Isordil

DESCRIPTION

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

Isordil® Titradose® (isosorbide dinitrate) Structural Formula Illustration

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 Isordil® Titradose® tablet contains 5 or 40 mg of isosorbide dinitrate. The inactive ingredients in each tablet are lactose, cellulose, and magnesium stearate. The 5 mg and 40 mg dosage strengths also contain the following: 5 mg . FD&C Red 40; 40 mg . D&C Yellow 10, FD&C Blue 1, and FD&C Yellow 6.

Indications & Dosage

INDICATIONS

Isordil (isosorbide dinitrate) Titradose 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

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 Isordil Titradose 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 Isordil Titradose 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 Isordil Titradose 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 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 normalseeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of its diagnosis and treatment is deferred (see OVERDOSE).

Data are not available to allow estimation of the frequency of adverse reactions during treatment with Isordil Titradose tablets.

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 Isordil Titradose with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS).

Concomitant use of Isordil Titradose with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS).

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