WARNINGS
Amplification of the vasodilatory
effects of dilatrate®
-
SR by sildenafil can result in severe
hypotension. The time course and dose dependence of this
interaction have not been studied. Appropriate supportive care
has not been studied, but it seems reasonable to treat this as a
nitrate overdose, with elevation of the extremities and with
central volume expansion.
The benefits of extended-release oral isosorbide dinitrate in
patients with acute myocardial infarction or congestive heart failure
have not been established. If one elects to use isosorbide dinitrate in
these conditions, careful clinical or hemodynamic monitoring must be
used to avoid the hazards of hypotension and tachycardia. Because the
effects of extended-release oral isosorbide dinitrate are so difficult
to terminate rapidly, this formulation is not recommended in these
settings.
PRECAUTIONS
General
Severe hypotension, particularly with upright posture,
may occur with even small doses of isosorbide dinitrate. 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 isosorbide dinitrate may be
accompanied by paradoxical bradycardia and increased angina
pectoris.
Nitrate therapy may aggravate the angina caused by
hypertrophic cardiomyopathy.
As tolerance to isosorbide dinitrate develops, the effect
of sublingual nitroglycerin on exercise tolerance, although
still observable, is somewhat blunted.
Some clinical trials in angina patients have provided
nitroglycerin for about 12 continuous hours of every 24-hour
day. During the interdosing intervals in some of these trials,
anginal attacks have been more easily provoked than before
treatment and patients have demonstrated hemodynamic rebound and
decreased exercise tolerance. The importance of these
observations to the routine, clinical use of controlled-release
oral isosorbide dinitrate is not known.
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.
Information for Patients
Patients should be told that the antianginal efficacy of
isosorbide dinitrate is strongly related to its dosing regimen,
so the prescribed schedule of dosing should be followed
carefully. In particular, daily headaches sometimes accompany
treatment with isosorbide dinitrate. In patients who get these
headaches, the headaches are a marker of the activity of the
drug. Patients should resist the temptation to avoid headaches
by altering the schedule of their treatment with isosorbide
dinitrate, since loss of headache may be associated with
simultaneous loss of antianginal efficacy. Aspirin and/or
acetaminophen, on the other hand, often successfully relieve
isosorbide dinitrate-induced headaches with no deleterious
effect on isosorbide dinitrate's antianginal efficacy.
Treatment with isosorbide dinitrate 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 consumed alcohol.
Drug Interactions
Concomitant use of dilatrate®-SR with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS).
Concomitant use of dilatrate®-SR with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS).
The vasodilating effects of isosorbide dinitrate may be
additive with those of other vasodilators. Alcohol, in
particular, has been found to exhibit additive effects of this
variety.
Carcinogenesis, Mutagenesis and
Impairment of Fertility
No long-term studies in animals have been performed to
evaluate the carcinogenic potential of isosorbide dinitrate. In
a modified two-litter reproduction study, there was no
remarkable gross pathology and no altered fertility or gestation
among rats fed isosorbide dinitrate at 25 or 100
mg/kg/day.
Pregnancy Category C
At oral doses 35 and 150 times the daily Maximum
Recommended Human Dose (MRHD), isosorbide dinitrate has been
shown to cause a dose related increase in embryotoxicity
(increase in mummified pups) in rabbits. There are no adequate,
well-controlled studies in pregnant women. Isosorbide dinitrate
should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether isosorbide dinitrate is excreted
in human milk. Because many drugs are excreted in human milk,
caution should be exercised when isosorbide dinitrate is
administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not
been established.
Geriatric Use
Clinical studies of dilatrate®-SR did not include
sufficient numbers of subjects aged 65 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.
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