Amplification of the vasodilatory effects of isosorbide dinitrate 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 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.
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 isosorbide dinitrate with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS ).
Concomitant use of isosorbide dinitrate tablets with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS ).
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 (LD 50 ) 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 5 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 (greater than or equal to 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 mg/hr to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to 4.8 mg 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 pO 2 .
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 mg/kg to 2 mg/kg intravenously.
Isosorbide dinitrate (ISDN) is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate, an organic nitrate whose structural formula is: The organic nitrates are vasodilators, active on both arteries and veins.
Isosorbide dinitrate is a white, crystalline, odorless compound which is stable in air and in solution, has a melting point of 70°C and has an optical rotation of +134° (c=1, alcohol, 20°C).
Isosorbide dinitrate is freely soluble in organic solvents such as acetone, alcohol, and ether, but is only sparingly soluble in water.
Isosorbide dinitrate is available as 5 mg, 10 mg, and 20 mg tablets for oral administration.
Inactive ingredients: lactose (monohydrate), magnesium stearate, microcrystalline cellulose.
The 5 mg also contains FD & C Red #40 Aluminum Lake.
The 20 mg also contains D & C Yellow #10 Aluminum Lake, FD & C Blue #1 Aluminum Lake, and FD & C Yellow #6 Aluminum Lake.
Isosorbide Dinitrate Chemical Structure
Clinical Trials In clinical trials, immediate-release oral isosorbide dinitrate has been administered in a variety of regimens, with total daily doses ranging from 30 mg to 480 mg.
Controlled trials of single oral doses of isosorbide dinitrate have demonstrated effective reductions in exercise-related angina for up to 8 hours.
Anti-anginal activity is present about 1 hour after dosing.
Most controlled trials of multiple-dose oral ISDN taken every 12 hours (or more frequently) for several weeks have shown statistically significant anti-anginal efficacy for only 2 hours after dosing.
Once-daily regimens, and regimens with one daily dose-free interval of at least 14 hours (e.g., a regimen providing doses at 0800, 1400, and 1800 hours), have shown efficacy after the first dose of each day that was similar to that shown in the single-dose studies cited above.
The effects of the second and later doses have been smaller and shorter-lasting than the effect of the first.
From large, well-controlled studies of other nitrates, it is reasonable to believe that the maximal achievable daily duration of anti-anginal effect from isosorbide dinitrate is about 12 hours.
No dosing regimen for isosorbide dinitrate, however, has ever actually been shown to achieve this duration of effect.
One study of 8 patients, who were administered a pretitrated dose (average 27.5 mg) of immediate-release ISDN at 0800, 1300, and 1800 hours for 2 weeks, revealed that significant anti-anginal effectiveness was discontinuous and totaled about 6 hours in a 24 hour period.
Isosorbide dinitrate tablets, USP are supplied as: 5 mg: Round, pink, scored tablets, debossed GG 259 on one side and plain on the reverse side, and supplied as: Unit dose packages of 30 (5 x 6) NDC 68084-894-25 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Protect from moisture.
FOR YOUR PROTECTION: Do not use if blister is torn or broken.
Geriatric Use Clinical studies of isosorbide dinitrate 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.
INDICATIONS AND USAGE
Isosorbide dinitrate 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.
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Pregnancy Pregnancy Category C 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.
INFORMATION FOR PATIENTS
Information for Patients Patients should be told that the anti-anginal 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 anti-anginal efficacy.
Aspirin and/or acetaminophen, on the other hand, often successfully relieve isosorbide dinitrate-induced headaches with no deleterious effect on isosorbide dinitrate’s anti-anginal 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.
DOSAGE AND 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 isosorbide dinitrate 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 isosorbide dinitrate 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 isosorbide dinitrate 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.