Severe hypotension, particularly with upright posture,
may occur with even small doses of nitroglycerin, particularly in the elderly.
The NITRO-DUR Transdermal Infusion 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
Elderly patients may be more susceptible to hypotension
and may be at greater risk of falling at the therapeutic doses of
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.
Information For Patients
Daily headaches sometimes accompany treatment with
nitroglycerin. In patients who get these headaches, the headaches may be a
marker of the activity of the drug. Patients should resist the temptation to
avoid headaches by altering the schedule of their treatment with nitroglycerin,
since loss of headache may be associated with simultaneous loss of antianginal
Treatment with nitroglycerin may be associated with
lightheadedness on standing, especially just after rising from a recumbent or
seated position. This effect may be more frequent in patients who have also
After normal use, there is enough residual nitroglycerin
in discarded patches that they are a potential hazard to children and pets.
A patient leaflet is supplied with the systems.
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, po, 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 6 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 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 nursing woman.
Safety and effectiveness in pediatric patients have not
Clinical studies of NITRO-DUR Transdermal Infusion System
did not include sufficient 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 the 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.