(glipizide extended release tablets)

Prescribing Information
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12 CLINICAL PHARMACOLOGY

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Glipizide primarily lowers blood glucose by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.

12.2 Pharmacodynamics

The insulinotropic response to a meal is enhanced with GLUCOTROL XL administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be enhanced after at least 6 months of treatment. In two randomized, double-blind, dose-response studies comprising a total of 347 patients, there was no significant increase in fasting insulin in all GLUCOTROL XL-treated patients combined compared to placebo, although minor elevations were observed at some doses.

In studies of GLUCOTROL XL in subjects with type 2 diabete mellitus, once daily administration produced reductions in hemoglobin A1c, fasting plasma glucose and postprandial glucose. The relationship between dose and reduction in hemoglobin A1c was not established, however subjects treated with 20 mg had a greater reduction in fasting plasma glucose compared to subjects treated with 5 mg.

12.3 Pharmacokinetics

Absorption

The absolute bioavailability of glipizide was 100% after single oral doses in patients with type 2 diabetes mellitus. Beginning 2 to 3 hours after administration of GLUCOTROL XL, plasma drug concentrations gradually rise reaching maximum concentrations within 6 to 12 hours after dosing. With subsequent once daily dosing of GLUCOTROL XL, plasma glipizide concentrations are maintained throughout the 24 hour dosing interval with less peak to trough fluctuation than that observed with twice daily dosing of immediate release glipizide.

The mean relative bioavailability of glipizide in 21 males with type 2 diabetes mellitus after administration of 20 mg GLUCOTROL XL, compared to immediate release Glucotrol (10 mg given twice daily), was 90% at steady-state. Steady-state plasma concentrations were achieved by at least the fifth day of dosing with GLUCOTROL XL in 21 males with type 2 diabetes mellitus and patients younger than 65 years. No accumulation of drug was observed in patients with type 2 diabetes mellitus during chronic dosing with GLUCOTROL XL.

Administration of GLUCOTROL XL with food has no effect on the 2 to 3 hour lag time in drug absorption. In a single dose, food effect study in 21 healthy male subjects, the administration of GLUCOTROL XL immediately before a high fat breakfast resulted in a 40% increase in the glipizide mean Cmax value, which was significant, but the effect on the AUC was not significant. There was no change in glucose response between the fed and fasting state. Markedly reduced GI retention times of the GLUCOTROL XL tablets over prolonged periods (e.g., short bowel syndrome) may influence the pharmacokinetic profile of the drug and potentially result in lower plasma concentrations.

In a multiple dose study in 26 males with type 2 diabetes mellitus, the pharmacokinetics of glipizide were linear with GLUCOTROL XL in that the plasma drug concentrations increased proportionately with dose. In a single dose study in 24 healthy subjects, four 5-mg, two 10-mg, and one 20-mg GLUCOTROL XL tablets were bioequivalent. In a separate single dose study in 36 healthy subjects, four 2.5-mg GLUCOTROL XL tablets were bioequivalent to one 10-mg GLUCOTROL XL tablet.

Distribution

The mean volume of distribution was approximately 10 liters after single intravenous doses in patients with type 2 diabetes mellitus. Glipizide is 98–99% bound to serum proteins, primarily to albumin.

Metabolism

The major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite, an acetylamino-ethyl benzene derivative, which accounts for less than 2% of a dose, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound.

Elimination

Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is excreted as unchanged drug in urine and feces; approximately 90% of a dose is excreted as biotransformation products in urine (80%) and feces (10%).

The mean total body clearance of glipizide was approximately 3 liters per hour after single intravenous doses in patients with type 2 diabetes mellitus. The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes mellitus.

Specific Populations

Pediatric:

Studies characterizing the pharmacokinetics of glipizide in pediatric patients have not been performed.

Geriatric:

There were no differences in the pharmacokinetics of glipizide after single dose administration to older diabetic subjects compared to younger healthy subjects [see Use in Specific Populations (8.5)].

Renal Impairment:

The pharmacokinetics of glipizide has not been evaluated in patients with varying degree of renal impairment. Limited data indicates that glipizide biotransformation products may remain in circulation for a longer time in subjects with renal impairment than that seen in subjects with normal renal function.

Hepatic Impairment:

The pharmacokinetics of glipizide has not been evaluated in patients with hepatic impairment.

Drug-drug Interactions

Miconazole

A potential interaction between oral miconazole and oral glipizide leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known [see Drug Interactions (7.2)].

Fluconazole

Concomitant treatment with fluconazole increases plasma concentrations of glipizide. The effect of concomitant administration of Diflucan® (fluconazole) and Glucotrol has been demonstrated in a placebo controlled crossover study in healthy volunteers. All subjects received Glucotrol alone and following treatment with 100 mg of Diflucan® as a single daily oral dose for 7 days. The mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81%) [see Drug Interactions (7.3)].

Colesevelam

Colesevelam can reduce the maximum plasma concentration and total exposure of glipizide when the two are coadministered. In studies assessing the effect of colesevelam on the pharmacokinetics of glipizide ER in healthy volunteers, reductions in glipizide AUC0–∞ and Cmax of 12% and 13%, respectively were observed when colesevelam was coadministered with glipizide ER. When glipizide ER was administered 4 hours prior to colesevelam, there was no significant change in glipizide AUC0–∞ or Cmax, -4% and 0%, respectively [see Drug Interactions (7.4)].

Medication Guide

MEDICATION GUIDE

This Patient Information has been approved by the U.S. Food and Drug Administration

Revised 08/2023       

PATIENT INFORMATION
GLUCOTROL XL (GL'UːKˌOTROL)
(glipizide)
extended release tablets

What is GLUCOTROL XL?

