"The U.S. Food and Drug Administration today approved Jardiance (empagliflozin) tablets as an addition to diet and exercise to improve glycemic control in adults with type 2 diabetes.
Type 2 diabetes affects approximately 26 million people a"...
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 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 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 GLUCOTROL XL (glipizide extended release) Extended Release Tablets in patients with preexisting 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.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOTROL XL (glipizide extended release) or any other anti-diabetic drug.
Renal and Hepatic Disease
The pharmacokinetics and/or pharmacodynamics of glipizide may be affected in patients with impaired renal or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted.
Markedly reduced GI retention times of the GLUCOTROL XL (glipizide extended release) Extended Release Tablets may influence the pharmacokinetic profile and hence the clinical efficacy of the drug.
All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may affect the disposition of glipizide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. 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, and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Therapy with a combination of glucose-lowering agents may increase the potential for hypoglycemia.
Loss of Control of Blood Glucose
When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to discontinue glipizide and administer insulin.
The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.
Blood and urine glucose should be monitored periodically. Measurement of hemoglobin A1C may be useful.
Information for Patients
Patients should be informed that GLUCOTROL XL (glipizide extended release) Extended Release Tablets should be swallowed whole. Patients should not chew, divide or crush tablets. Patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.
In the GLUCOTROL XL (glipizide extended release) Extended Release Tablet, the medication is contained within a nonabsorbable shell that has been specially designed to slowly release the drug so the body can absorb it. When this process is completed, the empty tablet is eliminated from the body.
Patients should be informed of the potential risks and advantages of GLUCOTROL XL 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.
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 XL (glipizide extended release) 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 XL (glipizide extended release) or other antidiabetic medications. Maintenance or discontinuation of GLUCOTROL XL (glipizide extended release) or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations.
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 Category C
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 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.
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.
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.
Safety and effectiveness in children have not been established.
Of the total number of patients in clinical studies of GLUCOTROL XL (glipizide extended release) , 33 percent were 65 and over. Approximately 1–2 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.
Last reviewed on RxList: 1/8/2009
This monograph has been modified to include the generic and brand name in many instances.
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