ISOSORBIDE DINITRATE

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 compound, has a melting point of 70°C and has an optical rotation of +140° (c=1, alcohol, 20°C). Isosorbide dinitrate is very slightly soluble in water; very soluble in acetone and sparingly soluble in alcohol. Each isosorbide dinitrate tablet, USP contains 5 mg, 10 mg, 20 mg or 30 mg of isosorbide dinitrate. The inactive ingredients in each tablet are lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. The 5 mg dosage strength also contains FD&C red no. 40 aluminium lake. The 20 mg dosage strength also contains FD&C blue no. 1 aluminium lake and D&C yellow no. 10 aluminium lake. The 30 mg dosage strength also contains FD&C blue no. 1 aluminium lake. Image

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.

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 tablets 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.

Isosorbide dinitrate tablets are 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.

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. To report SUSPECTED ADVERSE REACTIONS, contact NorthStar RxLLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 ).