Administration and Monitoring
Administration
Recommended Dosing
Glimepiride tablets should be administered with breakfast or the first main meal of the day.
The recommended starting dose of glimepiride tablet is 1 mg or 2 mg once daily. Patients at increased risk for hypoglycemia (e.g., the elderly or patients with renal impairment) should be started on 1 mg once daily.
After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently than every 1 to 2 weeks. A conservative titration scheme is recommended for patients at increased risk for hypoglycemia.
The maximum recommended dose is 8 mg once daily.
Patients being transferred to glimepiride from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 1 to 2 weeks and should be appropriately monitored for hypoglycemia.
When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, glimepiride should be administered at least 4 hours prior to colesevelam.
Dosage forms and strengths
Glimepiride tablet is formulated as tablets of:
1 mg tablets (pink coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 1’ on one side and break line on the other)
2 mg tablets (green coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 2’ on one side and break line on the other)
4 mg tablets (blue coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 4’ on one side and break line on the other)
Monitoring
There is limited information regarding Monitoring of Glimepiride in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Glimepiride in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Glimepiride in the drug label.
Pharmacology
There is limited information regarding Glimepiride Pharmacology in the drug label.
The usual starting dose of Glimepiride as initial therapy is 1 to 2 mg once daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1 mg once daily, and should be titrated carefully.
No exact dosage relationship exists between Glimepiride and the other oral hypoglycemic agents. The maximum starting dose of Glimepiride should be no more than 2 mg.
Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy.
