Mechanism of Action:

The primary mode of action of GLUCOTROL in experimental animals appears to be the stimulation of insulin secretion from the beta cells of pancreatic islet tissue and is thus dependent on functioning beta cells in the pancreatic islets. In humans, GLUCOTROL appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which GLUCOTROL lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by GLUCOTROL in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term GLUCOTROL administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of GLUCOTROL in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Blood sugar control persists in some patients for up to 24 hours after a single dose of GLUCOTROL, even though plasma levels have declined to a small fraction of peak levels by that time (see Pharmacokinetics below).

Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including GLUCOTROL. Alternatively, GLUCOTROL may be effective in some patients who have not responded or have ceased to respond to other sulfonylureas.

Other Effects:

It has been shown that GLUCOTROL therapy was effective in controlling blood sugar without deleterious changes in the plasma lipoprotein profiles of patients treated for NIDDM.

In a placebo-controlled, crossover study in normal volunteers, GLUCOTROL had no antidiuretic activity and, in fact, led to a slight increase in free water clearance.

Pharmacokinetics:

Gastrointestinal absorption of GLUCOTROL in man is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1–3 hours after a single oral dose. The half-life of elimination ranges from 2–4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the two routes of administration, indicating that first-pass metabolism is not significant. GLUCOTROL does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes. Thus, GLUCOTROL was more effective when administered about 30 minutes before, rather than with, a test meal in diabetic patients. Protein binding was studied in serum from volunteers who received either oral or intravenous GLUCOTROL and found to be 98–99% one hour after either route of administration. The apparent volume of distribution of GLUCOTROL after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. In mice, no GLUCOTROL or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labelled drug.

The metabolism of GLUCOTROL is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine. Less than 10% unchanged GLUCOTROL is found in the urine.

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 non-insulin-dependent 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 2½ 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 GLUCOTROL 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.

General

Laboratory Tests:

Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful.

Information for Patients:

Patients should be informed of the potential risks and advantages of GLUCOTROL 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 should also be explained.

Physician Counseling Information for Patients:

In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. Use of GLUCOTROL or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of GLUCOTROL or other antidiabetic medications. Maintenance or discontinuation of GLUCOTROL or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations.

Drug Interactions:

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents, some azoles, and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, quinolones and beta adrenergic blocking agents. When such drugs are administered to a patient receiving GLUCOTROL, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving GLUCOTROL, the patient should be observed closely for loss of control. In vitro binding studies with human serum proteins indicate that GLUCOTROL 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 GLUCOTROL 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 GLUCOTROL, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving GLUCOTROL, 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 DIFLUCAN® (fluconazole) and GLUCOTROL has been demonstrated in a placebo-controlled crossover study in normal 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 GLUCOTROL 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 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. Therefore, GLUCOTROL should be administered at least 4 hours prior to colesevelam to ensure that colesevelam does not reduce the absorption of glipizide.

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.

Pregnancy:

GLUCOTROL (glipizide) was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5–50 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 GLUCOTROL. In studies in rats and rabbits, no teratogenic effects were found. There are no adequate and well controlled studies in pregnant women. GLUCOTROL 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 GLUCOTROL 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 GLUCOTROL 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.

Pediatric Use:

Safety and effectiveness in children have not been established.

Geriatric Use:

A determination has not been made whether controlled clinical studies of GLUCOTROL included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hypoglycemia:

See PRECAUTIONS and OVERDOSAGE sections.

Gastrointestinal:

Gastrointestinal disturbances are the most common reactions. Gastrointestinal complaints were reported with the following approximate incidence: nausea and diarrhea, one in seventy; constipation and gastralgia, one in one hundred. They appear to be dose-related and may disappear on division or reduction of dosage. Cholestatic jaundice may occur rarely with sulfonylureas: GLUCOTROL should be discontinued if this occurs.

Dermatologic:

Allergic skin reactions including erythema, morbilliform or maculopapular eruptions, urticaria, pruritus, and eczema have been reported in about one in seventy patients. These may be transient and may disappear despite continued use of GLUCOTROL; if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic:

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic:

Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas. In the mouse, GLUCOTROL pretreatment did not cause an accumulation of acetaldehyde after ethanol administration. Clinical experience to date has shown that GLUCOTROL has an extremely low incidence of disulfiram-like alcohol reactions.

Endocrine Reactions:

Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with this and other sulfonylureas.

Miscellaneous:

Dizziness, drowsiness, and headache have each been reported in about one in fifty patients treated with GLUCOTROL. They are usually transient and seldom require discontinuance of therapy.

Laboratory Tests:

The pattern of laboratory test abnormalities observed with GLUCOTROL was similar to that for other sulfonylureas. Occasional mild to moderate elevations of SGOT, LDH, alkaline phosphatase, BUN, and creatinine were noted. One case of jaundice was reported. The relationship of these abnormalities to GLUCOTROL is uncertain, and they have rarely been associated with clinical symptoms.

Post-Marketing Experience

The following adverse events have been reported in post-marketing surveillance:

Initial Dose:

The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver disease may be started on 2.5 mg.

Titration:

Dosage adjustments should ordinarily be in increments of 2.5–5 mg, as determined by blood glucose response. At least several days should elapse between titration steps. If response to a single dose is not satisfactory, dividing that dose may prove effective. The maximum recommended once daily dose is 15 mg. Doses above 15 mg should ordinarily be divided and given before meals of adequate caloric content. The maximum recommended total daily dose is 40 mg.

Maintenance:

Some patients may be effectively controlled on a once-a-day regimen, while others show better response with divided dosing. Total daily doses above 15 mg should ordinarily be divided. Total daily doses above 30 mg have been safely given on a b.i.d. basis to long-term patients.

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).

Patients Receiving Insulin:

As with other sulfonylurea-class hypoglycemics, many stable non-insulin-dependent diabetic patients receiving insulin may be safely placed on GLUCOTROL. When transferring patients from insulin to GLUCOTROL, the following general guidelines should be considered:

 

For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and GLUCOTROL therapy may begin at usual dosages. Several days should elapse between GLUCOTROL titration steps.

 

For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and GLUCOTROL therapy may begin at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response. Several days should elapse between GLUCOTROL 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 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 GLUCOTROL. Patients should be observed carefully (1–2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to GLUCOTROL due to potential overlapping of drug effect.

When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced. Therefore, GLUCOTROL should be administered at least 4 hours prior to colesevelam.

RECOMMENDED STORAGE:

Store below 86°F (30°C).