Isosorbide dinitrate

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Isosorbide dinitrate
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

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Overview

Isosorbide dinitrate is an anti-anginal nitrate that is FDA approved for the {{{indicationType}}} of angina pectoris due to coronary artery disease. Common adverse reactions include hypotension, lightheadedness, and headache.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Prophylaxis of Angina Pectoris
  • Isosorbide dinitrate 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.
  • 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.
  • 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.
  • 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.
  • Dosing Information
  • Initial Dosage
  • 5–20 mg PO bid–tid
  • Maintenance Dosage
  • 10–40 mg PO bid–tid

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Ischemic Symptoms of Unstable Angina
  • Class of Recommendation: Class I
  • Strength of Evidence: Level C
  • Dosing Information
  • 5–80 mg, 2 or 3 times daily[1]

Non–Guideline-Supported Use

Cardiac Syndrome X
  • Dosing Information
  • 5 mg sublingual[2]
Congestive Heart Failure
  • Dosing Information
Myocardial Infarction
  • Dosing Information
  • Initial dose was 2 mg/hour, titrated every 10 minutes until systolic blood pressure decreased 10% or a maximum infusion rate of 10 mg/hour.[6]
Pulmonary Edema
  • Dosing Information
  • Repeated boluses of IV isosorbide dinitrate 4 mg every 4 min, until oxygen saturation increased above 96% or systolic blood pressure fell below 110 mm Hg or 30% below baseline.[7]

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

  • Safety and effectiveness in pediatric patients have not been established.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Isosorbide dinitrate in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Isosorbide dinitrate in pediatric patients.

Contraindications

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

Warnings

  • Amplification of the vasodilatory effects of Isordil 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 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.

Precautions

  • 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.
  • 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 and decreased exercise 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.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Isosorbide dinitrate in the drug label.

Postmarketing Experience

  • 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 normal-seeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of its diagnosis and treatment is deferred.
  • 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category C
  • At 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.


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isosorbide dinitrate in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Isosorbide dinitrate during labor and delivery.

Nursing Mothers

  • It 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.

Pediatric Use

  • Safety and effectiveness in pediatric patients have not been established.

Geriatic Use

  • Clinical studies of Isordil (isosorbide dinitrate) Titradose 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.

Gender

There is no FDA guidance on the use of Isosorbide dinitrate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Isosorbide dinitrate with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Isosorbide dinitrate in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Isosorbide dinitrate in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Isosorbide dinitrate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Isosorbide dinitrate in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral

Monitoring

Hemodynamic Monitoring
  • 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.

IV Compatibility

There is limited information regarding IV Compatibility of Isosorbide dinitrate in the drug label.

Overdosage

Hemodynamic Effects
  • The ill effects of isosorbide dinitrate overdose are generally the results of isosorbide dinitrate'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 isosorbide dinitrate and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of isosorbide dinitrate overdose.
  • There are no data suggesting what dose of isosorbide dinitrate 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 isosorbide dinitrate 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 isosorbide dinitrate is known, and no intervention has been subject to controlled studies as a therapy for isosorbide dinitrate overdose. Because the hypotension associated with isosorbide dinitrate 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 isosorbide dinitrate overdose in these patients may be subtle and difficult, and invasive monitoring may be required.
Methemoglobinemia
  • Nitrate ions liberated during metabolism of isosorbide dinitrate can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moieties of isosorbide dinitrate are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of isosorbide dinitrate should be required before any of these patients manifests clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of isosorbide dinitrate. In one study in which 36 patients received 2 to 4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to 4.8 to 6.9 mg of bioavailable isosorbide dinitrate per hour), the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo.
  • 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 pO2. 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.

