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  • CLASSES

    Nitrites and Nitrates, Plain

    DEA CLASS

    Rx

    DESCRIPTION

    Moderate- to long-acting oral organic nitrate; used for relief and prophylaxis of angina pectoris; also used as an adjunctive agent for CHF (off-label use); in combination with hydralazine, it improves mortality in patients with CHF, but to a lesser degree than observed with the first-line ACE inhibitor therapy for CHF.

    COMMON BRAND NAMES

    Dilatrate SR, Isochron, IsoDitrate, Isordil Titradose, Sorbitrate, Wesorbide

    HOW SUPPLIED

    Isochron/IsoDitrate/Isosorbide Dinitrate Oral Tab ER: 40mg
    Isordil Titradose/Isosorbide Dinitrate/Sorbitrate/Wesorbide Oral Tab: 5mg, 10mg, 20mg, 30mg, 40mg

    DOSAGE & INDICATIONS

    For the prevention or treatment of angina pectoris due to coronary artery disease.
    For long-term prevention of angina pectoris.
    Oral dosage (immediate-release capsules or tablets)
    Adults

    The manufacturer recommends an initial dosage of 5 to 20 mg PO twice daily or 3 times daily. For maintenance therapy, 10 to 40 mg, 2 or 3 times daily has been suggested. Some patients require higher doses. One review has recommended a maintenance dosage of 10 to 60 mg PO, given twice daily or 3 times daily. The optimal dosage and frequency to maximize anginal efficacy and minimize nitrate tolerance have not been established. Although isosorbide dinitrate has been administered 4 times daily, significant nitrate tolerance has been associated with this regimen. In 1 study, tolerance was prevented by administering isosorbide dinitrate 3 times daily with a nitrate-free interval of 14 hours. For immediate-release ISDN, an interdosing (nitrate-free) interval of 14 hours is recommended to prevent nitrate tolerance. The optimal nitrate-free interval will vary with the individual patient, dose, and regimen. Doses administered in clinical studies have ranged from 30 to 480 mg/day. High-dose isosorbide dinitrate at a dosage of 120 mg PO 4 times daily was administered to 24 patients with anginal attacks that did not respond to 10 mg PO 4 times daily. Twenty of the patients tolerated and responded to this dose while 14 were maintained on this dose for a mean of 62 weeks; weekly anginal attacks fell by 74% (from 6.04 to 1.6 attacks/week). Exercise performance was not improved; however, patients reported an improvement in quality of life.

    Oral dosage (sustained-release capsules or tablets)
    Adults

    Initially, 40 mg PO once daily. Dosage may be increased up to 160 mg/day PO. An interdosing interval of more than 14 hours may be necessary to avoid nitrate tolerance. The onset of action of controlled-release isosorbide dinitrate is not sufficiently rapid enough in aborting an acute anginal episode.

    For the prevention of effort-induced or stress-induced angina.
    Sublingual dosage (sublingual tablets)
    Adults

    A patient anticipating an activity that is likely to cause angina should take 2.5 to 5 mg SL about 15 minutes prior to the expected activity.

    Oral dosage (chewable tablets)

    NOTE: Chewable tablets are no longer commercially available in the United States.

    Adults

    A patient anticipating an activity that is likely to cause angina should chew one 5-mg tablet about 15 minutes prior to the expected activity.

    Geriatric

    See adult dosage. In general, the initial dose for a geriatric patient should start at the low end of the dosing range. Adjust dosage based on clinical response. Some geriatric patients may be more sensitive to hypotensive effects of nitrates.

    For the treatment of acute episodes of angina.
    Sublingual dosage (sublingual tablets)
    Adults

    SL nitroglycerin is first-line therapy. Because the onset of action of sublingual ISDN is significantly slower than that of SL nitroglycerin, use of SL ISDN to abort an episode of acute angina is only recommended in patients who fail to respond to SL nitroglycerin. If ISDN is used, a dose of 2.5 to 10 mg SL given as needed or every 2 to 3 hours is recommended.

    Geriatric

    See adult dosage. In general, the initial dose for a geriatric patient should start at the low end of the dosing range. Adjust dosage based on clinical response. Some geriatric patients may be more sensitive to hypotensive effects of nitrates.

