Class: Sulfonylureas
VA Class: HS502
Chemical Name: 1-cyclohexyl-3-[[p-[2-(5-methylpyrazine-carboxamido)ethyl]phenyl]sulfonyl]urea
Molecular Formula: C₂₁H₂₇N₅O₄S
CAS Number: 29094-61-9
Brands: Glucotrol, Glucotrol XL

Medically reviewed by Drugs.com on Jun 21, 2021. Written by ASHP.

Introduction

Antidiabetic agent; sulfonylurea.

Uses for Glipizide

Type 2 Diabetes Mellitus

Used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Used in combination with one or more other oral antidiabetic agents or insulin as an adjunct to diet and exercise in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy.

Used in fixed combination with metformin as initial therapy in patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone and as second-line therapy in patients with type 2 diabetes mellitus who have inadequate glycemic control with either sulfonylurea or metformin monotherapy.

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia due to its well-established safety and efficacy (e.g., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).

In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA_1c (>7.5% or ≥1.5% above target). In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other antidiabetic drug classes with complementary mechanisms of action.

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.

For patients with inadequate glycemic control on metformin monotherapy, consider patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preferences when selecting additional antidiabetic agents for combination therapy.

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose of ≥300 mg/dL or HbA_1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.

Manufacturer states that glipizide is not recommended for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis.

Glipizide Dosage and Administration

General

• Adjust dosage according to tolerance and urine and/or fasting blood glucose determinations. Monitor HbA_1c to determine minimum effective dosage or detect primary or secondary failure.

Administration

Oral Administration

Administer extended-release or conventional (immediate-release) tablets once daily, generally with breakfast or the first main meal of the day. Administer conventional tablets approximately 30 minutes before a meal.

Administer the fixed combination of glipizide and metformin once daily with a meal.

Some patients may have a more satisfactory response when conventional tablets are administered in 2 or 3 divided doses daily. When dosage exceeds 15 mg daily as conventional tablets, administer in divided doses before meals of sufficient caloric content.

Extended-release tablets should be swallowed whole and should not be divided, chewed, or crushed.

Administer glipizide at least 4 hours prior to colesevelam when drugs given concomitantly. (See Specific Drugs under Interactions.)

Dosage

Adults

Type 2 Diabetes Mellitus

Initial Dosage in Previously Untreated Patients

Oral

Conventional or extended-release tablets: Initially, 5 mg daily. Titrate dosage of conventional tablets in increments of 2.5–5 mg daily at intervals of at least several days (usually 3–7 days). Maximum once daily dosage, 15 mg.

For extended-release tablets, titrate dosage based on the patient's glycemic control.

Initial Dosage in Patients Transferred from Conventional to Extended-release Glipizide Tablets

Oral

When transferring, administer the nearest equivalent total daily dosage of the extended-release tablets once daily.

Initial Dosage in Patients Transferred from Other Oral Antidiabetic Agents

Oral

Individualize initial dosage of glipizide; usually 5–10 mg daily. The other oral antidiabetic agent may be discontinued abruptly; no transition period generally required.

It has been recommended that patients being transferred from a sulfonylurea agent with a longer half-life (e.g., chlorpropamide [no longer commercially available in the US]) be closely monitored during the initial 1–2 weeks due to potential for overlapping drug effects. A drug-free interval of 2–3 days has been advised before glipizide therapy is initiated as conventional tablets in patients being transferred from chlorpropamide, particularly if blood glucose concentration was adequately controlled with chlorpropamide.

Initial Dosage in Patients Transferred from Insulin

Oral

Insulin requirement ≤20 units daily: Initially, 5 mg of glipizide once daily. May discontinue insulin abruptly.

Insulin requirement >20 units daily: Initially, 5 mg of glipizide once daily and reduce insulin dosage by 50%. Withdraw insulin gradually and adjust daily glipizide dosage at intervals of at least several days according to tolerance and response.

Maintenance Dosage

Oral

Maintenance dosage varies considerably, ranging from 2.5–40 mg daily.

Conventional tablets: Generally, 5–25 mg daily.

Extended-release tablets: Generally, 5–10 mg daily.

Combination Therapy with Other Oral Antidiabetic Agents

Oral

When added to therapy with other antidiabetic agents, may initiate glipizide extended-release tablets at a dosage of 5 mg daily. May use lower initial dosages in patients at risk for hypoglycemia.

May initiate fixed combination of 2.5 mg of glipizide and 250 mg of metformin hydrochloride once daily with a meal in treatment-naive patients.

For more severe hyperglycemia (i.e., fasting plasma glucose concentrations of 280–320 mg/dL), consider 2.5 mg of glipizide and 500 mg of metformin hydrochloride as fixed combination twice daily. Efficacy of fixed combination in patients with fasting plasma glucose concentrations >320 mg/dL not established.

