Isosorbide Dinitrate

Pronunciation

(eye soe SOR bide dye NYE trate)

U.S. Brand Names

Dilatrate®-SR; Isochron™; Isordil®

Synonyms

ISD; ISDN

Generic Available

Yes: Tablet, sublingual tablet

Canadian Brand Names

Apo-ISDN®; Cedocard®-SR; Coronex®; Novo-Sorbide; PMS-Isosorbide

Use

Prevention and treatment of angina pectoris; for congestive heart failure; to relieve pain, dysphagia, and spasm in esophageal spasm with GE reflux

Use - Unlabeled/Investigational

Esophageal spastic disorders

Pregnancy Risk Factor

Lactation

Excretion in breast milk unknown

Contraindications

Hypersensitivity to isosorbide dinitrate or any component of the formulation; hypersensitivity to organic nitrates; concurrent use with phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil, or vardenafil); angle-closure glaucoma (intraocular pressure may be increased); head trauma or cerebral hemorrhage (increase intracranial pressure); severe anemia

Warnings/Precautions

Severe hypotension can occur. Use with caution in volume depletion, hypotension, and right ventricular infarctions. Paradoxical bradycardia and increased angina pectoris can accompany hypotension. Postural hypotension can also occur. Tolerance does develop to nitrates and appropriate dosing is needed to minimize this. Safety and efficacy have not been established in pediatric patients. Nitrate may aggravate angina caused by hypertrophic cardiomyopathy. Avoid concurrent use with sildenafil.

Adverse Reactions

Frequency not defined.

Cardiovascular: Hypotension (infrequent), postural hypotension, crescendo angina (uncommon), rebound hypertension (uncommon), pallor, cardiovascular collapse, tachycardia, shock, flushing, peripheral edema, syncope (uncommon)

Central nervous system: Headache (most common), lightheadedness (related to blood pressure changes), dizziness, restlessness

Gastrointestinal: Nausea, vomiting, bowel incontinence, xerostomia

Genitourinary: Urinary incontinence

Hematologic: Methemoglobinemia (rare, overdose)

Neuromuscular & skeletal: Weakness

Ocular: Blurred vision

Miscellaneous: Cold sweat

The incidence of hypotension and adverse cardiovascular events may be increased when used in combination with sildenafil (Viagra®).

Overdosage/Toxicology

Symptoms of overdose include hypotension, throbbing headache, palpitations, visual disturbances, tachycardia, methemoglobinemia, flushing, diaphoresis, metabolic acidosis, and coma. High levels or methemoglobinemia can cause signs or symptoms of hypoxemia. Treat symptomatically.

Drug Interactions

Substrate of CYP3A4 (major)

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of isosorbide dinitrate. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of isosorbide dinitrate. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Sildenafil, tadalafil, vardenafil: Significant reduction of systolic and diastolic blood pressure with concurrent use (contraindicated). Do not administer sildenafil, tadalafil, or vardenafil within 24 hours of a nitrate preparation.

Ethanol/Nutrition/Herb Interactions

Ethanol: Caution with ethanol (may increase risk of hypotension).

Mechanism of Action

Stimulation of intracellular cyclic-GMP results in vascular smooth muscle relaxation of both arterial and venous vasculature. Increased venous pooling decreases left ventricular pressure (preload) and arterial dilatation decreases arterial resistance (afterload). Therefore, this reduces cardiac oxygen demand by decreasing left ventricular pressure and systemic vascular resistance by dilating arteries. Additionally, coronary artery dilation improves collateral flow to ischemic regions; esophageal smooth muscle is relaxed via the same mechanism.

Pharmacodynamics/Kinetics

Onset of action: Sublingual tablet: 2-10 minutes; Chewable tablet: 3 minutes; Oral tablet: 45-60 minutes

Duration: Sublingual tablet: 1-2 hours; Chewable tablet: 0.5-2 hours; Oral tablet: 4-6 hours

Metabolism: Extensively hepatic to conjugated metabolites, including isosorbide 5-mononitrate (active) and 2-mononitrate (active)

Half-life elimination: Parent drug: 1-4 hours; Metabolite (5-mononitrate): 4 hours

Excretion: Urine and feces

Dosage

Adults (elderly should be given lowest recommended daily doses initially and titrate upward): Oral:

Angina: 5-40 mg 4 times/day or 40 mg every 8-12 hours in sustained-release dosage form

Congestive heart failure:

Initial dose: 10 mg 3 times/day

Target dose: 40 mg 3 times/day

Maximum dose: 80 mg 3 times/day

Sublingual: 2.5-10 mg every 4-6 hours

Chewable tablet: 5-10 mg every 2-3 hours

Esophageal spastic disorders (unlabeled use):

