Glimepiride

Pronunciation: (glye-MEP-ir-ide)
Class: Sulfonylurea

Trade Names

Amaryl
- Tablets 1 mg
- Tablets 2 mg
- Tablets 4 mg

Pharmacology

Decreases blood glucose by stimulating insulin release from pancreas. May also decrease hepatic glucose production as well as increase sensitivity to insulin.

Pharmacokinetics

Absorption

Bioavailability is 100%. C _max is about 103 to 591 ng/mL (dose dependent). T _max is about 2 to 3 h.

Food

T _max increased, and C _max and AUC are slightly decreased.

Distribution

Vd is 8.8 L. Protein binding is more than 99.5%.

Metabolism

Completely metabolized by oxidation via CYP-450 2C9. Major metabolites are cyclohexylhydroxymethyl (M1) (about one-third of the activity of the parent) and carboxyl (M2) derivatives.

Elimination

About 60% is excreted in urine and about 40% in feces as metabolites. The half-life is about 5 to 9.2 h.

Peak

2 to 3 h.

Duration

24 h.

Special Populations

Renal Function Impairment

Serum levels decrease, M1 and M2 levels increase, and half-lives for M1 and M2 increase.

Elderly

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

Children

Mean AUC, C _max , and half-life are comparable with adults.

Gender

No differences in pharmacokinetics when adjustment was made for differences in body weight.

Race

Does not appear to affect the pharmacokinetics.

Indications and Usage

Adjunct to diet and exercise in patients with type 2 diabetes whose hyperglycemia cannot be controlled by diet and exercise alone.

Contraindications

Hypersensitivity to sulfonylureas; diabetic ketoacidosis with or without coma.

Dosage and Administration

Adults

PO 1 to 2 mg daily (max, 2 mg/day initial dose) with breakfast or the first main meal of the day. Increase by 1 to 2 mg/dose. Titrate at 1- to 2-wk intervals based on blood glucose response.

Maintenance

1 and 4 mg daily (max, 8 mg/day). Combination therapy with insulin is appropriate for secondary failure to oral sulfonylureas. The same dosing recommendations apply.

In Combination With Metformin
Adults

PO Obtain desired control of blood glucose by adjusting the dose of each drug; however, make attempts to determine the minimum effective dose of each drug.

In Combination With Insulin
Adults

PO The fasting glucose level for instituting combination therapy is greater than 150 mg/dL. The recommended glimepiride dosage is 8 mg once daily with the first main meal. Start with low-dose insulin and adjust the insulin dose weekly, as guided by fasting blood glucose. Once stabilized, monitor capillary blood glucose daily. Periodic adjustments in insulin may be necessary, as determined by glucose and glycosylated hemoglobin levels.

Renal Impairment, Hepatic Impairment, Debilitated or Malnourished Patients, or Patients With Adrenal or Pituitary Insufficiency
Adults

PO Start at 1 mg once daily and titrate carefully to avoid hypoglycemic reactions.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

ACE inhibitors, beta-blockers, chloramphenicol, clofibrate, diazoxide, fenfluramine, histamine H ₂ antagonists, MAOIs, miconazole, NSAIDs, probenecid, quinolones (eg, ciprofloxacin), salicylates, sulfinpyrazone, sulfonamides, tricyclic antidepressants, urinary acidifiers

May increase hypoglycemic effect.

Alcohol

Produces disulfiram-like reaction (eg, breathlessness, facial flushing, headache).

Corticosteroids, estrogens, isoniazid, nicotinic acid, oral contraceptives, phenothiazines, phenytoin, sympathomimetics, thiazide and other diuretics, thyroid products

These agents may produce hyperglycemia, leading to loss of glycemic control.

Fluconazole, fluvastatin, fluvoxamine, gemfibrozil, ketoconazole

May elevate glimepiride blood levels, increasing the risk of hypoglycemia.

Rifamycins

Glimepiride blood levels may be decreased, increasing the risk of hyperglycemia.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Asthenia, dizziness, headache (2%).

GI

Nausea (1%).

Hematologic-Lymphatic

Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia.

Metabolic

Hepatic porphyria reactions and disulfiram-like reactions, hyponatremia.

Precautions

Monitor

Monitor fasting blood glucose to determine therapeutic response, monitor glycosylated hemoglobin every 3 to 6 mo.

Pregnancy

Category C . Insulin is recommended to maintain blood glucose levels during pregnancy. Prolonged severe neonatal hypoglycemia can occur if sulfonylureas are administered at the time of delivery.

Lactation

Undetermined.

Children

Data are insufficient to recommend the use of glimepiride in children.

Elderly

Increased risk for development of hypoglycemia. Hypoglycemia may be difficult to detect in elderly patients.

Renal Function

Use with caution; lower doses may be adequate.

Hepatic Function

Use with caution; lower doses may be adequate.

Cardiovascular

Oral hypoglycemic agents have been associated with an increase in CV mortality compared with diet alone or diet plus insulin.

G6PD deficiency

Use with caution. May cause hemolytic anemia. Consider a nonsulfonylurea alternative.

Hemolytic anemia

Treatment of patients with G6PD deficiency with sulfonylurias can lead to hemolytic anemia.

Hypoglycemia

All sulfonylurea drugs may cause severe hypoglycemia. Debilitated or malnourished patients; elderly patients; and patients with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to these effects. Combined use of glimepiride with insulin or metformin may increase the potential for hypoglycemia.

Loss of control of blood glucose

Consider combined therapy with metformin or with insulin if diminished responsiveness from secondary failure occurs.

Macrovascular outcomes

No clinical studies establishing conclusive evidence of macrovascular risk reduction.

Overdosage

Symptoms

Coma, confusion, convulsions, hunger, hypoglycemia, lethargy, nausea, stupor, sweating, tachycardia, tingling of lips and tongue, tremor.

Patient Information

Instruct patient in signs, symptoms, and treatment of hypoglycemic reaction.
Review dietary and exercise guidelines for diabetes with patient.
Instruct patient to take dose with breakfast.
Teach patient to self-monitor urine or blood glucose.
Instruct patients to inform all health care providers that they are taking this medicine and to carry medical identification (eg, card, bracelet).
Instruct patient to notify health care provider if symptoms of hypoglycemia occur (eg, excessive hunger, fatigue, numbness of extremities, profuse sweating) or if blood glucose is below 60 mg/dL.
Tell patient to notify health care provider if symptoms of hyperglycemia occur (eg, excessive thirst or urination, urinary glucose or ketones).
Instruct patient to report the following symptoms to health care provider: diarrhea, heartburn, nausea, rash, sore throat, unusual bleeding or bruising, vomiting, or any other adverse reactions.
Advise patient to avoid exposure to sunlight or sunlamps, and to use sunscreen or wear protective clothing to avoid photosensitivity reaction.
Advise patient to check with health care provider before drinking alcohol.