Isosorbide Dinitrate / Mononitrate

Administration

Isosorbide Dinitrate

Administer sublingually, intrabuccally, or orally.b

Sublingual or intrabuccal nitrates may be inadequately absorbed, with resultant decreased efficacy, in patients with dry oral mucous membranes (e.g., xerostomia).219 220

Do not chew extended-release preparations.b

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

Isosorbide Mononitrate

Administer orally.290 291 292

Extended-release tablets can be administered as whole or halved tablets, but swallow intact and do not chew or crush.292

Administer extended-release tablets with adequate amounts of fluid (e.g., 120 mL) on arising in the morning.292

Dosage

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

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.c Supplementary sublingual nitroglycerin doses should be given if necessary during dosage reduction.302

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.224 290 291 292

Sublingual

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

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.b

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.200

Intrabuccal

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

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.b

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.200

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).302 b

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.302 b

May need to adjust schedule for those arising earlier than 7 a.m. since early morning angina is common.324

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

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.224

Do not exceed daily Dilatrate-SR dosages of 160 mg (4 capsules).224

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.290 291

Particularly small stature, initially: 5 mg (½ of a 10-mg tablet) twice daily, for no longer than initial 2 days.291

Particularly small stature, maintenance: Increased to at least 10 mg twice daily by the second or third day.291

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.292

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.292

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.336 524 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.336 524 Rapid titration (over 3–5 days) may be possible; however, slower titration may be needed due to adverse effects.336 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.336

Isosorbide Dinitrate Therapy† 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.524 Titrate dosages to levels similar to those recommended for the fixed-combination preparation and administer both drugs at least 3 times daily.524

Diffuse Esophageal Spasm Oral (Isosorbide Dinitrate Conventional Tablets)

10–30 mg 4 times daily.b

Prescribing Limits

Adults

Angina Acute Symptomatic Relief and Prophylactic Management Sublingual

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

Intrabuccal

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

Long-term Prophylactic Management Oral (Isosorbide Dinitrate Extended-release Capsules)

Maximum daily dosage of Dilatrate-SR: 160 mg (4 capsules).224

Oral (Isosorbide Mononitrate Extended-release Tablets)

Dosages of 240 mg are rarely needed.292

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.336

Isosorbide Dinitrate Therapy† Oral (Isosorbide Dinitrate Conventional Tablets)

Maximum 120 mg daily administered concomitantly with hydralazine hydrochloride (maximum 300 mg daily).524

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment.b

Renal Impairment

No specific dosage recommendations for renal impairment.b

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.325

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.336

Contraindications

• Known hypersensitivity to isosorbide or any ingredient in the respective formulation.302

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

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

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.c

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,262 or nitric oxide donors since severe, potentially fatal hypotensive episodes can occur.260 261 262 263 266 271 272 282 284 285 288

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.260 264 271

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),281 or illicitly.260 281 282

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.260 282

Cardiovascular Effects

Severe hypotension, particularly in upright position, can occur even with low doses.302

Caution in volume depletion or preexisting hypotension.302

Paradoxical bradycardia and angina exacerbation may accompany hypotension.302

Benefits in acute MI and heart failure not established.302

Careful clinical or hemodynamic monitoring for possible hypotension or tachycardia if used in acute MI or heart failure.302

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.c

Sensitivity Reactions

Occur extremely rarely.302

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.c

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

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.c

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

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

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

Use of Fixed Combinations

When isosorbide dinitrate is used in fixed combination with hydralazine, consider the cautions, precautions, and contraindications associated with hydralazine.336

Specific Populations

Pregnancy

Category C.PDH

Lactation

Not known whether isosorbide dinitrate and isosorbide mononitrate are distributed into milk.200 224 290 291 292 302 Caution if used in nursing women.302

Geriatric Use

Not known whether geriatric patients respond differently than younger patients.325 336 (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.c Aspirin or acetaminophen may relieve.c

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.