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GLUCOTROL XL is a prescription medicine you take by mouth used along with diet and exercise to lower blood sugar in adults with type 2 diabetes mellitus.
•
GLUCOTROL XL is not for people with type 1 diabetes or people with diabetic ketoacidosis.

It is not known if GLUCOTROL XL is safe and effective in children under 18 years of age.

Who Should Not Take GLUCOTROL XL?
Do not use GLUCOTROL XL if you:

•
have a condition called diabetic ketoacidosis
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have ever had an allergic reaction to glipizide or any of the other ingredients in GLUCOTROL XL. See the end of this Patient Information for a complete list of ingredients in GLUCOTROL XL.

What should I tell my doctor before taking GLUCOTROL XL?
Before you take GLUCOTROL XL, tell your healthcare provider if you:

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Have ever had a condition called diabetic ketoacidosis
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Have kidney or liver problems
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Have had a blockage or narrowing of your intestines due to illness or past surgery
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Have chronic (continuing) diarrhea
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Have glucose-6-phosphate dehydrogenase (G6PD) deficiency. This condition usually runs in families. People with G6PD deficiency who take GLUCOTROL XL may develop hemolytic anemia (fast breakdown of red blood cells).
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Are pregnant or might be pregnant. It is not known if GLUCOTROL XL will harm your unborn baby. If you are pregnant, talk to your healthcare provider about the best way to control your blood sugar while you are pregnant. You should not take GLUCOTROL XL during the last two weeks of pregnancy.
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Are breastfeeding or plan to breastfeed. It is not known if GLUCOTROL XL passes into your breast milk. You and your healthcare provider should decide the best way to feed your baby during treatment with GLUCOTROL XL.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
GLUCOTROL XL may affect the way other medicines work, and other medicines may affect how GLUCOTROL XL works.
Some medicines can affect how well GLUCOTROL XL works or may affect you blood sugar level.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take GLUCOTROL XL?

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Take GLUCOTROL XL exactly as your healthcare provider tells you to take it.
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Your healthcare provider will tell you how much GLUCOTROL XL to take and when to take it.
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Take GLUCOTROL XL by mouth, 1 time each day with breakfast or your first meal of the day.
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Each GLUCOTROL XL tablet will release the medicine slowly over 24 hours. This is why you take it only 1 time each day.
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Swallow the GLUCOTROL XL whole. Do not break, crush, dissolve, chew, or cut the tablet in half. This will damage the tablet and release too much medicine into your body at one time.
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When you take GLUCOTROL XL you may see something in your stool that looks like a tablet. This is the empty shell from the tablet. It is normal for the empty shell to pass with your bowel movement after medicine has been absorbed by your body.
•
It is important to take GLUCOTROL XL every day to help keep your blood sugar level under good control. Your healthcare provider may change your dose depending on your blood sugar test results. If your blood sugar level is not under control, call your healthcare provider. Do not change your dose unless your healthcare provider tells you to.
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If you take too much GLUCOTROL XL, call your healthcare provider or go to the nearest emergency room right away.
Your healthcare provider may tell you to take GLUCOTROL XL with other diabetes medicines. Low blood sugar can happen more often when GLUCOTROL XL is taken with other diabetes medicines. See "What are the possible side effects of GLUCOTROL XL?"
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Check your blood sugar as your healthcare provider tells you to.
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Stay on your prescribed diet and exercise program while taking GLUCOTROL XL.

What should I avoid while taking GLUCOTROL XL?

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Do not drink alcohol while taking GLUCOTROL XL. It can increase your chances of getting serious side effects.
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Do not drive, operate machinery, or do other dangerous activities until you know how GLUCOTROL XL affects you.

What are the possible side effects of GLUCOTROL XL?
GLUCOTROL XL can cause serious side effects, including:

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Low blood sugar. GLUCOTROL XL may cause low blood sugar. Signs and symptoms of low blood sugar may include:
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a cold clammy feeling
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unusual sweating
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dizziness
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weakness
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trembling
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shakiness
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hunger
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fast heartbeat
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headache
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blurred vision
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slurred speech
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tingling in the lips or hands

If you have signs or symptoms of low blood sugar, eat or drink something with sugar in it right away. If you do not feel better or your blood sugar level does not go up, call your healthcare provider or go to the nearest emergency room.
The most common side effects of GLUCOTROL XL include: dizziness, diarrhea, nervousness, tremor, and gas.
These are not all the possible side effects of GLUCOTROL XL. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How to store GLUCOTROL XL?

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Store GLUCOTROL XL at room temperature between 68°F to 77°F (20°C to 25°C).
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Store GLUCOTROL XL in a dry place, in its original container.

Keep GLUCOTROL XL and all medicines out of reach of children.

General information about the safe and effective use of GLUCOTROL XL.
Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use GLUCOTROL XL for a condition for which it was not prescribed. Do not give GLUCOTROL XL to other people, even if they have the same symptoms you have. It may harm them.
This Patient Information summarizes the most important information about GLUCOTROL XL. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about GLUCOTROL XL that is written for healthcare professionals.
For more information about GLUCOTROL XL, you can visit the Pfizer internet site at www.pfizer.com.

What are the ingredients in GLUCOTROL XL?
Active ingredient: glipizide
Inactive ingredients: polyethylene oxide, hypromellose, magnesium stearate, sodium chloride, red ferric oxide, cellulose acetate, polyethylene glycol, Opadry® blue (OY-LS-20921), (2.5 mg tablets) Opadry® white (YS 2 7063), (5 mg and 10 mg tablet) Opacode® Black Ink (S-1-17823).

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