Isosorbide Dinitrate

Description

DESCRIPTION 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. Isosorbide dinitrate is a white, crystalline powder compound which is stable in air and in solution, has a melting point of 69°C to 72°C and optically active. Isosorbide dinitrate is very soluble in acetone, sparingy soluble in alcohol and very slightly soluble in water. Each Isosorbide dinitrate tablet contains 10 mg of isosorbide dinitrate. The inactive ingredients in each tablet are microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. The 10 mg dosage strength also contains anhydrous lactose and sodium starch glycolate Type A. Additionally, 10 mg contains FD & C Blue 1 Al lake and D & C Yellow 10 Al lake. FDA approved dissolution test specifications differ from USP. Isosorbide Dinitrate Chemical Structure

What Is Isosorbide Dinitrate Used For?

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.

Dosage and Administration

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.

Side Effects (Adverse Reactions)

ADVERSE REACTIONS 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 OVERDOSAGE ). Data are not available to allow estimation of the frequency of adverse reactions during treatment with isosorbide dinitrate tablets.

Drug Interactions

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 with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS ).

Contraindications

CONTRAINDICATIONS Isosorbide dinitrate is contraindicated in patients who are allergic to isosorbide dinitrate or any of its ingredients. Do not use isosorbide dinitrate 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 isosorbide dinitrate in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.

Pregnancy and Breastfeeding

Pregnancy At oral doses 35 and 150 times the maximum recommendedhuman 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.

Overdosage

OVERDOSAGE 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...

How Supplied

HOW SUPPLIED Isosorbide dinitrate Tablets are available as follows: 10 mg, Light green to green mottled round tablets, debossed with, "Λ" on one side and score line on the other side. 22 NDC 82804-117-90, bottles of 90 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Keep bottles tightly closed. Dispense in a light-resistant, tight container. All trademarks are the property of their respective owners. Manufactured by: Rubicon Research Private Limited Ambernath, Dist: Thane, 421506 India Distributed by: Advagen Pharma Ltd 666 Plainsboro Road Suite 605 Plainsboro, NJ 08536, US Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320 Revision: 06/22