May increase dosage of fixed combination in increments of one tablet (using the tablet strength at which therapy was initiated, either 2.5 mg glipizide/250 mg metformin hydrochloride or 2.5 mg glipizide/500 mg metformin hydrochloride) daily every 2 weeks until the minimum effective dosage required to achieve adequate glycemic control is reached.

Maximum daily dosage of fixed combination in treatment-naive patients is 10 mg of glipizide and 2 g of metformin hydrochloride given in divided doses.

In previously treated patients with inadequate glycemic control on sulfonylurea (e.g., glipizide) or metformin monotherapy, initiate fixed-combination therapy with 2.5 mg of glipizide and 500 mg of metformin hydrochloride or 5 mg of glipizide and 500 mg of metformin hydrochloride twice daily with the morning and evening meals.

To minimize hypoglycemia risk, do not exceed the initial daily dosage of glipizide or metformin hydrochloride already being taken.

Titrate dosage upward in increments not exceeding 5 mg of glipizide and 500 mg of metformin hydrochloride until adequate glycemic control or a maximum daily dosage of 20 mg of glipizide and 2 g of metformin hydrochloride is reached in patients on sulfonylurea or metformin monotherapy.

For patients being switched from therapy with both glipizide (or another sulfonylurea antidiabetic agent) and metformin, the initial dosage of the fixed-combination preparation should not exceed the daily dosages of glipizide (or equivalent dosage of another sulfonylurea) and metformin hydrochloride currently being taken. Monitor for signs and symptoms of hypoglycemia following the switch. In the transfer, base decision on whether to switch to the nearest equivalent dosage or to titrate dosage on clinical judgment.

Prescribing Limits

Adults

Type 2 Diabetes Mellitus

Oral

Maximum once-daily dosage as conventional tablets is 15 mg.

Maximum total daily dosage is 40 mg as divided doses of conventional tablets or 20 mg as extended-release tablets.

Maximum total daily dosage of fixed combination in treatment-naive patients is 10 mg of glipizide and 2 g of metformin hydrochloride in divided doses.

Maximum total daily dosage of fixed combination in patients with inadequate glycemic control on sulfonylurea and/or metformin therapy is 20 mg of glipizide and 2 g of metformin hydrochloride in divided doses.

Special Populations

Hepatic Impairment

Conventional tablets: Initially, 2.5 mg daily; conservative maintenance dosage.

Extended-release tablets: Use conservative initial and maintenance dosage.

Adjust dosage carefully.

Generally, do not use in patients with severe hepatic impairment.

Renal Impairment

Use conservative initial and maintenance dosage.

Use generally not recommended in patients with severe renal impairment.

Cautious dosing recommended.

Geriatric Patients

Conventional tablets: Initially, 2.5 mg daily.

Initially, 5 mg (extended-release tablets) may be used.

Use conservative initial and maintenance dosage of glipizide-containing formulations.

Adjust dosage carefully. Any dosage adjustment of glipizide in fixed combination with metformin hydrochloride requires careful assessment of renal function.

Dosage of glipizide and metformin hydrochloride in fixed combination should not be titrated to the maximum dosage.

Debilitated or Malnourished Patients

Conservative initial and maintenance dosage of conventional and extended-release tablets.

Dosage of glipizide and metformin hydrochloride in fixed combination should not be titrated to the maximum dosage.

Cautions for Glipizide

Contraindications

• Known hypersensitivity to glipizide or any ingredient in the formulation.

• Hypersensitivity to sulfonamide derivatives.

Warnings/Precautions

Hypoglycemia

Reported infrequently; usually mild.

Possible severe and/or prolonged hypoglycemia, especially in geriatric or malnourished patients and those with adrenal, pituitary, hepatic, or renal insufficiency. Strenuous exercise, alcohol ingestion (see Interactions), insufficient caloric intake, or use in combination with other antidiabetic agents (see Interactions) may increase hypoglycemia risk. Severe hypoglycemia can lead to unconsciousness or seizures; may result in temporary or permanent impairment of brain function or death.

Appropriate patient selection and careful attention to dosage are important to avoid glipizide-induced hypoglycemia.

Loss of Glycemic Control

Possible loss of glycemic control during periods of stress (e.g., fever of any cause, trauma, infection, surgery).

Temporary discontinuance of glipizide and administration of insulin may be required.

Hematologic Effects

Hemolytic anemia may develop in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency who receive sulfonylureas; consider a non-sulfonylurea antidiabetic agent in patients with G6PD deficiency.

Cardiovascular Effects

Possible increased cardiovascular mortality reported with other sulfonylurea antidiabetic agents (i.e., tolbutamide or phenformin). However, the American Diabetes Association (ADA) has stated that the benefits of intensive glycemic control with insulin or sulfonylureas outweigh the risks overall.

Macrovascular Outcomes

Manufacturer states that no clinical studies have conclusively established macrovascular risk reduction with glipizide or any other antidiabetic drug.

GI Obstruction

Use extended-release tablets with caution in patients with severe preexisting GI narrowing, since obstruction may occur.

Use of Fixed Combinations

When use in fixed combination with metformin hydrochloride, consider the cautions, precautions, contraindications, and interactions associated with metformin.

