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warnings
WARNINGS 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.
ADVERSE REACTIONS In U.S. controlled studies the frequency of serious adverse experiences reported was very low and causal relationship has not been established. The 580 patients from 31 to 87 years of age who received glipizide extended-release tablets in doses from 5 mg to 60 mg in both controlled and open trials were included in the evaluation of adverse experiences. All adverse experiences reported were tabulated independently of their possible causal relation to medication. Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections. Only 3.4% of patients receiving glipizide extended-release tablets had hypoglycemia documented by a blood-glucose measurement <60 mg/dL and/or symptoms believed to be associated with hypoglycemia. In a comparative efficacy study of glipizide extended-release tablets and glipizide tablets, hypoglycemia occurred rarely with an incidence of less than 1% with both drugs. In double-blind, placebo-controlled studies the adverse experiences reported with an incidence of 3% or more in glipizide extended-release tablet-treated patients include: Glipizide ER (%) Placebo (%) Adverse Effect (N= 278) (N=69) Asthenia 10.1 13.0 Headache 8.6 8.7 Dizziness 6.8 5.8 Nervousness 3.6 2.9 Tremor 3.6 0.0 Diarrhea 5.4 0.0 Flatulence 3.2 1.4 The following adverse experiences occurred with an incidence of less than 3% in glipizide extended-release tablet-treated patients: Body as a whole–pain Nervous system–insomnia, paresthesia, anxiety, depression and hypesthesia Gastrointestinal–nausea, dyspepsia, constipation and vomiting Metabolic–hypoglycemia Musculoskeletal–arthralgia, leg cramps and myalgia Cardiovascular–syncope Skin–sweating and pruritus Respiratory–rhinitis Special senses–blurred vision Urogenital–polyuria Other adverse experiences occurred with an incidence of less than 1% in glipizide extended-release tablet-treated patients: Body as a whole–chills Nervous system–hypertonia, confusion, vertigo, somnolence, gait abnormality and decreased libido Gastrointestinal–anorexia and trace blood in stool Metabolic–thirst and edema Cardiovascular–arrhythmia, migraine, flushing and hypertension Skin–rash and urticaria Respiratory–pharyngitis and dyspnea Special senses–pain in the eye, conjunctivitis and retinal hemorrhage Urogenital–dysuria Although these adverse experiences occurred in patients treated with glipizide extended-release tablets, a causal relationship to the medication has not been established in all cases. There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug in this non-deformable sustained release formulation, although causal relationship to the drug is uncertain. Postmarketing Experience The following adverse events have been reported in postmarketing surveillance: Gastrointestinal: abdominal pain Hepatobiliary: Cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely in association with glipizide; glipizide extended-release tablets should be discontinued if this occurs. The following are adverse experiences reported with immediate release glipizide and other sulfonylureas, but have not been observed with glipizide extended-release tablets: 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, glipizide pretreatment did not cause an accumulation of acetaldehyde after ethanol administration. Clinical experience to date has shown that glipizide 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 glipizide and other sulfonylureas. Laboratory Tests: The pattern of laboratory test abnormalities observed with glipizide 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 glipizide is uncertain, and they have rarely been associated with clinical symptoms.