FDA label 332692e8-dbb8-4178-94bf-ea63b937b1ad

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 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 2 ½ 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 chlorproPAMIDE 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.

ADVERSE REACTIONS Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections. Gastrointestinal Reactions: Cholestatic jaundice may occur rarely; chlorproPAMIDE should be discontinued if this occurs. Gastrointestinal disturbances are the most common reactions; nausea has been reported in less than 5% of patients and diarrhea, vomiting, anorexia, and hunger in less than 2%. Other gastrointestinal disturbances have occurred in less than 1% of patients including proctocolitis. They tend to be dose related and may disappear when dosage is reduced. Dermatologic Reactions: Pruritus has been reported in less than 3% of patients. Other allergic skin reactions, e.g., urticaria and maculopapular eruptions have been reported in approximately 1% or less of patients. These may be transient and may disappear despite continued use of chlorproPAMIDE; if skin reactions persist the drug should be discontinued. Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas. Skin eruptions rarely progressing to erythema multiforme and exfoliative dermatitis have also been reported. Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia, and eosinophilia have been reported with sulfonylureas. Metabolic Reactions: Hepatic porphyria and disulfiram-like reactions have been reported with chlorproPAMIDE. See Drug Interactions section. Endocrine Reactions: On rare occasions, chlorproPAMIDE has caused a reaction identical to the syndrome of inappropriate antidiuretic hormone (ADH) secretion. The features of this syndrome result from excessive water retention and include hyponatremia, low serum osmolality, and high urine osmolality. This reaction has also been reported for other sulfonylureas.