displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3
Isosorbide dinitrate (ISDN) is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate, an organic nitrate whose structural formula is:
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). Isosorbidedinitrate is freely soluble in organic solvents such as acetone, alcohol, and, but is only sparingly soluble in water.
Each isosorbide dinitrate tablet contains 30 mg of ISDN.
Inactive ingredients are as follows: Ammonium Phosphate Dibasic, Colloidal Silicon Dioxide, FD&C Blue No. 1 Aluminum Lake, Lactose Monohydrate, Magnesium Stearate and Microcrystalline Cellulose.
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1
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 resistance, 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
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9
Isosorbide Dinitrate Tablets, USP, 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.
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3
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
displayName: WARNINGS SECTION
FDA Article Code: 34071-1
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.
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4
Adverse reactions to ISDN are generally dose-related, and almost 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
Data are not available to allow estimation of the frequency of adverse reactions during treatment of isosorbide dinitrate tablets.
To report SUSPECTED ADVERSE REACTIONS, contact West-ward Pharmaceutical Corp. at 1-877-233-2001, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5
Hemodynamic Effects: The ill effects of ISDN overdose are generally the results of ISDN”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 ISDN and it metabolites are not widely available, and such determinations have, in any event, no established role in the management of ISDN overdose.
There are no data suggesting what dose of ISDN is likely to be life-threatening in humans. In rats, the median acute lethal dose (LD50) 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 ISDN 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 ISDN is known, and no intervention has been subject to controlled studies as a therapy for ISDN overdose. Because the hypotension associated with ISDN 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 ISDN overdose in these patients may be subtle and difficult, and invasive monitoring may be required.
DOSAGE AND ADMINISTRATION
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7
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 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
, 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 minimum dose which produces the desired clinical effect. The usual starting dose of isosorbide dinitrate tablets is 5 mg to 40 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.
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5
Isosorbide Dinitrate Tablets, USP (Oral) 30 mg: Blue, Round, Scored Tablets;
Debossed “WW 773” on Scored side.
Bottles of 30 tablets.
Bottles of 100 tablets.
Bottles of 500 tablets.
Bottles of 1000 tablets.
Store at 20-25°C (68-77°F) [See USP Controlled Room Temperature]. Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
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.
Also available: Isosorbide Dinitrate Oral Tablets in the following dosage strengths:
5 mg: in bottles of 100, 500, 1000 or unit dose boxes of 100 tablets.
10 mg: in bottles of 100, 500, 1000 or unit dose boxes of 100 tablets.
20 mg: in bottles of 100, 1000 or unit dose boxes of 100 tablets.
West-ward Pharmaceutical Corp.
Eatontown, NJ 07724
Revised December 2010
PACKAGE DISPLAY PANEL
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
Isosorbide Dinitrate Tablets 30 mg