    Oral dosage (chewable tablets)

    NOTE: Chewable tablets are no longer commercially available in the United States.

    Adults

    SL nitroglycerin is first-line therapy. Because the onset of action of chewable ISDN is longer than that of SL nitroglycerin, use of chewable ISDN to abort an episode of acute angina is only recommended in patients who fail to respond to SL nitroglycerin. A dose of 2.5 to 10 mg PO given as needed or every 2 to 3 hours is recommended.

    For the treatment of heart failure†.
    Oral dosage (immediate-release tablets)
    Adults

    Initially, 20 to 30 mg PO 3 to 4 times daily. Titrate dose at weekly intervals up to a target dose of 40 mg PO 3 times daily. Guidelines recommend hydralazine plus isosorbide dinitrate in combination with angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI) for black patients with reduced ejection fraction heart failure (HFrEF) NYHA class III or IV to reduce morbidity and mortality. The combination of isosorbide dinitrate and hydralazine with an ARNI has not been robustly tested; blood pressure response should be carefully monitored.

    For the treatment of diffuse esophageal spasm† without gastroesophageal reflux.
    Oral dosage
    Adults

    10 to 30 mg PO twice daily; long-acting nitrates can decrease the high-amplitude contractions seen in diffuse esophageal spasm, but may not consistently relieve associated chest pain. In general, the initial dose for a geriatric patient should start at the low end of the dosing range, since some patients may be more sensitive to hypotensive effects. Adjust dosage based on clinical response.

    For the treatment of achalasia†.
    Oral dosage (sublingual tablets)
    Adults

    5 mg SL, administered 10 to 15 minutes before meals. Reserve for patients who refuse or are not candidates for more definitive therapies (pneumatic dilation or surgical myotomy) or who fail to respond to botulinum toxin injections. According to treatment guidelines, ISDN effectively decreases lower esophageal sphincter (LES) pressure by 30% to 65%, resulting in symptomatic improvement ranging from 53% to 87%. A comparative study of SL ISDN versus SL nifedipine, demonstrated a nonsignificant advantage in the LES pressure reduction associated with ISDN treatment (65% vs. 49%, respectively). In addition, SL ISDN has a shorter time to maximum reduction in LES pressure (3 to 27 minutes) compared to SL nifedipine, but a shorter duration of effect (30 to 90 minutes).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    480 mg/day PO for immediate-release preparations; 160mg/day PO for sustained-release preparations; maximum dosage for SL route is not available.

    Elderly

    480 mg/day PO for immediate-release preparations; 160mg/day PO for sustained-release preparations; maximum dosage for SL route is not available.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; however, because isosorbide dinitrate plasma concentrations are elevated in patients with cirrhosis, cautious use of isosorbide dinitrate in this population may be prudent.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
     
    Intermittent hemodialysis
    It appears that a supplemental dose after intermittent hemodialysis is not needed.

    ADMINISTRATION

    NOTE: When using isosorbide dinitrate chronically, an interdosing ('nitrate-free') interval sufficient to avoid nitrate tolerance is required. For immediate-release products, an interdosing interval of 14 hours has been used successfully to prevent nitrate tolerance. Suggested dosage times include 0700 and 1200 or 0700, 1200, and 1700. An interdosing interval sufficient to avoid tolerance with sustained-release products has not been demonstrated. In an eccentric dosing schedule (i.e., 0800 & 1400), extended-release isosorbide dinitrate was no more effective than placebo after four weeks of therapy. Thus, the necessary interdosing interval sufficient to avoid tolerance when using extended-release products is unknown, but it may be greater than 18 hours. Large controlled trials suggest that no dosing regimen of isosorbide dinitrate (immediate- or extended-release) should be expected to provide more than about 12 hours of continuous anti-anginal efficacy per day.
     

    Oral Administration

    Isosorbide dinitrate is administered sublingually, intrabuccally, or PO.
    Sublingual (intrabuccal) tablets: Do not crush or chew. Administer while patient is sitting.
    Chewable tablets: Chew thoroughly before swallowing; do not crush chewable tablets before administering. Administer while patient is sitting. NOTE: Chewable tablets are no longer available in the US.
    Extended-release tablets or capsules: Administer intact; should not be chewed. If headache occurs and cannot be effectively controlled, oral doses may be given with meals.

