Overdose
Hemodynamic Effects
The ill effects of isosorbide dinitrate overdose are generally the results of isosorbide dinitrate’s
capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension. These
hemodynamic changes may have protean manifestations, including increased intracranial pressure, with
any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; visual
disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially
in the upright posture); air hunger and dyspnea, later followed by reduced ventilatory effort;
diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis;
coma; seizures; and death.
Laboratory determinations of serum levels of isosorbide dinitrate and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
isosorbide dinitrate overdose.
There are no data suggesting what dose of isosorbide dinitrate is likely to be life-threatening in humans.
In rats, the median acute lethal dose (LD50 ) was found to be 1100 mg/kg.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the
urine) that might accelerate elimination of isosorbide dinitrate and its active metabolites. Similarly, it is
not known which, if any, of these substances can usefully be removed from the body by hemodialysis.
No specific antagonist to the vasodilator effects of isosorbide dinitrate is known, and no intervention
has been subject to controlled studies as a therapy for isosorbide dinitrate overdose. Because the
hypotension associated with isosorbide dinitrate overdose is the result of venodilatation and arterial
hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid
volume. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal
saline or similar fluid may also be necessary.
The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than
good.
In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion
is not without hazard. Treatment of isosorbide dinitrate overdose in these patients may be subtle and
difficult, and invasive monitoring may be required.
Methemoglobinemia
Nitrate ions liberated during metabolism of isosorbide dinitrate can oxidize hemoglobin into
methemoglobin. Even in patients totally without cytochrome b reductase activity, however, and even
assuming that the nitrate moieties of isosorbide dinitrate are quantitatively applied to oxidation of
hemoglobin, about 1 mg/kg of isosorbide dinitrate should be required before any of these patients
manifests clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function,
significant production of methemoglobin should require even larger doses of isosorbide dinitrate. In
one study in which 36 patients received 2 to 4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4
mg/hr (equivalent, in total administered dose of nitrate ions, to 4.8 to 6.9 mg of bioavailable isosorbide
dinitrate per hour), the average methemoglobin level measured was 0.2%; this was comparable to that
observed in parallel patients who received placebo.
Notwithstanding these observations, there are case reports of significant methemoglobinemia in
association with moderate overdoses of organic nitrates. None of the affected patients had been thought
to be unusually susceptible.
Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected
in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate
arterial pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color
change on exposure to air.
When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg
intravenously.
Contraindications
Isordil Titradose is contraindicated in patients who are allergic to isosorbide dinitrate or any of its
ingredients.
Do not use Isordil Titradose in patients who are taking certain drugs for erectile dysfunction
(phosphodiesterase inhibitors), such as sildenafil, tadalafil, or vardenafil. Concomitant use can cause
severe hypotension, syncope, or myocardial ischemia.
Do not use Isordil Titradose in patients who are taking the soluble guanylate cyclase stimulator
riociguat. Concomitant use can cause hypotension.
Undesirable effects
Adverse reactions to isosorbide dinitrate are generally dose-related, and almost all of these reactions
are the result of isosorbide dinitrate’s activity as a vasodilator. Headache, which may be severe, is the
most commonly reported side effect. Headache may be recurrent with each daily dose, especially at
higher doses. Transient episodes of lightheadedness, occasionally related to blood pressure changes,
may also occur. Hypotension occurs infrequently, but in some patients it may be severe enough to
warrant discontinuation of therapy. Syncope, crescendo angina, and rebound hypertension have been
reported but are uncommon.
Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normalseeming
patients. Methemoglobinemia is so infrequent at these doses that further discussion of its
diagnosis and treatment is deferred (see OVERDOSE).
Data are not available to allow estimation of the frequency of adverse reactions during treatment with
Isordil Titradose tablets.
To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North
America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Therapeutic indications
Isordil (isosorbide dinitrate) Titradose tablets are indicated for the prevention of angina pectoris due to
coronary artery disease. The onset of action of immediate-release oral isosorbide dinitrate is not
sufficiently rapid for this product to be useful in aborting an acute anginal episode.
Pharmacokinetic properties
Absorption of isosorbide dinitrate after oral dosing is nearly complete, but bioavailability is highly
variable (10% to 90%), with extensive first-pass metabolism in the liver. Serum levels reach their
maxima about an hour after ingestion. The average bioavailability of ISDN is about 25%; most studies
have observed progressive increases in bioavailability during chronic therapy.
