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Isosorbide Dinitrate

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Overview

What is Dilatrate?

Isosorbide dinitrate (ISDN) is 1,4:3,6-dianhydro-D-glucitol 2,5 dinitrate, an organic nitrate whose structural formula is:

and whose molecular weight is 236.14. The organic nitrates are vasodilators, active on both arteries and veins. Each dilatrate-SR sustained release capsule contains 40 mg of isosorbide dinitrate, in a microdialysis delivery system that causes the active drug to be released over an extended period. Each capsule also contains ethylcellulose, lactose, pharmaceutical glaze, starch, sucrose and talc. The capsule shells contain D&C Red 33, D&C Yellow 10, gelatin and titanium dioxide.



What does Dilatrate look like?



What are the available doses of Dilatrate?

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What should I talk to my health care provider before I take Dilatrate?

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How should I use Dilatrate?

dilatrate-SR sustained release capsules are indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action of controlled-release oral isosorbide dinitrate is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

As noted above (), multiple studies with ISDN and other nitrates have shown that maintenance of continuous 24-hour plasma levels results in refractory tolerance. Every dosing regimen for organic nitrates including dilatrate-SR must provide a daily nitrate-free interval to avoid the development of tolerance. To achieve the necessary nitrate-free interval with immediate-release oral ISDN, it appears that at least one of the daily interdose intervals must be at least 14 hours long. The necessary interdose interval for dilatrate-SR has not been clearly identified, but it must be greater than 18 hours.

As noted under Clinical Pharmacology, only one trial has ever studied the use of extended-release isosorbide dinitrate for more than one dose. In that trial, 40 mg of dilatrate-SR was administered twice daily in doses given 6 hours apart. After 4 weeks, dilatrate-SR could not be distinguished from placebo.

Large controlled studies with other nitrates suggest that no dosing regimen with dilatrate-SR should be expected to provide more than about 12 hours of continuous antianginal efficacy per day.

In clinical trials, immediate-release oral isosorbide dinitrate has been administered in a variety of regimens, with total daily doses ranging from 30 to 480 mg.

Do not exceed 160 mg (4 capsules) per day.


What interacts with Dilatrate?

Isosorbide dinitrate is contraindicated in patients who are allergic to it.


Do not use dilatrate-SR in patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), such as sildenafil, tadalafil, vardenafil, or avanafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia.


Do not use dilatrate-SR in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.



What are the warnings of Dilatrate?

The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ).

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.


What are the precautions of Dilatrate?

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What are the side effects of Dilatrate?

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 normal-seeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of its diagnosis and treatment is deferred (see ).

Data are not available to allow estimation of the frequency of adverse reactions during treatment with dilatrate-SR sustained release capsules.


What should I look out for while using Dilatrate?

Isosorbide dinitrate is contraindicated in patients who are allergic to it.

Do not use dilatrate-SR in patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), such as sildenafil, tadalafil, vardenafil, or avanafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia.

Do not use dilatrate-SR in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.

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.


What might happen if I take too much Dilatrate?


How should I store and handle Dilatrate?

ZERBAXA vials should be stored refrigerated at 2 to 8°C (36 to 46°F) and protected from light.The reconstituted solution, once diluted, may be stored for 24 hours at room temperature or for 7 days under refrigeration at 2 to 8° C (36 to 46°F).ZERBAXA vials should be stored refrigerated at 2 to 8°C (36 to 46°F) and protected from light.The reconstituted solution, once diluted, may be stored for 24 hours at room temperature or for 7 days under refrigeration at 2 to 8° C (36 to 46°F).dilatrate-SR (isosorbide dinitrate) 40 mg sustained-release capsules are opaque pink and colorless capsules with white beadlets and are imprinted "AP" and "0920". They are supplied as follows:Bottles of 100        NDC 52244-920-10dilatrate-SR (isosorbide dinitrate) 40 mg sustained-release capsules are opaque pink and colorless capsules with white beadlets and are imprinted "AP" and "0920". They are supplied as follows:Bottles of 100        NDC 52244-920-10


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Clinical Information

Chemical Structure

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Clinical Pharmacology

Pharmacokinetics

The kinetics of absorption of isosorbide dinitrate from dilatrate-SR sustained release capsules have not been well studied. Studies of immediate-release formulations of ISDN have found highly variable bioavailability (10 to 90%), with extensive first-pass metabolism in the liver. Most such studies have observed progressive increases in bioavailability during chronic therapy; it is not known whether similar increases in bioavailability appear during the course of chronic therapy with dilatrate-SR sustained release capsules.

Once absorbed, the distribution volume of isosorbide dinitrate is 2-4 L/kg and this volume is cleared at the rate of 2-4 L/min, so ISDN's half-life in serum is about an hour. Since the clearance exceeds hepatic blood flow, considerable extrahepatic 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 interdosing interval sufficient to avoid tolerance to ISDN has not been well defined. Studies of nitroglycerin (an organic nitrate with a very short half-life) have shown that dosing intervals of 10-12 hours are usually sufficient to prevent or attenuate tolerance. Dosing intervals that have succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediate release 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.

An interdosing interval sufficient to avoid tolerance with dilatrate-SR has not been demonstrated. In an eccentric dosing study, 40 mg capsules of dilatrate-SR were administered daily at 0800 and 1400 hours. After two weeks of this regimen, dilatrate-SR was statistically indistinguishable from placebo. Thus, the necessary interdosing interval sufficient to avoid tolerance remains unknown, but it must be greater than 18 hours.

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 interdosing interval than the parallel group receiving placebo. The incidence, magnitude, and clinical significance of similar phenomena in patients receiving ISDN have not been studied.

Non-Clinical Toxicology
Isosorbide dinitrate is contraindicated in patients who are allergic to it.

Do not use dilatrate-SR in patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), such as sildenafil, tadalafil, vardenafil, or avanafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia.

Do not use dilatrate-SR in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.

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.





Concomitant use of dilatrate-SR with phosphodiesterase inhibitors in any form is contraindicated (see ).

Concomitant use of dilatrate-SR with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see ).

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.

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.

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 normal-seeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of its diagnosis and treatment is deferred (see ).

Data are not available to allow estimation of the frequency of adverse reactions during treatment with dilatrate-SR sustained release capsules.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

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Interactions

Interactions

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