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Isorbide Dinitrate

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Overview

What is Isorbide Dinitrate?

Isosorbide dinitrate (ISDN), an organic nitrate, is a vasodilator with effects on both arteries and veins. Isosorbide dinitrate is available as 40 mg extended-release tablets. The chemical name for isosorbide dinitrate 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.

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=1.0, alcohol, 20°C). Isosorbide dinitrate is freely soluble in organic solvents, such as acetone, alcohol, and ether, but is only sparingly soluble in water.

Each Isosorbide Dinitrate Extended-release tablet, for oral administration, contains 40 mg of isosorbide dinitrate, in a matrix that causes the active drug to be released over a sustained period. In addition, each tablet also contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, FD&C Yellow #6 Aluminum Lake, hydroxypropyl methylcellulose, magnesium stearate, and stearic acid.

Conformance of Isosorbide Dinitrate Extended-release Tablets with the USP release test is pending.



What does Isorbide Dinitrate look like?



What are the available doses of Isorbide Dinitrate?

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

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How should I use Isorbide Dinitrate?

Isosorbide Dinitrate Extended-release Tablets 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 under 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 Extended-release 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. The necessary dose-free interval for Isosorbide Dinitrate Extended-release Tablets has not been clearly identified, but is presumably somewhat longer.

As also noted under only one trial has ever studied the use of controlled-release isosorbide dinitrate for more than one dose. In that trial, 40 mg of a different formulation of controlled-release ISDN was administered twice daily in doses given 6 hours apart. After 4 weeks, active treatment could not be distinguished from placebo.

Large controlled studies with other nitrates suggest that no dosing regimen with Isosorbide Dinitrate Extended-release Tablets should be expected to provide more than about 12 hours of continuous anti-anginal 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 mg to 480 mg.


What interacts with Isorbide Dinitrate?

Allergic reactions to organic nitrates are extremely rare, but they do occur. Isosorbide Dinitrate Extended-release Tablets are contraindicated in patients who are allergic to isosorbide dinitrate or to any of its other ingredients.



What are the warnings of Isorbide Dinitrate?

Lithium generally should not be given with diuretics (see ).

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 nitrate overdose, with elevation of the extremities and with central volume expansion.

The benefits of controlled-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 controlled-release oral isosorbide dinitrate are so difficult to terminate rapidly, this formulation is not recommended in these settings.


What are the precautions of Isorbide Dinitrate?

General:

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 intervals in some of these trials, anginal attacks have been more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and 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 (presumable 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:

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:

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Pregnancy Category C

Nursing Mothers:

Pediatric Use:

Geriatric Use:


What are the side effects of Isorbide Dinitrate?

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 Isosorbide Dinitrate Extended-release Tablets.


What should I look out for while using Isorbide Dinitrate?

Allergic reactions to organic nitrates are extremely rare, but they do occur. Isosorbide Dinitrate Extended-release Tablets are contraindicated in patients who are allergic to isosorbide dinitrate or to any of its other ingredients.

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 nitrate overdose, with elevation of the extremities and with central volume expansion.

The benefits of controlled-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 controlled-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 Isorbide Dinitrate?


How should I store and handle Isorbide Dinitrate?

Refrigerate the product upon receipt at 2°C to 8°C.Isosorbide Dinitrate Extended–release Tablets, USP 40 mg are available as round, scored, peach colored tablets, debossed IL/3613, in bottles of 100 (NDC 0258–3613–01) and 1000 (NDC 0258–3613–10).


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Clinical Information

Chemical Structure

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Clinical Pharmacology

The kinetics of absorption of isosorbide dinitrate has 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 Isosorbide Dinitrate Extended-release Tablets.

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 extrahepatic metabolism must also occur. Clearance is effected 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 ISDN 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 (., 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. A dose-free interval sufficient to avoid tolerance with Isosorbide Dinitrate Extended-release Tablets has not been demonstrated. Clinical trials using Isosorbide Dinitrate Extended-release Tablets in a regimen designed to avoid tolerance have not been conducted, but in a multiple-dose study of another controlled-release isosorbide dinitrate product, 40 mg capsules were administered at 0800 and 1400 hours. After two weeks of this regimen, the controlled-release isosorbide dinitrate product was statistically indistinguishable from placebo. For the formulation of controlled-release isosorbide dinitrate that was tested, the necessary dose-free interval must therefore be greater than 18 hours; the necessary interval for Isosorbide Dinitrate Extended-release Tablets remains unknown.

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 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.

Non-Clinical Toxicology
Allergic reactions to organic nitrates are extremely rare, but they do occur. Isosorbide Dinitrate Extended-release Tablets are contraindicated in patients who are allergic to isosorbide dinitrate or to any of its other ingredients.

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 nitrate overdose, with elevation of the extremities and with central volume expansion.

The benefits of controlled-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 controlled-release oral isosorbide dinitrate are so difficult to terminate rapidly, this formulation is not recommended in these settings.

Drug Interactions:

General:

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 intervals in some of these trials, anginal attacks have been more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and 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 (presumable 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 Isosorbide Dinitrate Extended-release Tablets.

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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

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72
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Interactions

Interactions

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