FDA Label for Isosorbide

Description

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

Structural Formula - isosorbide dinitr 01

and whose molecular weight is 236.14. The organic nitrates are vasodilators, active on both arteries and veins.

ISDN 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). ISDN is freely soluble in organic solvents such as acetone, alcohol, and ether, but is only sparingly soluble in water.

Each isosorbide dinitrate tablet contains 5 mg, 10 mg, or 20 mg of ISDN.

Inactive ingredients are as follows:

5 mg and 10 mg: Ammonium phosphate dibasic, anhydrous lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate.

20 mg: Ammonium phosphate dibasic, anhydrous lactose, D&C Yellow No. 10 Lake. FD&C Blue No. 1 Lake, FD&C Yellow No. 6 Lake, magnesium stearate, microcrystalline cellulose, sodium starch glycolate.

Clinical Pharmacology

The principal pharmacological action of ISDN is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular lesistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined.

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were no more effective than placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their anti-anginal efficacy been restored.

Indications And Usage

Isosorbide dinitrate oral tablets are indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action of immediate-release oral ISDN is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

Contraindications

Allergic reactions to organic nitrates are extremely rare, but they do occur. The isosorbide dinitrate tablet is contraindicated in patients who are allergic to ISDN or any of its other ingredients.

Warnings

Amplification of the vasodilatory effects of ISDN 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 a nitrate overdose, with elevation of the extremities and with central volume expansion.

The benefits of immediate-release oral ISDN in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use ISDN in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia. Because the effects of oral ISDN are so difficult to terminate rapidly, this formulation is not recommended in these settings.

Adverse Reactions

Adverse reactions to ISDN are generally dose-related, and most all of these reactions are the result of ISDN'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 of isosorbide dinitrate oral tablets.

Dosage And Administration

As noted under CLINICAL PHARMACOLOGY, multiple 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 oral 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 oral 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 oral 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.

How Supplied

Isosorbide Dinitrate Tablets USP (Oral) 5 mg: White, round, scored tablets imprinted "West-ward 769".

Isosorbide Dinitrate Tablets USP (Oral) 10 mg: White, round, scored tablets imprinted "WW" on one side and "771" on the other side.

Isosorbide Dinitrate Tablets USP (Oral) 20 mg: Green, round, scored tablet imprinted "WW" on one side and "772" on the other side.

They are supplied by State of Florida DOH Central Pharmacy as follows:

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Store at 20-25°C (68-77°F) [See USP Controlled Room Temperature]. Protect from light and moisture.

Also available: Isosorbide Dinitrate Sublingual Tablets in the following dosage strengths:

2.5 mg; in bottles of 100, 1000 or unit dose boxes of 100 tablets.

5 mg; in bottles of 100, 1000 or unit dose boxes of 100 tablets.

Manufactured by:
West-ward Pharmaceutical Corp.
Eatontown, NJ 07724

This Product was Repackaged By:

State of Florida DOH Central Pharmacy
104-2 Hamilton Park Drive
Tallahassee, FL 32304
United States