Glipizide XL

: Immediate-release tablets; 5 and 10 mg. Extended-release tablets; 2.5, 5, and 10 mg.

Glipizide should be stored between 15 C and 30 C (59 F and 86 F).

Glipizide XL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use

Glipizide XL is not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Glipizide is contraindicated in patients with:

• Known hypersensitivity to glipizide or any of the product's ingredients.
• Hypersensitivity to sulfonamide derivatives.

Glipizide XL (glipizide) is an oral sulfonylurea.

The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl] phenyl]sulfonyl]urea. The molecular formula is C21H27N5O4S; the molecular weight is 445.55; the structural formula is shown below:

Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide.

Inert ingredients in the 2.5 mg, 5 mg and 10 mg formulations are: 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) and Opacode® Black Ink (S-1-17823).

System Components and Performance

Glipizide XL Extended Release Tablet is similar in appearance to a conventional tablet. It consists, however, of an osmotically active drug core surrounded by a semipermeable membrane. The core itself is divided into two layers: an "active" layer containing the drug, and a "push" layer containing pharmacologically inert (but osmotically active) components. The membrane surrounding the tablet is permeable to water but not to drug or osmotic excipients. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and "pushes" against the drug layer, resulting in the release of drug through a small, laser-drilled orifice in the membrane on the drug side of the tablet.

The function of the Glipizide XL Extended Release Tablet depends upon the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the GI tract. The biologically inert components of the tablet remain intact during GI transit and are eliminated in the feces as an insoluble shell.

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.

Pharmacodynamics

The insulinotropic response to a meal is enhanced with Glipizide 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 Glipizide XL-treated patients combined compared to placebo, although minor elevations were observed at some doses.

In studies of Glipizide 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.

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 Glipizide XL, plasma drug concentrations gradually rise reaching maximum concentrations within 6 to 12 hours after dosing. With subsequent once daily dosing of Glipizide 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 Glipizide XL, compared to immediate release Glipizide (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 Glipizide 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 Glipizide XL.

Administration of Glipizide 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 Glipizide 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 Glipizide 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 Glipizide 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 Glipizide XL tablets were bioequivalent. In a separate single dose study in 36 healthy subjects, four 2.5-mg Glipizide XL tablets were bioequivalent to one 10-mg Glipizide 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 Glipizide has been demonstrated in a placebo controlled crossover study in healthy volunteers. All subjects received Glipizide 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)]

Carcinogenesis, Mutagenesis, Impairment of Fertility

A twenty month study in rats and an eighteen month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Inform patients of the potential adverse reactions of Glipizide XL including hypoglycemia. Explain the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development to patients and responsible family members. Also inform patients about the importance of adhering to dietary instructions, of a regular exercise program, and of regular testing of glycemic control.

Inform patients that Glipizide XL should be swallowed whole. Inform patients that they should not chew, divide or crush tablets and they may occasionally notice in their stool something that looks like a tablet. In the Glipizide XL tablet, the medication is contained within a non-dissolvable shell that has been specially designed to slowly release the drug so the body can absorb it.

Advise patients with diabetes to inform their healthcare provider if they are pregnant, contemplating pregnancy, breastfeeding, or contemplating breastfeeding.

For more information, go to www.greenstonellc.com or call 1-800-438-1985.

LAB-0330-12.0

NDC 59762-0542-1
100 Tablets

GREENSTONE® BRAND

Glipizide XL
(glipizide)
extended-release
tablets

10 mg

Rx only

Glipizide is an oral diabetes medicine that helps control blood sugar levels by helping your pancreas produce insulin.

Glipizide is used together with diet and exercise to treat type 2 diabetes.

Glipizide may also be used for purposes not listed in this medication guide.

Applies to glipizide: oral tablet, oral tablet extended release

Along with its needed effects, glipizide (the active ingredient contained in GlipiZIDE XL) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking glipizide:

• Anxiety
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chills
• cold sweats
• coma
• confusion
• cool, pale skin
• depression
• difficulty with moving
• dizziness
• fainting
• fast heartbeat
• headache
• increased hunger
• joint pain
• leg cramps
• muscle aching or cramping
• muscle pain or stiffness
• nausea
• nervousness
• nightmares
• pain in the joints
• problems in urination or increase in the amount of urine
• seizures
• shakiness
• slurred speech
• sweating
• swollen joints
• unusual tiredness or weakness

• Abdominal or stomach pain
• bloating
• bloody or black, tarry stools
• body aches or pain
• burning, dry, or itching eyes
• clay-colored stools
• congestion
• constipation
• cough
• dark urine
• decreased vision or other changes in vision
• diarrhea
• difficult or labored breathing
• difficult or painful urination
• dryness or soreness of the throat
• excessive tearing
• fainting
• fast, slow, or irregular heartbeat
• feeling of warmth
• fever
• heartburn
• hoarseness
• indigestion
• itching
• loss of appetite
• pain in the eye
• pounding in the ears
• rash
• redness of the face, neck, arms and occasionally, upper chest
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• runny nose
• severe stomach pain
• shortness of breath
• tender, swollen glands in the neck
• tightness in the chest
• trouble in swallowing
• unpleasant breath odor
• voice changes
• vomiting of blood or material that looks like coffee grounds
• wheezing
• yellow eyes or skin

• Agitation
• back or leg pains
• bleeding gums
• blood in the urine or stools
• chest pain
• convulsions
• decreased urine output
• fluid-filled skin blisters
• general body swelling
• general feeling of tiredness or weakness
• high fever
• hostility
• increased thirst
• irritability
• lethargy
• light-colored stools
• lower back or side pain
• muscle twitching
• nosebleeds
• pinpoint red pots on the skin
• rapid weight gain
• sensitivity to the sun
• skin thinness
• sores, ulcers, or white spots on the lips or in the mouth
• stupor
• swelling of the face, ankles, or hands
• unusual bleeding or bruising

Some side effects of glipizide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Indigestion
• passing of gas

• Acid or sour stomach
• belching
• excess air or gas in the stomach or intestines
• full feeling
• pain
• sleeplessness
• sneezing
• stuffy nose
• trouble sleeping
• unable to sleep

• Decreased interest in sexual intercourse
• dizziness or lightheadedness
• excessive muscle tone
• feeling of constant movement of self or surroundings
• flushing or redness of the skin
• headache, severe and throbbing
• hives or welts
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance
• mood or mental changes
• muscle stiffness
• muscle tension or tightness
• sensation of spinning
• skin rash, encrusted, scaly, and oozing
• sleepiness or unusual drowsiness
• unusually warm skin
• walking in unusual manner
• weight loss

• Increased sensitivity of the skin to sunlight
• severe sunburn