Oral: 5-10 mg before meals

Sublingual: 2.5 mg after meals

Tolerance to nitrate effects develops with chronic exposure: Dose escalation does not overcome this effect. Tolerance can only be overcome by short periods of nitrate absence from the body. Short periods (10-12 hours) of nitrate withdrawal help minimize tolerance. General recommendations are to take the last dose of short-acting agents no later than 7 PM; administer 2-3 times/day rather than 4 times/day. Sustained release preparations could be administered at times to allow a 15- to 17-hour interval between first and last daily dose. Example: Administer sustained release at 8 AM and 2 PM for a twice daily regimen.

Hemodialysis: During hemodialysis, administer dose postdialysis or administer supplemental 10-20 mg dose

Peritoneal dialysis: Supplemental dose is not necessary

Administration

Do not administer around-the-clock; the first dose of nitrates should be administered in a physician's office to observe for maximal cardiovascular dynamic effects and adverse effects (orthostatic blood pressure drop, headache); when immediate release products are prescribed twice daily (recommend 7 AM and noon); for 3 times/day dosing (recommend 7 AM, noon, and 5 PM); when sustained-release products are indicated, suggest once a day in morning or via twice daily dosing at 8 AM and 2 PM. Do not crush sublingual tablets.

Monitoring Parameters

Monitor for orthostasis

Test Interactions

Decreased cholesterol (S)

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed, at the same time each day. Do not chew or swallow sublingual tablets; allow them to dissolve under your tongue. Do not crush or chew sustained release capsules, swallow whole with 8 oz water. Do not change brands without consulting prescriber. Do not discontinue abruptly. Keep medication in original container, tightly closed. Avoid alcohol; combination may cause severe hypotension. May cause postural hypotension (take medication while sitting down and use caution when rising from sitting or lying position or climbing stairs); dizziness, weakness, or blurred vision (use caution when driving or engaging in hazardous activities until response to drug is known); or nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). If chest pain occurs, seek emergency medical help at once. Report acute headache, rapid heartbeat, unusual restlessness or dizziness, muscular weakness, or blurring vision. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Anesthesia and Critical Care Concerns/Other Considerations

Nitrates used in right ventricular infarction may induce acute hypotension. Nitrate use in severe pericardial effusion may reduce cardiac filling pressure and precipitate cardiac tamponade. In the management of heart failure, the combination of isosorbide dinitrate and hydralazine confers beneficial effects on disease progression and cardiac outcomes.

Cardiovascular Considerations

Nitrates improve the balance between myocardial oxygen supply and demand, primarily by decreasing oxygen demand. Nitrates decrease myocardial oxygen demand by reducing preload via dilation of peripheral veins, and moderately reducing afterload by dilating peripheral arteries. Nitrates improve myocardial oxygen supply by dilating epicardial coronary arteries and collateral vessels, leaving resistance vessels alone. Nitrates are unlikely to induce a coronary steal syndrome. Nitrates improve exercise tolerance in stable angina patients. An adequate nitroglycerin-free period must be provided with all nitrate products to prevent nitrate tolerance from developing. Caution should be observed if administering nitrates to individuals who are volume depleted or are experiencing a right ventricular infarction. Additionally, nitrates should not be given to an individual who has received a phosphodiesterase-5 (PDE-5) enzyme inhibitor within the past 24 hours.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness

Mental Health: Effects on Psychiatric Treatment

None reported

Dosage Forms

[DSC] = Discontinued product

Capsule, sustained release (Dilatrate®-SR): 40 mg

Tablet: 5 mg, 10 mg, 20 mg, 30 mg,

Isordil®: 5 mg, 10 mg [DSC], 20 mg [DSC], 30 mg [DSC], 40 mg

Tablet, extended release (Isochron™): 40 mg

Tablet, sublingual: 2.5 mg, 5 mg

Isordil®: 2.5 mg, 5 mg, 10 mg [DSC]

References

Cheitlin MD, Hutter AM Jr, Brindis RG, et al, "ACC/AHA Expert Consensus Document. Use of Sildenafil (Viagra) in Patients With Cardiovascular Disease. American College of Cardiology/American Heart Association," J Am Coll Cardiol , 1999, 33(1):273-82.

"Consensus Recommendations for the Management of Chronic Heart Failure. On Behalf of the Membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure," Am J Cardiol , 1999, 83(2A):1A-38A.

Gibbons RJ, Abrams J, Chatterjee K, et al, "ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina)," J Am Coll Cardiol , 2003, 41(1):159-68. Available at: http://http://www.acc.org/clinical/guidelines/stable/stable_clean.pdf. Accessed May 5, 2004.

