Note: Dilatrate SR has been discontinued in the United States for >1 year.
Achalasia (alternative agent) (off-label use):
Sublingual [Canadian product]: Immediate release: 5 mg administered 10 to 15 minutes before meals. Note: Clinical response is short acting and use does not provide complete relief of symptoms; consider risks before use (ACG [Vaezi 2020]).
Angina pectoris, prevention:
Note: For prevention of recurrent angina, may use in combination with other anti-anginal therapy (eg, beta-blocker) (ACC/AHA [Amsterdam 2014]; ACCF/AHA [O'Gara 2013]).
Immediate release: Oral: Initial: 5 to 20 mg 2 to 3 times daily; maintenance dose: 10 to 40 mg 2 to 3 times daily; allow for a 14-hour nitrate-free period after the evening dose and before the morning dose to minimize risk of tolerance.
Sustained release: Oral: 40 to 160 mg/day; once daily dosing allows for an 18-hour nitrate-free period to minimize the risk of tolerance; maximum dose: 160 mg/day.
Sublingual [Canadian product]: 5 to 10 mg every 2 to 4 hours; consider supplementing with 5 to 10 mg prior to activities that may provoke angina.
Heart failure with reduced ejection fraction (off-label use):
Note: Alternative therapy for patients with persistent NYHA class III or IV heart failure with reduced ejection fraction (HFrEF) who cannot tolerate an angiotensin II receptor-neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker or additional therapy in patients who have residual hypertension despite an optimal medical regimen for HFrEF (ACC [Maddox 2021]; AHA/ACC/HFSA [Heidenreich 2022]; Colucci 2021).
Oral: Immediate release: Initial: 20 mg 3 times daily in combination with hydralazine; titrate dose every 2 to 4 weeks, as tolerated; target dose: 40 mg 3 times daily (ACC [Maddox 2021]; AHA/ACC/HFSA [Heidenreich 2022]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
Hemodialysis: Supplemental dose is not necessary.
Peritoneal dialysis: Supplemental dose is not necessary.
There are no dosage adjustments provided in the manufacturer's labeling.
Elderly patients should be given lowest recommended adult daily doses initially and titrate upward. Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule Extended Release, Oral:
Dilatrate-SR: 40 mg [DSC] [contains quinoline yellow (d&c yellow #10)]
Tablet, Oral:
Isordil Titradose: 5 mg [scored; contains fd&c red #40 (allura red ac dye)]
Isordil Titradose: 40 mg [scored; contains fd&c blue #1 (brilliant blue), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Generic: 5 mg, 10 mg, 20 mg, 30 mg, 40 mg
Tablet Extended Release, Oral:
Generic: 40 mg [DSC]
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 10 mg, 30 mg
Tablet Sublingual, Sublingual:
Generic: 5 mg
Dilatrate SR has been discontinued in the United States for >1 year.
Do not administer around the clock to prevent tolerance to nitrate effect; 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. Note: In patients with heart failure with reduced ejection fraction who are prescribed hydralazine in combination with isosorbide dinitrate, nitrate tolerance is prevented by coadministration of hydralazine (Gogia 1995). When prescribed for this indication and in combination with hydralazine, isosorbide dinitrate can be administered 3 or 4 times daily with no nitrate-free period.
IR 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.
Bariatric surgery: Capsule and tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Do not open capsule. Switch to IR tablet.
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.
Achalasia; Heart failure with reduced ejection fraction
Isordil may be confused with Inderal, Isuprel, Plendil
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined.
Cardiovascular: Hypotension, rebound hypertension, syncope, unstable angina pectoris
Central nervous system: Headache
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
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) (Rangel-Castilla 2008).
Disease-related concerns:
• Cardiovascular disease: Not recommended in patients with acute MI or HF (cannot easily reverse effects if adverse events develop).
• Hypertrophic cardiomyopathy: Avoid use in patients with hypertrophic cardiomyopathy with left ventricular outflow tract obstruction; nitrates may reduce preload, exacerbating obstruction and cause hypotension or syncope and/or worsening of heart failure (AHA/ACC [Ommen 2020]).
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).
Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Dapoxetine: May enhance the orthostatic hypotensive effect of Vasodilators (Organic Nitrates). Risk C: Monitor therapy
Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy
Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Vasodilators (Organic Nitrates). Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: 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. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: 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. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Risk X: 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. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Rilmenidine: Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Rilmenidine. Risk C: Monitor therapy
Riociguat: Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Riociguat. Risk X: 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. Risk C: 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. Risk C: Monitor therapy
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).
It is not known if isosorbide dinitrate is present in breast milk. The manufacturer recommends that caution be exercised when administering isosorbide dinitrate to breastfeeding women.
Blood pressure, heart rate
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.
Onset of action: Sublingual tablet: ~2 to 5 minutes; Oral tablet and capsule (includes extended-release formulations): ~1 hour
Duration: Sublingual tablet: 1 to 2 hours; Oral tablet and capsule (includes extended-release formulations): Up to 8 hours
Distribution: Vd: 2 to 4 L/kg
Metabolism: Extensively hepatic to conjugated active metabolites isosorbide 5-mononitrate and 2-mononitrate
Bioavailability: Highly variable (10% to 90%); increases with chronic therapy
Half-life elimination: Parent drug: ~1 hour; Metabolites (5-mononitrate: 5 hours; 2-mononitrate: 2 hours)
Tablets (Isordil Titradose Oral)
5 mg (per each): $11.00
40 mg (per each): $24.22
Tablets (Isosorbide Dinitrate Oral)
5 mg (per each): $0.95 - $0.99
10 mg (per each): $0.73 - $1.08
20 mg (per each): $0.86 - $1.19
30 mg (per each): $1.31
40 mg (per each): $20.54 - $21.78
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