[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.517]

[Page 35-36]
 
                        TITLE 21--FOOD AND DRUGS
 
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                           SERVICES--Continued
 
PART 310--NEW DRUGS--Table of Contents
 
        Subpart E--Requirements for Specific New Drugs or Devices
 
Sec. 310.517  Labeling for oral hypoglycemic drugs of the sulfonylurea class.

    (a) The University Group Diabetes Program clinical trial has 
reported an association between the administration of tolbutamide and 
increased cardiovascular mortality. The Food and Drug Administration has 
concluded that this reported association provides adequate basis for a 
warning in the labeling. In view of the similarities in chemical 
structure and mode of action, the Food and Drug Administration also 
believes it is prudent from a safety standpoint to consider that the 
possible increased risk of cardiovascular mortality from tolbutamide 
applies to all other sulfonylurea drugs as well. Therefore, the labeling 
for oral hypoglycemic drugs of the sulfonylurea class shall include a 
warning concerning the possible increased risk of cardiovascular 
mortality associated with such use, as set forth in paragraph (b) of 
this section.
    (b) Labeling for oral hypoglycemic drugs of the sulfonylurea class 
shall include in boldface type at the beginning of the ``Warnings'' 
section of the labeling the following statement:

      Special Warning on Increased Risk of Cardiovascular Mortality

    The administration of oral hypoglycemic drugs has been reported to 
be associated

[[Page 36]]

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\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 (name of drug) 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.

[49 FR 14331, Apr. 11, 1984]