    STORAGE

    Generic:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Dilatrate SR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Isochron:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    IsoDitrate :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Isordil Titradose:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Sorbitrate:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Wesorbide :
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Isosorbide dinitrate is contraindicated for use by patients with a hypersensitivity to isosorbide dinitrate or any its ingredients.

    Hypotension, hypovolemia, orthostatic hypotension, syncope

    Use isosorbide dinitrate with caution in patients with preexisting hypotension, particularly orthostatic hypotension, or in patients with hypovolemia (or dehydration), because the drug can worsen hypotension, cause tachycardia, and/or exacerbate angina. Severe orthostatic reactions have occurred with nitrates that have caused syncope or rarely resulted in fatalities.

    Geriatric

    Clinical experience has not identified differences in responses to isosorbide dinitrate between geriatric and younger adult patients. Severe hypotension, particularly with upright posture, may occur with even small doses of isosorbide dinitrate in any group. When dosing isosorbide dinitrate in the elderly, it may be prudent to start the dose at the low end of the dosing range and monitor the patients closely for hypotensive effects. Subsequent dosage adjustments should be made based on clinical response. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). The OBRA guidelines caution that nitrates may cause headaches, dizziness, lightheadedness, faintness, or symptomatic orthostatic hypotension, particularly when initially started or when taken with antihypertensives.

    Cardiomyopathy, myocardial infarction

    Nitrates may also aggravate angina in patients with hypertrophic cardiomyopathy. Patients who are receiving isosorbide dinitrate therapy should be advised to report to the hospital emergency room if anginal pain does not subside after three sublingual doses. Such resistance may indicate the development of severe ischemia such as an acute myocardial infarction. Isosorbide dinitrate should be used cautiously in patients with recent myocardial infarction because drug-induced hypotension and/or tachycardia can worsen ischemia, and the effects of long-acting nitrates are difficult to terminate quickly.

    Head trauma, increased intracranial pressure, intracranial bleeding

    Isosorbide dinitrate should not be used in patients with increased intracranial pressure (e.g., recent head trauma or intracranial bleeding) because it's vasodilatory effects on the meningeal blood vessels can exacerbate these conditions.

    Nitrate hypersensitivity

    Isosorbide dinitrate is absolutely contraindicated in patients who have known nitrate hypersensitivity.

    Closed-angle glaucoma

    Isosorbide dinitrate is contraindicated in patients with closed-angle glaucoma due to the risk of drug-induced increased intraocular pressure.

    Anemia

    Isosorbide dinitrate is contraindicated in patients with severe anemia because the drug causes oxidation of hemoglobin to methemoglobin, which could exacerbate this condition.

    Hepatic disease

    Because isosorbide dinitrate plasma concentrations increase in patients with cirrhosis, isosorbide dinitrate should be used cautiously in patients with hepatic disease as metabolism of the drug can be impaired; accumulation of isosorbide dinitrate can result in an increased risk of methemoglobinemia.

    GI disease

    Extended-release isosorbide dinitrate products should be avoided in patients with GI disease such as hypermotility or malabsorption syndromes. This dosage form may not dissolve and may be excreted intact in these conditions.

    Abrupt discontinuation

    When isosorbide dinitrate is to be discontinued following long-term or high-dose administration, avoid abrupt discontinuation to avoid potential for rebound angina.

    Pregnancy

    Isosorbide dinitrate (ISDN) is classified as FDA pregnancy risk category C. Animal studies have shown no hazard at doses approximating usual human dosage. At oral doses 35 and 150 times the daily Maximum Recommended Human Dose (MRHD), isosorbide dinitrate has been shown to cause a dose related increase in embryotoxicity (increase in mummified pups) in rabbits. Human data are limited. Limited case reports exist of the successful use of nitrates for cardiac ischemia during pregnancy when necessary; these reports do not indicate the possibility of adverse effects resulting from the use of nitrates during pregnancy. Safety in pregnancy however, has not been established. For chronic anti-anginal therapy, other drugs (e.g., cardioselective beta-blockers) may also be considered. In making the decision to administer ISDN during pregnancy, the potential risks to the fetus must be weighed against the potential benefits to the mother.

