SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY: 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 type 2 diabetes.
The study involved 823 patients who were randomly assigned to one of four treatment groups ( Diabetes , 19, SUPP.
2: 747-830, 1970).
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 glipizide 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.
As with any other non-deformable material, caution should be used when administering glipizide extended-release tablets in patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic).
There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug in this non-deformable sustained release formulation.
Drug Interactions: The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents.
When such drugs are administered to a patient receiving glipizide, the patient should be observed closely for hypoglycemia.
When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for loss of control.
In vitro binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicumarol.
However, caution must be exercised in extrapolating these findings to the clinical situation and in the use of glipizide with these drugs.
Certain drugs tend to produce hyperglycemia and may lead to loss of control.
These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.
When such drugs are administered to a patient receiving glipizide, the patient should be closely observed for loss of control.
When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for hypoglycemia.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported.
Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known.
The effect of concomitant administration of fluconazole and glipizide has been demonstrated in a placebo-controlled crossover study in normal volunteers.
All subjects received glipizide alone and following treatment with 100 mg of fluconazole 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%).
In studies assessing the effect of colesevelam on the pharmacokinetics of glipizide ER in healthy volunteers, reductions in glipizide AUC 0-∞ and C max 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 AUC 0-∞ or C max , -4% and 0%, respectively.
Therefore, glipizide ER should be administered at least 4 hours prior to colesevelam to ensure that colesevelam does not reduce the absorption of glipizide.
There is no well-documented experience with glipizide extended-release tablets overdosage in humans.
There have been no known suicide attempts associated with purposeful overdosing with glipizide extended-release tablets.
In nonclinical studies the acute oral toxicity of glipizide was extremely low in all species tested (LD 50 greater than 4 g/kg).
Overdosage of sulfonylureas including glipizide can produce hypoglycemia.
Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns.
Close monitoring should continue until the physician is assured that the patient is out of danger.
Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization.
If hypoglycemic coma is diagnosed or suspected, the patient should be given rapid intravenous injection of concentrated (50%) glucose solution.
This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL.
Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.
Clearance of glipizide from plasma may be prolonged in persons with liver disease.
Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.
Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.
The Chemical Abstracts name of glipizide is 1-Cyclohexyl-3-[[ p -[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea.
The molecular formula is C 21 H 27 N 5 O 4 S; 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.
Glipizide extended-release tablets are formulated as a polymer matrix based once-a-day controlled release tablet for oral use and is designed to deliver 5 mg or 10 mg of glipizide.
Each tablet contains the following inactive ingredients: acetyltributyl citrate, edible black ink, hydroxyethyl cellulose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type A and polyethylene glycol.
The 5 mg tablet also contains FD&C Yellow #6.
Glipizide Extended-Release Tablets are supplied as 5 mg, and 10 mg round, film-coated tablets and are printed with black ink as follows: 5 mg tablets are orange and printed with WPI and 844 , and are supplied in bottles of 100 (NDC 10370-190-01) and 500 (NDC 10370-190-05).
10 mg tablets are white to off-white and printed with WPI and 845 , and are supplied in bottles of 100 (NDC 10370-191-01) and 500 (NDC 10370-191-05).
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Protect from moisture and humidity.
for: Par Pharmaceutical Companies, Inc.
Spring Valley, NY 10977 U.S.A.
by: Patheon Pharmaceuticals Inc.
Cincinnati, OH 45237 U.S.A.
Issued: December 2014 0S190A-01-85-01
Geriatric Use: Of the total number of patients in clinical studies of glipizide extended-release tablets, 33 percent were 65 and over.
Approximately 1 to 2 days longer were required to reach steady-state in the elderly.
(See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION .)There were no overall differences in effectiveness or safety between younger and older patients, but greater sensitivity of some individuals cannot be ruled out.
As such, it should be noted that elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.
Hypoglycemia may be difficult to recognize in the elderly.
In addition, in elderly, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions.
INDICATIONS AND USAGE
Glipizide extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Pediatric Use: Safety and effectiveness in children have not been established.
Pregnancy: Pregnancy Category C: Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5 to 50 mg/kg).
This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide.
The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide.
In studies in rats and rabbits no teratogenic effects were found.
There are no adequate and well controlled studies in pregnant women.
Glipizide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Because recent information suggests that abnormal blood-glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood-glucose levels as close to normal as possible.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery.
