P : Caution - during pregnancy
L : Caution - during lactation
|| See TERMINOLOGY & ABBREVIATIONS ||
Amplification of the vasodilatory effects of isosorbide dinitrate 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 isosorbide dinitrate in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use isosorbide dinitrate in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia. Because the effects of oral isosorbide dinitrate are so difficult to terminate rapidly, this formulation is not recommended in these settings.
|Indication(s) & Dosage||
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.
Management of angina
|Administration||Should be taken on an empty stomach. Take on an empty stomach Â½ hr before meals.|
|Overdosage||Symptoms: Increased intracranial pressure, throbbing headache, confusion, moderate fever; vertigo; palpitations; visual disturbances; nausea and vomiting; syncope; air hunger and dyspnoea; diaphoresis; heart block and bradycardia; paralysis; coma; seizures; and death. Methaemoglobinaemia.|
|Contraindications||Severe hypotension or anaemia, hypovolaemia, heart failure due to obstruction, or raised intracranial pressure due to head trauma or cerebral haemorrhage.|
Severe hypotension, particularly with upright posture, may occur with even small doses of isosorbide dinitrate. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide dinitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.
Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
As tolerance to isosorbide dinitrate 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 anddecreasedexercise tolerance. The importance of these observations to the routine, clinical use of immediate-release oral isosorbide dinitrate 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.
Patients should be told that the anti-anginal efficacy of isosorbide dinitrate is strongly related to its dosing regimen, so the prescribed schedule of dosing should be followed carefully. In particular, daily headaches sometimes accompany treatment with isosorbide dinitrate. In patients who get these headaches, the headaches are a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with isosorbide dinitrate, since loss of headache may be associated with simultaneous loss of anti-anginal efficacy. Aspirin and/or acetaminophen, on the other hand, often successfully relieve isosorbide dinitrate-induced headaches with no deleterious effect on isosorbide dinitrate's anti-anginal efficacy.
Treatment with isosorbide dinitrate 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.
No long-term studies in animals have been performed to evaluate the carcinogenic potential of isosorbide dinitrate. In a modified two-litter reproduction study, there was no remarkable gross pathology and no altered fertility or gestation among rats fed isosorbide dinitrate at 25 or 100 mg/kg/day.
|Adverse Drug Reactions||Hypotension, tachycardia, flushing, headache, dizziness, palpitation, syncope, confusion. Nausea, vomiting, abdominal pain. Apprehension, restlessness, weakness and vertigo.
Potentially Fatal: Severe hypotension, circulatory collapse.
|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. Marked orthostatic hypotension may occur when used with calcium channel blockers. Vasodilatory effect may be reduced with dihydroergotamine. Ergotamine effects may be enhanced. Reduced effectiveness of sublingual form with disopyramide.
Potentially Fatal: Significant hypotension may occur with phosphodiesterase-5 inhibitors. Please consult detailed drug interactions before prescribing.
|Lab Interference||False decrease in serum cholesterol.|
|Pregnancy Category (FDA) and use in Specific Population||
Pregnancy Category CAt oral doses 35 and 150 times the maximum recommended human daily dose, isosorbide dinitrate has been shown to cause a dose-related increase in embryotoxicity (increase in mummified pups) in rabbits. There are no adequate, well-controlled studies in pregnant women. Isosorbide dinitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing MothersIt is not known whether isosorbide dinitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isosorbide dinitrate is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
Geriatric UseClinical studies of isosorbide dinitrate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
|Storage||Oral: Store at room temperature (25Â°C). Sublingual: Store at room temperature (25Â°C).|
The principal pharmacological action of isosorbide dinitrate 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.
Absorption of isosorbide dinitrate after oral dosing is nearly complete, but bioavailability is highly variable (10% to 90%), with extensive first-pass metabolism in the liver. Serum levels reach their maxima about an hour after ingestion. The average bioavailability of isosorbide dinitrate is about 25%; most studies have observed progressive increases in bioavailability during chronic therapy.
Once absorbed, the volume of distribution of isosorbide dinitrate is 2 to 4 L/kg, and this volume is cleared at the rate of 2 to 4 L/min, so isosorbide dinitrate's half-life in serum is about an hour. Since the clearance exceeds hepatic blood flow, considerable extra hepatic metabolism must also occur. Clearance is affected primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%).
Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life of about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronide, and denitration/hydration to sorbitol. The 2-mononitrate has been less well studied, but it appears to participate in the same metabolic pathways, with a half-life of about 2 hours.
The daily dose-free interval sufficient to avoid tolerance to organic nitrates has not been well defined. Studies of nitroglycerin (an organic nitrate with a very short half-life) have shown that daily dose-free intervals of 10 to 12 hours are usually sufficient to minimize tolerance. Daily dose-free intervals that have succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediate-release isosorbide dinitrate have generally been somewhat longer (at least 14 hours), but this is consistent with the longer half-lives of isosorbide dinitrate and its active metabolites.
Few well-controlled clinical trials of organic nitrates have been designed to detect rebound or withdrawal effects. In one such trial, however, subjects receiving nitroglycerin hadlessexercise tolerance at the end of the daily dose-free interval than the parallel group receiving placebo. The incidence, magnitude, and clinical significance of similar phenomena in patients receiving isosorbide dinitrate have not been studied.
In clinical trials, immediate-release oral isosorbide dinitrate has been administered in a variety of regimens, with total daily doses ranging from 30 mg to 480 mg. Controlled trials of single oral doses of isosorbide dinitrate have demonstrated effective reductions in exercise-related angina for up to 8 hours. Anti-anginal activity is present about 1 hour after dosing.
Most controlled trials of multiple-dose oral isosorbide dinitrate taken every 12 hours (or more frequently) for several weeks have shown statistically significant anti-anginal efficacy for only 2 hours after dosing. Once-daily regimens, and regimens with one daily dose-free interval of at least 14 hours (e.g., a regimen providing doses at 0800, 1400 and 1800 hours), have shown efficacy after the first dose of each day that was similar to that shown in the single-dose studies cited above. The effects of the second and later doses have been smaller and shorter-lasting than the effect of the first.
From large, well-controlled studies of other nitrates, it is reasonable to believe that the maximal achievable daily duration of anti-anginal effect from isosorbide dinitrate is about 12 hours. No dosing regimen for isosorbide dinitrate, however, has ever actually been shown to achieve this duration of effect. One study of 8 patients, who were administered a pretitrated dose (average 27.5 mg) of immediate-release isosorbide dinitrate at 0800, 1300, and 1800 hours for 2 weeks, revealed that significant anti-anginal effectiveness was discontinuous and totaled about 6 hours in a 24 hour period.
|ATC Classification||C05AE02 - isosorbide dinitrate;
C01DA08 - isosorbide dinitrate; Belongs to the class of organic nitrate vasodilators. Used in the treatment of cardiac disease.
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