ISOSORBIDE DINITRATE

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Overview

What is ISOSORBIDE 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, hypromellose, magnesium stearate, and stearic acid.

The product meets USP Dissolution Test 2.

What does ISOSORBIDE DINITRATE look like?

What are the available doses of ISOSORBIDE DINITRATE?

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

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How should I use ISOSORBIDE DINITRATE?

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 ISOSORBIDE 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 ISOSORBIDE DINITRATE?

Concentrated extracts must be diluted with sterile diluent prior to first use on a patient for treatment or intradermal testing. All concentrates of glycerinated allergenic extracts have the ability to cause serious local and systemic reactions including death in sensitive patients. Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and /or death. An allergenic extract should be temporarily withheld from patients or the dose of the extract adjusted downward if any of the following conditions exist: (1) Severe symptoms of rhinitis and/or asthma (2) Infections or flu accompanied by fever and (3) Exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection. When switching patients to a new lot of the same extract the initial dose should be reduced 3/4 so that 25% of previous dose is administered.

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 ISOSORBIDE DINITRATE?

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 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 (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

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 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

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, 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

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 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.

What are the side effects of ISOSORBIDE DINITRATE?

Adverse reactions to isosorbide dinitrate are generally dose-related, and almost all of these reactions are the result of isosorbide dinitrates 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 ISOSORBIDE DINITRATE?

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What might happen if I take too much ISOSORBIDE DINITRATE?

Hemodynamic Effects:

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) was found to be 1100mg/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:

Not with standing 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.

How should I store and handle ISOSORBIDE DINITRATE?

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP] .Isosorbide Dinitrate Extended–release Tablets, USP 40 mg are available as round, scored, peach colored tablets, debossed IL/3613, in bottles of 100 (NDC 57664–600–88) and 1000 (NDC 57664–600–18).STORAGEStore at 25°C (77°F); excursions permitted to 15-30°C (59–86°F) [see USP Controlled Room Temperature]. Dispense in well closed container.Manufactured by:Isosorbide Dinitrate Extended–release Tablets, USP 40 mg are available as round, scored, peach colored tablets, debossed IL/3613, in bottles of 100 (NDC 57664–600–88) and 1000 (NDC 57664–600–18).STORAGEStore at 25°C (77°F); excursions permitted to 15-30°C (59–86°F) [see USP Controlled Room Temperature]. Dispense in well closed container.Manufactured by:Isosorbide Dinitrate Extended–release Tablets, USP 40 mg are available as round, scored, peach colored tablets, debossed IL/3613, in bottles of 100 (NDC 57664–600–88) and 1000 (NDC 57664–600–18).STORAGEStore at 25°C (77°F); excursions permitted to 15-30°C (59–86°F) [see USP Controlled Room Temperature]. Dispense in well closed container.Manufactured by:Isosorbide Dinitrate Extended–release Tablets, USP 40 mg are available as round, scored, peach colored tablets, debossed IL/3613, in bottles of 100 (NDC 57664–600–88) and 1000 (NDC 57664–600–18).STORAGEStore at 25°C (77°F); excursions permitted to 15-30°C (59–86°F) [see USP Controlled Room Temperature]. Dispense in well closed container.Manufactured by:

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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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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

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