Once absorbed, the volume of distribution of isosorbide dinitrate is 2 to 4 L/kg, and this volume is
cleared at the rate of 2 to 4 L/min, so ISDN’s half-life in serum is about an hour. Since the clearance
exceeds hepatic blood flow, considerable extra hepatic metabolism must also occur. Clearance is
affected primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%).
Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life of
about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide, glucuronidation
to the 5-mononitrate glucuronide, and denitration/hydration to sorbitol. The 2-mononitrate has been less
well studied, but it appears to participate in the same metabolic pathways, with a half-life of about 2
hours.
The daily dose-free interval sufficient to avoid tolerance to organic nitrates has not been well defined.
Studies of nitroglycerin (an organic nitrate with a very short half-life) have shown that daily dose-free
intervals of 10 to 12 hours are usually sufficient to minimize tolerance. Daily dose-free intervals that
have succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediaterelease
ISDN have generally been somewhat longer (at least 14 hours), but this is consistent with the
longer half-lives of ISDN and its active metabolites.
Few well-controlled clinical trials of organic nitrates have been designed to detect rebound or
withdrawal effects. In one such trial, however, subjects receiving nitroglycerin had less exercise
tolerance at the end of the daily dose-free interval than the parallel group receiving placebo. The
incidence, magnitude, and clinical significance of similar phenomena in patients receiving ISDN have
not been studied.
Date of revision of the text
Oct 2016
Fertility, pregnancy and lactation
At oral doses 35 and 150 times the maximum recommended human daily dose, 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.
Special warnings and precautions for use
WARNINGS
Amplification of the vasodilatory effects of Isordil by sildenafil can result in severe hypotension.
The time course and dose dependence of this interaction have not been studied. Appropriates upportive 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 immediate-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 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 daily dose-free interval 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
immediate-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.
Carcinogenesis, Mutagenesis, 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
At oral doses 35 and 150 times the maximum recommended human daily dose, 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 Isordil (isosorbide dinitrate) Titradose 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.
Dosage (Posology) and method of administration
As noted under CLINICAL PHARMACOLOGY, multiple-dose studies with ISDN and other nitrates
have shown that maintenance of continuous 24-hour plasma levels results in refractory tolerance. Every
dosing regimen for Isordil Titradose tablets must provide a daily dose-free interval to minimize the
development of this tolerance. With immediate-release ISDN, it appears that one daily dose-free
interval must be at least 14 hours long.
As also noted under CLINICAL PHARMACOLOGY, the effects of the second and later doses have
been smaller and shorter-lasting than the effects of the first.
Large controlled studies with other nitrates suggest that no dosing regimen with Isordil Titradose
tablets should be expected to provide more than about 12 hours of continuous anti-anginal efficacy per
day.
As with all titratable drugs, it is important to administer the minimum dose which produces the desired
clinical effect. The usual starting dose of Isordil Titradose is 5 mg to 20 mg, two or three times daily.
For maintenance therapy, 10 mg to 40 mg, two or three times daily is recommended. Some patients may
require higher doses. A daily dose-free interval of at least 14 hours is advisable to minimize tolerance.
The optimal interval will vary with the individual patient, dose and regimen.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
Adverse reactions to isosorbide dinitrate are generally dose-related, and almost all of these reactions
are the result of isosorbide dinitrate’s activity as a vasodilator. Headache, which may be severe, is the
most commonly reported side effect. Headache may be recurrent with each daily dose, especially at
higher doses. Transient episodes of lightheadedness, occasionally related to blood pressure changes,
may also occur. Hypotension occurs infrequently, but in some patients it may be severe enough to
warrant discontinuation of therapy. Syncope, crescendo angina, and rebound hypertension have been
reported but are uncommon.
Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normalseeming
patients. Methemoglobinemia is so infrequent at these doses that further discussion of its
diagnosis and treatment is deferred (see OVERDOSE).
Data are not available to allow estimation of the frequency of adverse reactions during treatment with
Isordil Titradose tablets.
To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North
America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
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.
Concomitant use of Isordil Titradose with phosphodiesterase inhibitors in any form is contraindicated
(see CONTRAINDICATIONS).
Concomitant use of Isordil Titradose with riociguat, a soluble guanylate cyclase stimulator, is
contraindicated (see CONTRAINDICATIONS).
