Version May 2024
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 (Ref).
Angina, prevention:
Note: For prevention of recurrent angina, may use in combination with other anti-anginal therapy (eg, beta-blocker) (Ref).
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.
Extended 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 (Ref).
Oral: Immediate release: Initial: 20 mg 3 times daily in combination with hydralazine; titrate dose as tolerated every ≥1 to 2 weeks; target dose: 40 mg 3 times daily (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (Ref).
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (Ref): No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: Not likely to be significantly dialyzed (large Vd): No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
There are no dosage adjustments provided in the manufacturer's labeling.
Administer the lowest recommended adult daily dose initially and titrate upward. Refer to adult dosing.
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.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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).
Dilatrate SR has been discontinued in the United States for >1 year.
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
May be product dependent
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
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Generic: 10 mg, 30 mg
Tablet Sublingual, Sublingual:
Generic: 5 mg [DSC]
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 (Ref). 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.
ER 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
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
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. 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
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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 cervical ripening and induction of labor (Abu-Zaid 2022; Ghosh 2016); however, use of isosorbide dinitrate is not currently recommended for this indication (ACOG 2009; NICE 2021). Nitric oxide donors have also been evaluated for the prevention of preterm birth (Duckitt 2014; Wilson 2022); additional study is needed for this indication and use is not currently recommended (McDougall 2023; WHO 2022).
It is not known if isosorbide dinitrate is present in breast milk.
The manufacturer recommends that caution be exercised when administering isosorbide dinitrate to patients who are breastfeeding.
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)
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