Skip to Content

Isosorbide Dinitrate

Pronunciation

Pronunciation

(eye soe SOR bide dye NYE trate)

Index Terms

  • ISD
  • ISDN

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release, Oral:

Dilatrate-SR: 40 mg [contains fd&c yellow #10 (quinoline yellow)]

Tablet, Oral:

Isordil Titradose: 5 mg [scored; contains fd&c red #40]

Isordil Titradose: 40 mg [scored; contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Generic: 5 mg, 10 mg, 20 mg, 30 mg

Tablet Extended Release, Oral:

Isochron: 40 mg [DSC]

IsoDitrate ER: 40 mg

Generic: 40 mg

Tablet Sublingual, Sublingual:

Generic: 2.5 mg [DSC], 5 mg [DSC]

Brand Names: U.S.

  • Dilatrate-SR
  • Isochron [DSC]
  • IsoDitrate ER
  • Isordil Titradose

Pharmacologic Category

  • Antianginal Agent
  • Vasodilator

Pharmacology

Isosorbide dinitrate and other nitrates form free radical nitric oxide. In smooth muscle, nitric oxide activates guanylate cyclase which increases guanosine 3’5’ monophosphate (cGMP) leading to dephosphorylation of myosin light chains and smooth muscle relaxation. Produces a vasodilator effect on the peripheral veins and arteries with more prominent effects on the veins. Primarily reduces cardiac oxygen demand by decreasing preload (left ventricular end-diastolic pressure); may modestly reduce afterload. Additionally, coronary artery dilation improves collateral flow to ischemic regions.

Distribution

Vd: 2 to 4 L/kg

Metabolism

Extensively hepatic to conjugated active metabolites isosorbide 5-mononitrate and 2-mononitrate

Onset of Action

Sublingual tablet: ~2 to 5 minutes; Oral tablet and capsule (includes extended-release formulations): ~1 hour

Duration of Action

Sublingual tablet: 1 to 2 hours; Oral tablet and capsule (includes extended-release formulations): Up to 8 hours

Half-Life Elimination

Parent drug: ~1 hour; Metabolites (5-mononitrate: 5 hours; 2-mononitrate: 2 hours)

Use: Labeled Indications

Angina pectoris, prevention: Prevention of angina pectoris due to coronary artery disease.

Note: Due to slower onset of action, isosorbide dinitrate is not the drug of choice to abort an acute anginal episode.

Use: Unlabeled

Patients with heart failure with reduced ejection fraction (HFrEF) who do not tolerate an ACE inhibitor or an angiotensin receptor blocker (ARB) (in combination with hydralazine); African-American (self-identified) patients with HFrEF NYHA class III-IV remaining symptomatic despite optimal guideline-directed medical therapy (in combination with hydralazine); esophageal spastic disorders

Contraindications

Hypersensitivity to isosorbide dinitrate or any component of the formulation; concurrent use with phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil, or avanafil); concurrent use with riociguat

Canadian labeling: Additional contraindications (not in US labeling): Cardiogenic shock or risk of cardiogenic shock developing

Dosing: Adult

Angina pectoris (prevention): Note: Due to slower onset of action, isosorbide dinitrate is not the drug of choice to abort an acute anginal episode. 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. Nitrate-free intervals of ≥14 hours (immediate release products) or >18 hours (sustained release products) may help minimize tolerance.

Oral:

Immediate release: Initial: 5 to 20 mg 2 to 3 times daily; Maintenance: 10 to 40 mg 2 to 3 times daily or 5 to 80 mg 2 to 3 times daily (Anderson 2011)

Sustained release: 40 to 160 mg/day has been used in clinical trials (a nitrate free interval of >18 hours is recommended; however, a clinically efficacious dosage interval has not been clearly established) or 40 mg 1 to 2 times daily (Anderson 2011). Maximum dose: 160 mg/day (Dilatrate-SR only).

Sublingual [Canadian product]: 5 to 10 mg every 2 to 4 hours for prophylaxis of acute angina; may supplement with 5 to 10 mg prior to activities which may provoke an anginal episode.

Heart failure (off-label use; ACCF/AHA [Yancy 2013]): Oral: Immediate release (Note: Use in combination with hydralazine):

Initial dose: 20 to 30 mg 3 to 4 times daily

Maximum dose: 120 mg daily in divided doses

Esophageal spastic disorders (off-label use; Goyal, 1998): Oral, sublingual: Immediate release: 10 to 30 mg before meals

Dosing: Geriatric

Elderly patients should be given lowest recommended adult daily doses initially and titrate upward. Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Hemodialysis: Supplemental dose is not necessary.

Peritoneal dialysis: Supplemental dose is not necessary.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Administration

Do not administer around the clock; allow nitrate-free interval ≥14 hours (immediate release products) and >18 hours (sustained release products). Do not chew or crush sublingual tablets or sustained release formulations.

Immediate release products: For twice daily dosing, consider administering at 8 AM and 1 PM. For 3 times daily dosing, consider 8 AM, 1 PM, and 6 PM.

Sustained release products: Consider once daily in morning or twice-daily dosing at 8 AM and between 1 PM and 2 PM.

Storage

Extended-release tablets: Store at 20°C to 25°C (68°F to 77°F).

Sustained-release capsules and immediate-release tablets: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Alcohol (Ethyl): May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the orthostatic hypotensive effect of Vasodilators (Organic Nitrates). Monitor therapy

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Vasodilators (Organic Nitrates). Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Avoid combination

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Riociguat: Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Riociguat. Avoid combination

Rosiglitazone: Vasodilators (Organic Nitrates) may enhance the adverse/toxic effect of Rosiglitazone. Specifically, a greater risk of ischemia and other adverse effects has been associated with this combination in some pooled analyses. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

Frequency not defined.

Cardiovascular: Crescendo angina (uncommon), hypotension, orthostatic hypotension, rebound hypertension (uncommon), syncope (uncommon)

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

Hematologic: Methemoglobinemia (rare, overdose)

Warnings/Precautions

Concerns related to adverse effects:

• Hypotension/bradycardia: Severe hypotension can occur; paradoxical bradycardia and increased angina pectoris can accompany hypotension. Orthostatic hypotension can also occur; ethanol can accentuate this. Use with caution in volume depletion and hypotension, and use with extreme caution with inferior wall MI and suspected right ventricular infarctions. Severe hypotension, particularly with upright posture, may occur with even small doses.

• Intracranial pressure increased: Nitrates may precipitate or aggravate increased intracranial pressure and subsequently may worsen clinical outcomes in patients with neurologic injury (eg, intracranial hemorrhage, traumatic brain injury).

Disease-related concerns:

• Cardiovascular disease: Not recommended in patients with acute MI or HF (cannot easily reverse effects if adverse events develop).

• Hypertrophic cardiomyopathy (HCM): Avoid use in patients with HCM with outflow tract obstruction; nitrates may reduce preload, exacerbating obstruction and cause hypotension or syncope and/or worsening of heart failure (ACCF/AHA [Gersh 2011]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Tolerance: Appropriate dosing intervals are needed to minimize tolerance development. Tolerance can only be overcome by short periods of nitrate absence from the body. Dose escalation does not overcome this effect. When used for HF in combination with hydralazine, tolerance is less of a concern (Gogia 1995).

Monitoring Parameters

Blood pressure, heart rate

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Nitric oxide donors, such as isosorbide, have been evaluated for pre-eclampsia and cervical ripening; isosorbide dinitrate use in these conditions is not currently recommended (Kalidindi 2012; Ramirez 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber angina, severe dizziness, syncope, considerable headache, bradycardia, or tachycardia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Hide