Isosorbide Dinitrate/Mononitrate (Monograph)

Brand names: Dilatrate, Imdur, Ismo, Isordil, Monoket
Drug class: Nitrates and Nitrites
VA class: CV250

Introduction

Isosorbide dinitrate and isosorbide mononitrate: Organic nitrates; vasodilating agents.

Uses for Isosorbide Dinitrate/Mononitrate

Angina

Isosorbide dinitrate or mononitrate is used for the acute relief of angina pectoris, for prophylactic management in situations likely to provoke angina attacks, and for long-term prophylactic management of angina pectoris.

Conventional measures in the management of angina pectoris are aimed at reducing the frequency, duration, and severity of attacks, and include coronary risk reduction (e.g., discontinuance of smoking, weight control, antilipemic strategies), rest, avoidance of precipitating circumstances (e.g., eating heavy meals, getting emotionally upset, performing strenuous exercise, exposure to cold air) and, if possible, treatment of the underlying cause.

β-Adrenergic blocking agents (β-blockers) generally are considered among the initial antianginal drugs of choice in the long-term prophylactic management of chronic stable angina with or without prior MI to reduce symptoms and to prevent MI and/or death.

Isosorbide dinitrate or mononitrate can be used alone or in combination as either second-line or third-line therapy in patients previously treated with a β-blocker.

Prolonged use of oral nitrates has been associated with the development of tolerance to the hemodynamic and antianginal effects and possibly with cross-tolerance to sublingual nitrates. (See Tolerance and Dependence under Cautions.)

Generally considered for monotherapy in the prophylactic management of angina pectoris only when β-blockers or calcium-channel blocking agents are contraindicated, associated with unacceptable adverse effects, or are ineffective.

If a β-blocker is not effective in controlling chronic stable angina, long-acting nitrates may be added to β-blocker therapy.

Heart Failure

Isosorbide dinitrate used in fixed combination with hydralazine (BiDil) as adjunct to standard therapy for the treatment of heart failure in self-identified black patients to improve survival, decrease rate of hospitalization for worsened heart failure, and improve patient-reported functional status.

Current guidelines recommend a combination of drug therapies (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) in adults with heart failure to reduce morbidity and mortality.

Combination of isosorbide dinitrate and hydralazine recommended by ACCF and AHA for self-identified black patients with NYHA class III or IV heart failure and reduced ejection fraction who are receiving optimal therapy with ACE inhibitors and β-blockers, unless contraindicated.

ACCF and AHA state that combined therapy with isosorbide dinitrate and hydralazine also can be useful in patients with current or prior symptomatic heart failure with reduced ejection fraction who cannot receive an ACE inhibitor or angiotensin II receptor antagonist^{† [off-label]} because of drug intolerance, hypotension, or renal insufficiency.

Diffuse Esophageal Spasm

Isosorbide dinitrate has been used effectively for diffuse esophageal spasm^{† [off-label]} without gastroesophageal reflux to relieve pain, dysphagia, and spasm.

Isosorbide Dinitrate/Mononitrate Dosage and Administration

Administration

Isosorbide Dinitrate

Administer sublingually, intrabuccally, or orally.

Sublingual or intrabuccal nitrates may be inadequately absorbed, with resultant decreased efficacy, in patients with dry oral mucous membranes (e.g., xerostomia).

Do not chew extended-release preparations.

The patient should be sitting immediately after sublingual or intrabuccal administration.

Isosorbide Mononitrate

Administer orally.

Extended-release tablets can be administered as whole or halved tablets, but swallow intact and do not chew or crush.

Administer extended-release tablets with adequate amounts of fluid (e.g., 120 mL) on arising in the morning.

Dosage

Adjust dosage of isosorbide dinitrate and isosorbide mononitrate carefully according to the patient’s requirements and response; use the smallest effective dosage.

Although many clinicians do not gradually reduce the dosage when discontinuance of oral nitrates is planned, it appears prudent that dosage be gradually reduced (e.g., over a period of about 1–2 weeks) to avoid withdrawal manifestations. Supplementary sublingual nitroglycerin doses should be given if necessary during dosage reduction.

Adults

Angina

Acute Symptomatic Relief and Prophylactic Management

Do not use extended-release isosorbide dinitrate preparations or any isosorbide mononitrate preparation to abort an acute anginal episode or for acute relief of angina or in the prophylactic management in situations likely to provoke angina attacks; onset is not sufficiently rapid.

