Severe hypotension, particularly with upright posture, may
occur with even small doses of nitroglycerin, particularly in the elderly.
The MINITRAN Transdermal Delivery System should therefore be
used with caution in elderly patients who may be volume depleted,
are on multiple medications, or who, for whatever reason, are already
hypotensive. Hypotension induced by nitroglycerin may be accompanied
by paradoxical bradycardia and increased angina pectoris.
Elderly patients may be more susceptible to hypotension and may be
at greater risk of falling at the therapeutic doses of nitroglycerin.
Nitrate therapy may aggravate the angina caused by hypertrophic
cardiomyopathy, particularly in the elderly.
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 dependence.
Several clinical trials in patients with angina pectoris have evaluated
nitroglycerin regimens which incorporated a 10 to 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 had
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
carcinogenesis studies with topically applied nitroglycerin have not
Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2years
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 363mg/kg/day, p.o., or in vitro cytogenetic
tests in rat and dog tissues.
In a three-generation reproduction study, rats received dietary
nitroglycerin at doses up to about 434mg/kg/day for 6months 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 high-dose 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 well-controlled
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
Safety and effectiveness in pediatric patients have not
Clinical studies of MINITRAN Transdermal Delivery
System did not include suficient information to determine whether
subjects 65 years and older respond differently from younger
subjects. Additional clinical data from the published literature
indicate that the elderly demonstrate increased sensitivity to nitrates,
which may result in hypotension and increased risk of falling. In
general, dose selection for an elderly patient should be cautious,
usually starting at low end of the dosing range, reflecting the greater
frequency of the decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.