Parker JO, Fanell B, Lahey KA, et al, "Effect of Intervals Between Doses on the Development to Tolerance to Isosorbide Dinitrate," N Engl J Med , 1987, 316(23):1440-4.

International Brand Names

Acordin® (CH); Aerosonit® (PL, RU); Angi-Spray® (ZA); Angitak® (GB); Angitrit® (TH); Apo-ISDN® (CA, CZ, PL); Apo-Isosorbide dinitrate® (ZA); Cardiket retard® (CZ); Cardioket® (TR); Cardiosorbid® (PL); Cardipine® (EG, KW, LB, SY); Cardonit® (HU, PL, RO); Cardopax® (DK); Carvasin® (IT, NZ); Cedocard® (AT, BE, HK, ID, IE, LU, NL); Cedocard Retard® (GB, ID); Cedocard®-SR (CA); Cordil® (IL, RO); Cornilat® (YU); Coronex® (CA); Diconpin® (DE); Difutrat® (YU); Diniket® (IT); Dinisan® (CZ); Dinit® (FI); Dinospray® (ZA); duranitrat® (DE); Esconitro® (CH); Farsorbid® (ID); Flindix® (PT); Hartsorb® (TH); Hexanitrat® (AT); Imtack® (IE); ISDN AL® (DE); ISDN-AL® (HU); ISDN Basics® (DE); ISDN-beta® (DE); ISDN Heumann® (DE); ISDN Hexal® (DE); ISDN Intermuti® (DE); ISDN-ISIS® (DE); ISDN-ratiopharm® (DE, LU); ISDN Sandoz® (DE); ISDN Stada® (DE); ISDN von ct® (DE); Isobar® (HK); Isobinate® (TH); Isobin® (SG); Isocard® (FR, GB, LB, LU, RO); Isocardide® (IL); Isocord® (BR, CO); Isodinit® (BG, LU, PL, RO); Isoket® (AR, AT, CH, CR, CZ, DE, DO, EC, GB, GT, HK, HN, HU, ID, IE, IL, LU, MX, PA, PL, PT, RU, SG, SV, TH); Isoket Retard® (CH, GB, IE, PL); Isoket Roztok® (CZ); Isoket Spray® (CZ, IL, TH); Iso Lacer® (ES); Isomack® (AT); Iso Mack® (CH); Isomack® (CL); Iso Mack® (CY, CZ, DE, EC, EG); Isomack® (HK); Iso Mack® (HU, ID, JO, KW, LB); Isomack® (LU); Iso Mack® (PL, RO, RU, SI); Iso Mack Retard® (CZ, HU, PL, RO, SG, TH); Iso Mack Spray® (SG, TH); Iso Mack TD® (HU); Iso-Mack® (TR); Iso-Puren® (DE); Isorbid® (MX); Isordil® (AR, AU, BE, BR, CO, CR, DO, GB, GT, HN, ID, IE, IN, LU, NL, PA, SG, SV, TH, TR, ZA); Isorem® (CY, HK, JO, TH); Isosifar® (CH); Isosorbiddinitrat Lindo® (DE); Isosorbid Dinitrat® (RO); Isosorbid-DN-Cophar® (CH); Isosorbidedinitraat FNA® (NL); Isosorbide Dinitrate BPRL® (SG); Isosorbide Dinitrate® (GB, ID, RO, RU); Isosorbide Dinitrato® (CL); Isosorbid® (ID, RO); Isosorb retard® (RU, YU); Isostad® (AT); Isostenase® (DE); Isotard® (DE, IL); Isotonax® (LU); Isotrate® (TH); Izo® (TH); Jenacard® (DE); Kardiket® (RU); Langoran® (FR); Maycor Retard® (CZ, RO); Nitorol R® (HK, JP); Nitrosid® (FI); Nitrosorbide® (IT); Nitrosorbid® (RU); Nitrosorbon® (DE, HU); Nosim® (AR); Novo-Sorbide (CA); PMS-Isosorbide (CA); Prodicard® (NL); Risordan® (FR); Rolab-Isosorbide Dinitrate® (ZA); Romisodin® (RO); Sorbangil® (NO, SE); Sorbid® (BD); Sorbidilat® (CH); Sorbidin® (AU, ID, TH); Sorbitrate® (HK, IN, LU); Sorbonit® (HU, PL); Sornil® (TH); TD Spray Iso Mack® (DE, LU); Tinidil® (HR, SI); Vascardin® (ID); Wesorbide® (CZ)

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