Sublingual

Patients who fail to respond to nitroglycerin lingual or sublingual: 2.5–5 mg of isosorbide dinitrate.

If relief is not attained after a single dose during an acute attack, may give additional doses at 5- to 10-minute intervals; give no more than 3 doses in a 15- to 30-minute period.

Prophylactic management in situations likely to provoke angina attacks in patients who fail to respond to sublingual nitroglycerin: place 2.5–5 mg of isosorbide dinitrate under the tongue about 15 minutes prior to engaging in such activities.

Intrabuccal

Patients who fail to respond to nitroglycerin lingual or sublingual: 2.5–5 mg of isosorbide dinitrate.

If relief is not attained after a single dose during an acute attack, may give additional doses at 5- to 10-minute intervals; no more than 3 doses should be given in a 15- to 30-minute period.

Prophylactic management in situations likely to provoke angina attacks in patients who fail to respond to sublingual nitroglycerin: 2.5–5 mg of isosorbide dinitrate should be placed under the tongue approximately 15 minutes prior to engaging in such activities.

Long-term Prophylactic Management

Oral (Isosorbide Dinitrate Conventional Tablets)

Initially, isosorbide dinitrate conventional tablets (e.g., Isordil Titradose) 5–20 mg administered 2–3 times daily, followed by maintenance dosage of 10–40 mg administered 2–3 times daily (some patients may require higher dosages).

Suggested schedules: Usually, at 7 a.m., 12 p.m., and 5 p.m. in chronic stable angina or at 7 a.m. and 12 p.m. in less severely symptomatic angina in order to allow for a nitrate-free interval of 10–14 hours.

May need to adjust schedule for those arising earlier than 7 a.m. since early morning angina is common.

Less frequent administration of isosorbide dinitrate may reduce the development of tolerance to the drug’s antianginal effects.

Oral (Isosorbide Dinitrate Extended-release Capsules)

An interdosing interval sufficient to avoid tolerance to Dilatrate-SR extended-release capsules is not known, but it must exceed 18 hours.

Do not exceed daily Dilatrate-SR dosages of 160 mg (4 capsules).

Oral (Isosorbide Mononitrate Conventional Tablets)

Usual initial dosage of conventional tablets (e.g., Monoket): 20 mg twice daily, with the 2 doses administered 7 hours apart.

Particularly small stature, initially: 5 mg (½ of a 10-mg tablet) twice daily, for no longer than initial 2 days.

Particularly small stature, maintenance: Increased to at least 10 mg twice daily by the second or third day.

Oral (Isosorbide Mononitrate Extended-release Tablets)

Initially, (e.g., Imdur): 30 mg (as a single 30-mg tablet or as ½ of a 60-mg tablet) or 60 mg (as a single 60-mg tablet) once daily.

May increase dosage to 120 mg (as a single 120-mg tablet or as two 60-mg tablets) once daily after several days; 240-mg dosages rarely needed.

Heart Failure

Fixed-combination Therapy with Hydralazine in Self-identified Black Patients

Oral

Initially, isosorbide dinitrate 20 mg and hydralazine hydrochloride 37.5 mg (1 tablet of BiDil) 3 times daily. May titrate dosage to a maximum tolerated dosage not to exceed 2 tablets (a total of 40 mg of isosorbide dinitrate and 75 mg of hydralazine hydrochloride) 3 times daily. Rapid titration (over 3–5 days) may be possible; however, slower titration may be needed due to adverse effects. May decrease dosage to as little as ½ of the fixed-combination tablet 3 times daily in patients who experience intolerable effects, but attempt to titrate dosage up once adverse effects subside.

Isosorbide Dinitrate Therapy† [off-label]

Oral (Isosorbide Dinitrate Conventional Tablets)

ACCF and AHA recommend initial dosage of 20–30 mg 3 or 4 times daily; give concomitantly with hydralazine hydrochloride 25–50 mg 3 or 4 times daily. Titrate dosages to levels similar to those recommended for the fixed-combination preparation and administer both drugs at least 3 times daily.

Diffuse Esophageal Spasm

Oral (Isosorbide Dinitrate Conventional Tablets)

10–30 mg 4 times daily.