    Breast-feeding

    It is not known whether isosorbide dinitrate or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isosorbide dinitrate is administered to a woman who is breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children

    The safety and effectiveness of isosorbide dinitrate in children have not been established.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / Incidence not known
    cyanosis / Early / Incidence not known
    methemoglobinemia / Early / Incidence not known

    Moderate

    hypotension / Rapid / 5.0-10.0
    orthostatic hypotension / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    tolerance / Delayed / Incidence not known

    Mild

    headache / Early / 3.0-40.0
    dizziness / Early / 1.0-30.1
    nausea / Early / 2.0-4.0
    vomiting / Early / 0-1.0
    xerostomia / Early / 0-1.0
    syncope / Early / Incidence not known
    flushing / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetaminophen; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Acetazolamide: (Moderate) Nitrates can cause hypotension. This action may be additive with other agents that can cause hypotension such as diuretics.
    Acrivastine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Alfuzosin: (Moderate) The manufacturer of alfuzosin warns that concurrent use with nitrates has the potential to cause hypotension, orthostatic hypotension, or syncope. Caution is advisable when coadministering alfuzosin and a nitrate to patients with symptomatic hypotension or those who have had a previous hypotensive response to either agent.
    Alpha-blockers: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Amphetamine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Amphetamine; Dextroamphetamine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Angiotensin II receptor antagonists: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Angiotensin-converting enzyme inhibitors: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Apomorphine: (Major) Coadministration of apomorphine and nitrates can cause large decreases in blood pressure. The effect is especially of concern with use of sublingual nitroglycerin products. Instruct patients to lie down before taking a sublingual nitroglycerin dose and to remain supine for at least 45 minutes after to reduce orthostatic risk. In one evaluation, the largest mean decreases in standing systolic and diastolic blood pressure during use of apomorphine and sublingual nitroglycerin were 14.3 mmHg and 13.5 mmHg, respectively. The largest recorded decreases in standing systolic and diastolic blood pressures were 65 mmHg and 43 mmHg during use of apomorphine and sublingual nitroglycerin together.
    Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Benzalkonium Chloride; Benzocaine: (Moderate) Rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine products. Nitrates may also induce methemoglobin formation that will be additive to that formed by benzocaine products. Therefore, caution is warranted when combining nitrate medications with topical or oromucosal benzocaine products. Patients using OTC benzocaine gels and liquids should be advised to seek immediate medical attention if signs or symptoms of methemoglobinemia develop. In addition, clinicians should closely monitor patients for the development of methemoglobinemia when benzocaine sprays are used during a procedure.
    Benzocaine: (Moderate) Rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine products. Nitrates may also induce methemoglobin formation that will be additive to that formed by benzocaine products. Therefore, caution is warranted when combining nitrate medications with topical or oromucosal benzocaine products. Patients using OTC benzocaine gels and liquids should be advised to seek immediate medical attention if signs or symptoms of methemoglobinemia develop. In addition, clinicians should closely monitor patients for the development of methemoglobinemia when benzocaine sprays are used during a procedure.
    Benzocaine; Butamben; Tetracaine: (Moderate) Rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine products. Nitrates may also induce methemoglobin formation that will be additive to that formed by benzocaine products. Therefore, caution is warranted when combining nitrate medications with topical or oromucosal benzocaine products. Patients using OTC benzocaine gels and liquids should be advised to seek immediate medical attention if signs or symptoms of methemoglobinemia develop. In addition, clinicians should closely monitor patients for the development of methemoglobinemia when benzocaine sprays are used during a procedure.
    Benzphetamine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Beta-adrenergic blockers: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Bosentan: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Brompheniramine; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Brompheniramine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Epinephrine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Meloxicam: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Cabergoline: (Moderate) Cabergoline should be used cautiously with drugs that can lower blood pressure, including systemic nitrates. Cabergoline has been associated with hypotension. Initial doses of cabergoline higher than 1 mg may produce orthostatic hypotension. It may be advisable to monitor blood pressure.
    Calcium-channel blockers: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbetapentane; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbetapentane; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbinoxamine; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbinoxamine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Carbonic anhydrase inhibitors: (Moderate) Nitrates can cause hypotension. This action may be additive with other agents that can cause hypotension such as diuretics.
    Central-acting adrenergic agents: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Cetirizine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlorpheniramine; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Codeine; Phenylephrine; Promethazine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dapsone: (Moderate) Coadministration of dapsone with nitrates may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