This has been reported more frequently with the use of agents with prolonged half-lives.
If glipizide is used during pregnancy, it should be discontinued at least one month before the expected delivery date.
Nursing Mothers: Although it is not known whether glipizide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk.
Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
INFORMATION FOR PATIENTS
Information for Patients: Patients should be informed that glipizide extended-release tablets should be swallowed whole.
Patients should not chew, divide or crush tablets.
Patients should be informed of the potential risks and advantages of glipizide extended-release tablets and of alternative modes of therapy.
They should also be informed about the importance of adhering to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.
Primary and secondary failure also should be explained.
DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of diabetes mellitus with glipizide extended-release tablets or any other hypoglycemic agent.
Glycemic control should be monitored with hemoglobin A 1C and/or blood-glucose levels to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness.
Home blood-glucose monitoring may also provide useful information to the patient and physician.
Short-term administration of glipizide extended-release tablets may be sufficient during periods of transient loss of control in patients usually controlled on diet.
In general, glipizide extended-release tablets should be given with breakfast.
Recommended Dosing: The usual starting dose of glipizide extended-release tablets as initial therapy is 5 mg per day, given with breakfast.
Those patients who may be more sensitive to hypoglycemic drugs may be started at a lower dose.
Dosage adjustment should be based on laboratory measures of glycemic control.
While fasting blood-glucose levels generally reach steady-state following initiation or change in glipizide extended-release tablet dosage, a single fasting glucose determination may not accurately reflect the response to therapy.
In most cases, hemoglobin A 1C level measured at three month intervals is the preferred means of monitoring response to therapy.
Hemoglobin A 1C should be measured as glipizide extended-release tablet therapy is initiated and repeated approximately three months later.
If the result of this test suggests that glycemic control over the preceding three months was inadequate, the glipizide extended-release tablet dose may be increased.
Subsequent dosage adjustments should be made on the basis of hemoglobin A 1C levels measured at three month intervals.
If no improvement is seen after three months of therapy with a higher dose, the previous dose should be resumed.
Decisions which utilize fasting blood glucose to adjust glipizide extended-release tablet therapy should be based on at least two or more similar, consecutive values obtained seven days or more after the previous dose adjustment.
Most patients will be controlled with 5 mg to 10 mg taken once daily.
However, some patients may require up to the maximum recommended daily dose of 20 mg.
While the glycemic control of selected patients may improve with doses which exceed 10 mg, clinical studies conducted to date have not demonstrated an additional group average reduction of hemoglobin A 1C beyond what was achieved with the 10 mg dose.
Based on the results of a randomized crossover study, patients receiving immediate release glipizide may be switched safely to glipizide extended-release tablets once-a-day at the nearest equivalent total daily dose.
Patients receiving immediate release glipizide also may be titrated to the appropriate dose of glipizide extended-release tablets starting with 5 mg once daily.
The decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section).
Combination Use: When adding other blood-glucose-lowering agents to glipizide extended-release tablets for combination therapy, the agent should be initiated at the lowest recommended dose, and patients should be observed carefully for hypoglycemia.
Refer to the product information supplied with the oral agent for additional information.
When adding glipizide extended-release tablets to other blood-glucose-lowering agents, glipizide extended-release tablets can be initiated at 5 mg.
Those patients who may be more sensitive to hypoglycemic drugs may be started at a lower dose.
Titration should be based on clinical judgment.
When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced.
Therefore, glipizide ER should be administered at least 4 hours prior to colesevelam.
Patients Receiving Insulin: As with other sulfonylurea-class hypoglycemics, many patients with stable type 2 diabetes receiving insulin may be transferred safely to treatment with glipizide extended-release tablets.
When transferring patients from insulin to glipizide extended-release tablets, the following general guidelines should be considered: For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide extended-release tablet therapy may begin at usual dosages.
Several days should elapse between titration steps.
For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and glipizide extended-release tablet therapy may begin at usual dosages.
Subsequent reductions in insulin dosage should depend on individual patient response.
Several days should elapse between titration steps.
During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily.
Patients should be instructed to contact the prescriber immediately if these tests are abnormal.
In some cases, especially when the patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period.
Patients Receiving Other Oral Hypoglycemic Agents: As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to glipizide extended-release tablets.
Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide extended-release tablets due to potential overlapping of drug effect.