Prescribing Limits

Adults

Angina

Acute Symptomatic Relief and Prophylactic Management

Sublingual

No more than 3 doses in a 15- to 30-minute period.

Intrabuccal

No more than 3 doses in a 15- to 30-minute period.

Long-term Prophylactic Management

Oral (Isosorbide Dinitrate Extended-release Capsules)

Maximum daily dosage of Dilatrate-SR: 160 mg (4 capsules).

Oral (Isosorbide Mononitrate Extended-release Tablets)

Dosages of 240 mg are rarely needed.

Heart Failure

Fixed-combination Therapy with Hydralazine in Self-identified Black Patients

Oral

Maximum 40 mg of isosorbide dinitrate and 75 mg of hydralazine hydrochloride (2 tablets of BiDil) 3 times daily.

Isosorbide Dinitrate Therapy† [off-label]

Oral (Isosorbide Dinitrate Conventional Tablets)

Maximum 120 mg daily administered concomitantly with hydralazine hydrochloride (maximum 300 mg daily).

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment.

Renal Impairment

No specific dosage recommendations for renal impairment.

Geriatric Patients

One manufacturer of isosorbide mononitrate states that dosage should be selected with caution, usually initiating therapy at the low end of the range, although age, renal, hepatic, and cardiovascular dysfunction do not appear to have a significant effect on drug clearance.

The manufacturer of the fixed combination of isosorbide dinitrate and hydralazine hydrochloride states that dosage should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Isosorbide Dinitrate/Mononitrate

Contraindications

• Known hypersensitivity to isosorbide or any ingredient in the respective formulation.

• Manufacturers state that selective phosphodiesterase (PDE) inhibitors (e.g., sildenafil, tadalafil, vardenafil) are contraindicated in patients receiving nitrates. Complete avoidance may not be possible, provided sufficient time elapses between use of the drugs. (See Selective Phosphodiesterase (PDE) Inhibitors under Cautions.)

• Extended-release oral nitrate preparations should not be used in patients with functional or organic GI hypermotility or malabsorption syndrome.

• Isosorbide dinitrate is contraindicated in patients with shock or marked low blood pressure.

Warnings/Precautions

Warnings

Selective Phosphodiesterase (PDE) Inhibitors

Selective PDE inhibitors can potentiate the hypotensive effects of organic nitrates and nitrites, possibly resulting in potentially life-threatening hypotension and/or hemodynamic compromise.

Manufacturers of selective PDE inhibitors (e.g., sildenafil, tadalafil, vardenafil) state that the drugs are contraindicated in patients receiving organic nitrates or nitrites in any form (e.g., orally, sublingually, transmucosally, parenterally), given regularly or intermittently, or nitric oxide donors since severe, potentially fatal hypotensive episodes can occur.

Clinicians unfamiliar with their patients’ drug history, especially those involved in emergency care (e.g., for presumed myocardial infarction or ischemia), should take a careful history so that concomitant use of organic nitrates or nitrites with selective PDE inhibitors can be avoided.

Warn all patients receiving organic nitrates or nitrites about the potential interaction between the drugs and selective PDE inhibitors, even if they currently are not receiving the drugs, since there is substantial potential for patients to receive the drugs from another clinician, from a friend, with little or no clinical intervention (e.g., via the Internet), or illicitly.

Warn all patients taking either selective PDE inhibitors or organic nitrates or nitrites of the potential consequences of taking the drugs within close proximity (e.g., within 24 hours of sildenafil; possibly more prolonged periods of risk with longer-acting PDE inhibitors) of taking a nitrate- or nitrite-containing preparation.

Cardiovascular Effects

Severe hypotension, particularly in upright position, can occur even with low doses.

Caution in volume depletion or preexisting hypotension.

Paradoxical bradycardia and angina exacerbation may accompany hypotension.

Benefits in acute MI and heart failure not established.

Careful clinical or hemodynamic monitoring for possible hypotension or tachycardia if used in acute MI or heart failure.

Avoid long-acting dosage forms in the early management of acute MI or heart failure since the effects are difficult to terminate rapidly should excessive hypotension or tachycardia occur.

Sensitivity Reactions

Occur extremely rarely.