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.224 294 302

Conventional oral tablets: 25% unchanged drug; about half that following sublingual administration (40–50%).20 200 226 228

Bioavailability (Isosorbide Mononitrate)

Readily absorbed from the GI tract;291 294 295 does not undergo first-pass hepatic metabolism.290 291 292 294 295 296 297 298

Conventional tablets: Approximately 100%.b

Extended-release tablets: Approximately 77–80%.290 291 292 294 295 296 297 298

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:b

Antianginal Effects

Dosage Form	Onset	Duration
Sublingual ISDN	Within 3 min200 225	2 h200 225
Chewable ISDN	Within 3 min225	2–2.5 h225
Oral ISDN	1 h225	Up to 8 h225
Oral ISMN	1 h290 291	5–7 h290 291
Extended-release ISDN	1 h224	8 h224
Extended-release ISMN	1 h298	12 h298

Hemodynamic Effects

Dosage Form	Onset	Duration
Sublingual ISDN	Within 15–30 min	1.5–4 h
Chewable ISDN	5 min	2–3 h
Oral ISDN	Within 20–60 min	4–6 h
Oral ISMN	10–30 min314	At least 6 h314
Extended-release ISDN	Within 2 h313	Up to 12 h313
Extended-release ISMN	20–30 min314	At least 6 h314

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

Food

Isosorbide dinitrate: Food may decrease substantially mean peak plasma concentrations, yet total bioavailability does not seem to be affected.299 311 The effect of food on the bioavailability of isosorbide dinitrate when administered in fixed combination with hydralazine hydrochloride is not known.336

Isosorbide mononitrate: Generally, food delays the rate but not the extent of absorption (less than 10%) of conventional or extended-release tablets.292 295 298 299 300 301

Plasma Concentrations

Isosorbide dinitrate – sublingual, peak: 10–15 minutes.200 302

Isosorbide dinitrate – conventional tablets, peak: 60 minutes.200 302

Isosorbide dinitrate – fixed-combination tablets with hydralazine hydrochloride, peak: 60 minutes.336

Isosorbide mononitrate – conventional tablets, peak: 0.5–1 hour.292

Isosorbide mononitrate – extended-release tablets, peak: 3–4.5 hours.292

Special Populations

Risk of elevated blood concentrations of isosorbide dinitrate in patients with cirrhosis.336

Distribution

Extent

Distribution into human body tissues and fluids has not been fully characterized.294 302 303 304

Not known whether isosorbide dinitrate and isosorbide mononitrate are distributed into milk.200 224 290 291 292 302

Plasma Protein Binding

Isosorbide dinitrate: Approximately 28%.290 291 292 303

Isosorbide mononitrate: Approximately 4–5%.290 291 292 303

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; 200 224 290 291 292 302 both metabolites are pharmacologically active, especially isosorbide mononitrate.200 224 290 291 292 302

Isosorbide dinitrate: Also probably metabolized at extrahepatic sites.200 224 302

Isosorbide mononitrate: Metabolized principally in the liver, but unlike isosorbide dinitrate, does not undergo first-pass metabolism;290 291 292 metabolites appear to be pharmacologically inactive.291 292

Elimination Route

Isosorbide dinitrate and isosorbide mononitrate are mainly excreted in the urine.b 291

Half-life

Isosorbide dinitrate: About 1 hour.200 224 225 302

Isosorbide dinitrate in fixed combination with hydralazine hydrochloride: About 2 hours.336

Isosorbide mononitrate: About 5 hours.290 291 292

Storage

Oral (Isosorbide Dinitrate)

Tablets

Tight, light-resistant containers at room temperature (25°C); do not expose to extremes in temperature.b 302

Oral (Isosorbide Mononitrate)

Tablets (Extended-release and Conventional)

Conventional tablets (e.g., Monoket): Tight, light-resistant containers at 15–30°C.290 292 293

Oral (Isosorbide Dinitrate in Fixed Combination with Hydralazine Hydrochloride)

Tablets

Tight, light-resistant containers at 25°C; may be exposed to 15–30°C.336

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

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

• 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.c

• 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.c

• By decreasing myocardial oxygen consumption, nitrates and nitrites alter the imbalance of myocardial oxygen supply and consumption which is thought to cause angina pectoris.236 250

• Because of their hemodynamic profile, particularly beneficial in patients with left ventricular systolic dysfunction or heart failure.236 250

• Both direct vasodilatory effects on the coronary bed and drug-induced prevention of episodic coronary artery vasoconstriction increase total coronary blood flow.236

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

• 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.c