Pharmacology

Template:Px
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Isosorbide dinitrate
Systematic (IUPAC) name
1,4:3,6-dianhydro-2,5-di-O-nitro-D-glucitol
Identifiers
CAS number 87-33-2
ATC code C01DA08 C05AE02 (WHO)
PubChem 6883
DrugBank DB00883
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 236.136 g/mol
SMILES eMolecules & PubChem
Synonyms (3R,3aS,6S,6aS)-hexahydrofuro[3,2-b]furan-3,6-diyl dinitrate
Pharmacokinetic data
Bioavailability 10–90%, average 25%
Metabolism Hepatic
Half life 1 hour
Excretion Renal
Therapeutic considerations
Pregnancy cat.

C(US)

Legal status

Template:Unicode Prescription only

Routes Oral

Mechanism of Action

  • 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.

Structure

  • Isosorbide dinitrate (ISDN) is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate, an organic nitrate whose structural formula is
This image is provided by the National Library of Medicine.
  • The 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.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Isosorbide dinitrate in the drug label.

Pharmacokinetics

  • 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 ISDN 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 ISDN's half-life in serum is about an hour. Since the clearance exceeds hepatic blood flow, considerable extrahepatic 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 ISDN have generally been somewhat longer (at least 14 hours), but this is consistent with the longer half-lives of ISDN 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 had less exercise 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 ISDN have not been studied.

Nonclinical Toxicology

  • Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 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.

Clinical Studies

  • 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 ISDN 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 ISDN 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.

How Supplied

  • Isordil® (isosorbide dinitrate) Oral Titradose™ Tablets are available as follows:
5 mg, round, pink tablets imprinted "BPI 152" on one side and deeply scored on reverse side
NDC 64455-152-01, bottles of 100.
40 mg, round, light green tablets imprinted "BPI 192" on one side and deeply scored on reverse side:
NDC 64455-192-01, bottles of 100.
  • Store at controlled room temperature, 25°C (77°F); excursions permitted to 15 -30° (59-86°F)
  • Protect from light.
  • Keep bottles tightly closed.
  • Dispense in a light-resistant, tight container.

Storage

There is limited information regarding Isosorbide dinitrate Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

  • 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.

Precautions with Alcohol

  • Alcohol-Isosorbide dinitrate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

  • Isordil® — Plendil®[9]

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. Anderson, Jeffrey L. (2007-08-14). "ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine". Journal of the American College of Cardiology. 50 (7): –1-e157. doi:10.1016/j.jacc.2007.02.013. ISSN 1558-3597. PMID 17692738. Unknown parameter |coauthors= ignored (help)
  2. Lanza, G. A. (1994-12). "Acute effects of nitrates on exercise testing in patients with syndrome X. Clinical and pathophysiological implications". Circulation. 90 (6): 2695–2700. ISSN 0009-7322. PMID 7994810. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  3. Taylor, Anne L. (2004-11-11). "Combination of isosorbide dinitrate and hydralazine in blacks with heart failure". The New England Journal of Medicine. 351 (20): 2049–2057. doi:10.1056/NEJMoa042934. ISSN 1533-4406. PMID 15533851. Unknown parameter |coauthors= ignored (help)
  4. Cohn, J. N. (1986-06-12). "Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study". The New England Journal of Medicine. 314 (24): 1547–1552. doi:10.1056/NEJM198606123142404. ISSN 0028-4793. PMID 3520315. Unknown parameter |coauthors= ignored (help)
  5. Cohn, J. N. (1993-10). "Efficacy of vasodilators in the treatment of heart failure". Journal of the American College of Cardiology. 22 (4 Suppl A): 135–138A. ISSN 0735-1097. PMID 8376683. Check date values in: |date= (help)
  6. Hildebrandt, P. (1992-11). "Reduced infarct size in nonreperfused myocardial infarction by combined infusion of isosorbide dinitrate and streptokinase". American Heart Journal. 124 (5): 1139–1144. ISSN 0002-8703. PMID 1442478. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  7. Sharon, A. (2000-09). "High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema". Journal of the American College of Cardiology. 36 (3): 832–837. ISSN 0735-1097. PMID 10987607. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  8. "ISORDIL TITRADOSE (isosorbide dinitrate) tablet".
  9. "http://www.ismp.org". External link in |title= (help)


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