Severe hypotension, particularly with upright posture, may
occur with even small doses of nitroglycerin. This drug should therefore be used with
caution in patients who may be volume depleted or who, for whatever reason, are already
hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia
and increased angina pectoris.
Nitrate therapy may aggravate the angina caused by
As tolerance to other forms of nitroglycerin develops, the
effect of sublingual nitroglycerin on exercise tolerance, although still observable,
is somewhat blunted.
In industrial workers who have had long-term exposure to
unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest
pain, acute myocardial infarction, and even sudden death have occurred during temporary
withdrawal of nitrates from these workers, demonstrating the existence of true physical
Several clinical trials in patients with angina pectoris
have evaluated nitroglycerin regimens which incorporated a 10-12 hour nitrate-free
interval. In some of these trials, an increase in the frequency of anginal attacks during the
nitrate-free interval was observed in a small number of patients. In one trial, patients
demonstrated decreased exercise tolerance at the end of the nitrate-free interval. Hemodynamic rebound
has been observed only rarely; on the other hand, few studies were so designed that rebound,
if it had occurred, would have been detected. The importance of these observations to the routine,
clinical use of transdermal nitroglycerin is unknown.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal carcinogenesis studies with topically applied
nitroglycerin have not been performed.
Rats receiving up to 434 mg/kg/day of dietary nitroglycerin
for 2 years developed dose-related fibrotic and neoplastic changes in liver,
including carcinomas, and interstitial cell tumors in testes. At high dose, the incidences of
hepatocellular carcinomas in both sexes were 52% vs. 0% in controls, and incidences of testicular tumors
were 52% vs. 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of
nitroglycerin was not tumorigenic in mice.
Nitroglycerin was weakly mutagenic in Ames tests performed
in two different laboratories. Nevertheless, there was no evidence of
mutagenicity in an in vivo dominant lethal assay with male rats treated with doses up to about
363 mg/kg/day, p.o., or in in vitro cytogenetic tests in rat and dog tissues.
In a three-generation reproduction study, rats received
dietary nitroglycerin at doses up to about 434 mg/kg/day for six months prior to mating of the
F0 generation with treatment continuing through successive F1 and F2 generations. The
high dose was associated with decreased feed intake and body weight gain in both sexes at
all matings. No specific effect on the fertility of the F0 generation was seen. Infertility
noted in subsequent generations, however, was attributed to increased interstitial cell tissue
and aspermatogenesis in the highdose males. In this three-generation study there was no clear
evidence of teratogenicity.
Pregnancy Category C
Animal teratology studies have not been conducted with
nitroglycerin transdermal systems. Teratology studies in rats and rabbits, however, were
conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240
mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested.
There are no adequate and wellcontrolled studies in pregnant women. Nitroglycerin should be given to
a pregnant woman only if clearly needed.
It is not known whether nitroglycerin is excreted in human
milk. Because many drugs are excreted in human milk, caution should be exercised when
nitroglycerin is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been
Clinical studies of transdermal nitroglycerin did not
include sufficient numbers of subjects aged 65 years and over to determine whether they respond
differently 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.