Isosorbide Information
Isosorbide ()
Isosorbide () 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.
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:
Isosorbide () 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.
Isosorbide () 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.
Isosorbide () 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.
Isosorbide () Warnings
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.
Isosorbide () Precautions
General:
Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
As tolerance to ISDN develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted.
Some clinical trials in angina patients have provided nitroglycerin for about 12 continuous hours of every 24-hour day. During the daily dose-free interval in some of these trials, anginal attacks have been more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and exercise tolerance. The importance of these observations to the routine, clinical use of sublingual and immediate-release oral ISDN is not known.
In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence.
Information for Patients:
Treatment with ISDN may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol.
Drug Interactions:
Carcinogenesis. Mutagenesis. Impairment of Fertility:
Pregnancy Category C:
Nursing Mothers:
Pediatric Use:
Geriatric Use:
Isosorbide () 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 ).
Data are not available to allow estimation of the frequency of adverse reactions during treatment of Isosorbide () dinitrate oral tablets.
Isosorbide () Overdosage
Hemodynamic Effects:
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 (LD) was found to be 1100 mg/kg.
No data are available to suggest physiological maneuvers ( 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.
Methemoglobinemia:
5
Notwithstanding these observations, there are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. None of the affected patients had been thought to be unusually susceptible.
Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.
When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg intravenously.
Isosorbide () Dosage And Administration
As noted under , 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 , 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.
Isosorbide () 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.
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: Eatontown, NJ 07724Rev April 2006
Isosorbide () Dinitrate Tablets USP 10 mg and 20 mg
are available from Cardinal Health in unit dose cartons
of 30.
Cardinal Health
Zanesville, OH 43701
OI82950710
Isosorbide () Principal Display Panel - Mg Blister
Isosorbide () Dinitrate
Tablets, USP
10mg
Isosorbide () Principal Display Panel - Mg Carton
Isosorbide () Dinitrate
Tablets, USP
10 mg
QTY 30
Isosorbide () Principal Display Panel - Mg Blister
Isosorbide () Dinitrate
Tablets, USP
20mg
Isosorbide () Principal Display Panel - Mg Carton
Isosorbide () Dinitrate
Tablets, USP
20 mg
QTY 30