General Precautions

Tolerance and Dependence

Tolerance to the vascular and antianginal effects of individual nitrates and cross-tolerance among the drugs may occur with repeated, prolonged use.

Carefully individualize nitrate dosage to minimize the risk of tolerance; also consider potential risks of nitrate withdrawal.

Employ intermittent dosing of nitrates (e.g., use of a nitrate-free interval of 10–12 hours daily) to minimize or prevent the development of tolerance to the hemodynamic and antianginal effects of the drugs.

Possibility of an increased frequency or severity of angina during the nitrate-free interval should be considered.

Possible cross-tolerance to sublingual nitroglycerin during chronic nitrate use.

Nitrate dependence is possible (documented in daily industrial exposures); withdrawal manifestations (e.g., ischemic symptoms, MI, sudden death) can occur.

Use of Fixed Combinations

When isosorbide dinitrate is used in fixed combination with hydralazine, consider the cautions, precautions, and contraindications associated with hydralazine.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether isosorbide dinitrate and isosorbide mononitrate are distributed into milk. Caution if used in nursing women.

Geriatric Use

Not known whether geriatric patients respond differently than younger patients. (See Geriatric Patients under Dosage.)

Common Adverse Effects

Serious adverse reactions to the organic nitrates and nitrites are uncommon and their adverse effects mainly involve the CNS and cardiovascular system.

Headache, the most frequent adverse effect, may be severe (persistent or transient) and is perceived as a pulsating, throbbing sensation; frequent early in therapy, usually diminishes rapidly, and may disappear within several days to weeks of continuous therapy. Aspirin or acetaminophen may relieve.

Postural hypotension may occur and may cause dizziness, weakness, and other signs of cerebral ischemia.

Transient flushing may occur with the nitrates, and inhalation of amyl nitrite commonly causes cutaneous flushing of the head, neck, and clavicular area.

May cause a burning or tingling sensation when administered sublingually.

May cause blurred vision and should be discontinued if this symptom occurs.

Drug Interactions

Specific Drugs or Laboratory Tests

Isosorbide Dinitrate/Mononitrate Pharmacokinetics

Absorption

Bioavailability (Isosorbide Dinitrate)

Readily (and almost completely) absorbed from the GI tract and oral mucosa, but considerable variations in the bioavailability (10–90%) secondary to extensive first-pass metabolism in the liver.

Conventional oral tablets: 25% unchanged drug; about half that following sublingual administration (40–50%).

Bioavailability (Isosorbide Mononitrate)

Readily absorbed from the GI tract; does not undergo first-pass hepatic metabolism.

Conventional tablets: Approximately 100%.

Extended-release tablets: Approximately 77–80%.

Onset and Duration

The approximate onset and duration of action of various dosage forms of isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN) are as follows:

Onset and duration of action following intrabuccal administration are probably similar to those after sublingual administration of isosorbide dinitrate.

Food

Isosorbide dinitrate: Food may decrease substantially mean peak plasma concentrations, yet total bioavailability does not seem to be affected. The effect of food on the bioavailability of isosorbide dinitrate when administered in fixed combination with hydralazine hydrochloride is not known.

Isosorbide mononitrate: Generally, food delays the rate but not the extent of absorption (less than 10%) of conventional or extended-release tablets.

Plasma Concentrations

Isosorbide dinitrate – sublingual, peak: 10–15 minutes.

Isosorbide dinitrate – conventional tablets, peak: 60 minutes.

Isosorbide dinitrate – fixed-combination tablets with hydralazine hydrochloride, peak: 60 minutes.

Isosorbide mononitrate – conventional tablets, peak: 0.5–1 hour.

Isosorbide mononitrate – extended-release tablets, peak: 3–4.5 hours.

Special Populations

Risk of elevated blood concentrations of isosorbide dinitrate in patients with cirrhosis.

Distribution

Extent

Distribution into human body tissues and fluids has not been fully characterized.

Not known whether isosorbide dinitrate and isosorbide mononitrate are distributed into milk.

Plasma Protein Binding

Isosorbide dinitrate: Approximately 28%.

Isosorbide mononitrate: Approximately 4–5%.

Elimination

Metabolism

Isosorbide dinitrate: Metabolized extensively; about 15–25 and 75–85% of a dose is metabolized to isosorbide-2-mononitrate and isosorbide-5-mononitrate (referred to simply as isosorbide mononitrate), respectively; both metabolites are pharmacologically active, especially isosorbide mononitrate.