Specific Populations

Pregnancy

Category C.

Sulfonylureas cross the placenta and have been associated with neonatal adverse reactions (e.g., hypoglycemia); prolonged, severe hypoglycemia reported in some neonates born to women receiving sulfonylureas up to time of delivery. Observe neonates for symptoms of hypoglycemia and respiratory distress and manage accordingly.

Many experts recommend that insulin be used during pregnancy.

Lactation

Not known whether glipizide is distributed into milk; discontinue nursing or the drug.

If glipizide used during breast-feeding, monitor infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

Pediatric Use

Safety and efficacy not established. However, ADA has stated that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater compliance and convenience and lack of evidence demonstrating better efficacy of insulin for type 2 diabetes mellitus.

Geriatric Use

Increased risk of hypoglycemia. Cautious and conservative dosing recommended. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Increased risk of hypoglycemia. Cautious and conservative dosing recommended. (See Hepatic Impairment under Dosage and Administration.)

Avoidance in severe impairment has been recommended.

Renal Impairment

Increased risk of hypoglycemia. Cautious and conservative dosing recommended. (See Renal Impairment under Dosage and Administration.)

Avoidance in severe impairment has been recommended.

Common Adverse Effects

Conventional tablets: Nausea, anorexia, vomiting, pyrosis, gastralgia, diarrhea, constipation.

Extended-release tablets: Dizziness, diarrhea, nervousness, tremor, hypoglycemia, flatulence.

Glipizide/metformin hydrochloride fixed combination: Upper respiratory tract infection, diarrhea, dizziness, hypertension, nausea/vomiting, musculoskeletal pain, headache, abdominal pain, urinary tract infection.

Interactions for Glipizide

Protein-bound Drugs

Potential pharmacokinetic interaction with other protein-bound drugs.

Use with caution with protein-bound drugs.

Specific Drugs

Glipizide Pharmacokinetics

Absorption

Bioavailability

Absorption is essentially complete; 80–100% of an oral dose may be absorbed.

Onset

Conventional tablets: 15–30 minutes.

Duration

Conventional tablets: In nonfasting diabetic patients, the hypoglycemic action may persist for up to 24 hours.

Food

Glipizide conventional tablets: Food delays absorption but does not affect peak serum concentrations or extent of absorption. Peak serum concentrations following administration of conventional tablets generally are delayed 20–40 minutes in the nonfasting state compared with the fasting state.

Fixed combination of glipizide and metformin: Food delays peak plasma glipizide concentration by 1 hour.

Glipizide extended-release tablets: Food does not affect glycemic response or time to absorption. Peak blood concentration following administration of extended-release tablets with food increased.

Distribution

Extent

Following IV administration in mice, distributed into the liver and blood, with lower concentrations in the lungs, kidneys, adrenals, myocardium, salivary glands, and retroscapular fat. In humans, small amounts of glipizide are apparently distributed into bile and very small amounts are distributed into erythrocytes and saliva.

Not known if glipizide is distributed into milk.

Plasma Protein Binding

92–99%.

Elimination

Metabolism

Appears to be almost completely metabolized, mainly in the liver.

Elimination Route

Glipizide and its metabolites are excreted principally in urine (60–90%) and to a lesser extent in feces (5–20%).

Half-life

Terminal elimination half-life of glipizide averages 3–4.7 hours following oral administration in patients with normal renal and hepatic function.

Terminal elimination half-life of total glipizide metabolites ranges from 2–6 hours.

Special Populations

Renal or hepatic impairment may increase serum glipizide concentrations and reduce elimination.

Severe renal impairment may decrease the renal excretion of and increase the terminal elimination half-life of glipizide metabolites.

No differences in glipizide pharmacokinetics observed following single-dose administration to older diabetic patients compared with that in younger healthy individuals.

Stability

Storage

Oral

Tablets (conventional)

Tight, light-resistant containers at 20–25°C.

Tablets (extended-release)

20–25°C (may be exposed to 15–30°C); protect from moisture and humidity.

Tablets (fixed-combination)

20–25°C (may be exposed to 15–30°C).

Actions

• Sulfonylurea antidiabetic agent.

• Lowers blood glucose concentration in diabetic and nondiabetic individuals.

• Stimulates secretion of postprandial endogenous insulin from the beta cells of the pancreas.

• During prolonged administration, extrapancreatic effects such as enhanced peripheral sensitivity to insulin and reduction of basal hepatic glucose production contribute to the hypoglycemic action.

Advice to Patients

• Importance of regular clinical and laboratory evaluations, including blood and urine glucose determinations.

• Importance of adherence to diet and exercise regimen.

• Understanding of primary and secondary failure to oral sulfonylurea antidiabetic agents.

• Risks of hypoglycemia, the symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of hypoglycemic reactions.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of advising breast-feeding women taking glipizide to monitor breast-fed infants for signs of hypoglycemia. (See Lactation under Cautions.)

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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