Isosorbide dinitrate: Also probably metabolized at extrahepatic sites.

Isosorbide mononitrate: Metabolized principally in the liver, but unlike isosorbide dinitrate, does not undergo first-pass metabolism; metabolites appear to be pharmacologically inactive.

Elimination Route

Isosorbide dinitrate and isosorbide mononitrate are mainly excreted in the urine.

Half-life

Isosorbide dinitrate: About 1 hour.

Isosorbide dinitrate in fixed combination with hydralazine hydrochloride: About 2 hours.

Isosorbide mononitrate: About 5 hours.

Stability

Storage

Oral (Isosorbide Dinitrate)

Tablets

Tight, light-resistant containers at room temperature (25°C); do not expose to extremes in temperature.

Oral (Isosorbide Mononitrate)

Tablets (Extended-release and Conventional)

Conventional tablets (e.g., Monoket): Tight, light-resistant containers at 15–30°C.

Oral (Isosorbide Dinitrate in Fixed Combination with Hydralazine Hydrochloride)

Tablets

Tight, light-resistant containers at 25°C; may be exposed to 15–30°C.

Actions

• The exact mechanism of action in the relief of angina pectoris has not been fully elucidated.

• Principal pharmacologic property is relaxation of vascular smooth muscle, resulting in generalized vasodilation.

• Peripheral venous resistance is decreased via a selective action on venous capacitance vessels and results in venous pooling of blood and decreased venous return to the heart.

• Vasodilatory effect on arteriolar resistance is not as great as the action on the venous side; as a result of this combined action, both venous filling pressure (preload) and, to a lesser extent, arterial impedance (afterload) are reduced.

• By decreasing myocardial oxygen consumption, nitrates and nitrites alter the imbalance of myocardial oxygen supply and consumption which is thought to cause angina pectoris.

• Because of their hemodynamic profile, particularly beneficial in patients with left ventricular systolic dysfunction or heart failure.

• Both direct vasodilatory effects on the coronary bed and drug-induced prevention of episodic coronary artery vasoconstriction increase total coronary blood flow.

• After therapeutic doses, cardiac output may increase transiently and then decrease.

• In addition to vascular smooth muscle, nitrates and nitrites relax bronchial, biliary (including the gallbladder, biliary ducts, and sphincter of Oddi), GI (including the esophagus), ureteral, and uterine smooth muscle; nitrates relax all smooth muscle irrespective of autonomic innervation and are functional antagonists of norepinephrine, acetylcholine, and histamine.

Advice to Patients

• Advise patients of the likelihood of headache, particularly with initial nitrate therapy. Importance of consulting clinician if headache continues with repeated dosing.

• Advise patients to take nitrates as directed, particularly since tolerance can occur.

• Importance of instructing patients receiving isosorbide dinitrate for relief of acute attacks of angina pectoris to consult a clinician or go to a hospital emergency room immediately if chest pain is not relieved after 3 doses approximately every 5 minutes, because inability to relieve chest pain may indicate acute MI.

• Importance of informing patients receiving isosorbide dinitrate in fixed combination with hydralazine that inadequate fluid intake or excessive fluid loss due to diarrhea, vomiting, or perspiration may result in excessive hypotension, possibly leading to lightheadedness or syncope; if syncope occurs, discontinue treatment and notify clinician immediately.

• Importance of clinicians unfamiliar with their patients’ drug history, especially those involved in emergency care (e.g., for presumed myocardial infarction or ischemia), to take a careful history so that concomitant use with selective PDE inhibitors can be avoided.

• Importance of warning all patients receiving organic nitrates or nitrites about the potential interaction between the drugs and selective PDE inhibitors, even if they currently are not receiving the drugs, since there is substantial potential for patients to receive the drugs from another clinician, from a friend, with little or no clinical intervention (e.g., via the Internet), or illicitly.

• Importance of warning all patients taking either selective PDE inhibitors or organic nitrates or nitrites of the potentially severe and life-threatening hemodynamic consequences of taking the drugs within close proximity (e.g., within 24 hours of sildenafil; possibly more prolonged periods of risk with longer-acting PDE inhibitors) of taking a nitrate- or nitrite-containing preparation.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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