    Desloratadine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dexmethylphenidate: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dextroamphetamine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Diazoxide: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Diethylpropion: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dihydroergotamine: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dobutamine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Dopamine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Doxapram: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Ephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Ephedrine; Guaifenesin: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Epinephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Eplerenone: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Epoprostenol: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Ergoloid Mesylates: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Ergonovine: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Ergot alkaloids: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Ergotamine: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Ergotamine; Caffeine: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Fenoldopam: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Fexofenadine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Gallium Ga 68 Dotatate: (Moderate) Nitrates can cause hypotension. This action may be additive with other agents that can cause hypotension such as diuretics.
    Glimepiride; Rosiglitazone: (Major) The concomitant use of nitrates with rosiglitazone is not recommended. An increased risk of myocardial ischemia was observed in a subset of patients receiving nitrates with rosiglitazone. Most patients that were using nitrates had preexisting coronary artery disease. In patients with coronary artery disease that were not on nitrates, rosiglitazone therapy did not increase the risk of myocardial ischemia.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Halothane: (Moderate) General anesthetics can potentiate the hypotensive effects of other antihypertensive agents and nitrates.
    Hydralazine: (Moderate) Concomitant use of nitrates with antihypertensives can cause additive hypotensive effects. Dosage adjustments may be necessary. A study of 28 patients with heart failure indicated that concomitant administration of oral hydralazine prevented the development of tolerance to continuous nitroglycerin infusions.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of nitrates with antihypertensives can cause additive hypotensive effects. Dosage adjustments may be necessary. A study of 28 patients with heart failure indicated that concomitant administration of oral hydralazine prevented the development of tolerance to continuous nitroglycerin infusions.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with antihypertensives can cause additive hypotensive effects. Dosage adjustments may be necessary. A study of 28 patients with heart failure indicated that concomitant administration of oral hydralazine prevented the development of tolerance to continuous nitroglycerin infusions.
    Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Ibuprofen; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Iloprost: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Isoproterenol: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lidocaine; Epinephrine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lisdexamfetamine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Loop diuretics: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Loratadine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Mannitol: (Moderate) Nitrates can cause hypotension. This action may be additive with other agents that can cause hypotension such as diuretics.
    Mecamylamine: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Mepenzolate: (Moderate) Additive anticholinergic effects may be seen when mepenzolate is used concomitantly with nitrates. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mepivacaine; Levonordefrin: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Metformin; Rosiglitazone: (Major) The concomitant use of nitrates with rosiglitazone is not recommended. An increased risk of myocardial ischemia was observed in a subset of patients receiving nitrates with rosiglitazone. Most patients that were using nitrates had preexisting coronary artery disease. In patients with coronary artery disease that were not on nitrates, rosiglitazone therapy did not increase the risk of myocardial ischemia.
    Methamphetamine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Methazolamide: (Moderate) Nitrates can cause hypotension. This action may be additive with other agents that can cause hypotension such as diuretics.
    Methylergonovine: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Methylphenidate: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Methysergide: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Midodrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Minoxidil: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Naproxen; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with other vasodilators or hypotensive drugs, such as nitrates.
    Nitroprusside: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Norepinephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension and enhance the orthostatic effects of nitrates. Orthostatic vital signs should be monitored in patients receiving paliperidone and nitrates who are susceptible to hypotension.
    Pemoline: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Pergolide: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Phendimetrazine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Phentermine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Phentermine; Topiramate: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Phosphodiesterase inhibitors: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Potassium-sparing diuretics: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Promethazine; Phenylephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Pseudoephedrine; Triprolidine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Racepinephrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Reserpine: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Riociguat: (Contraindicated) Coadministration of riociguat and nitrates or nitric oxide donors (e.g., amyl nitrite) is contraindicated due to the risk of hypotension. The blood pressure lowering effect of sublingual nitroglycerin was potentiated when administered 4 and 8 hours after riociguat. Syncope was reported in some patients.
    Ritodrine: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Rosiglitazone: (Major) The concomitant use of nitrates with rosiglitazone is not recommended. An increased risk of myocardial ischemia was observed in a subset of patients receiving nitrates with rosiglitazone. Most patients that were using nitrates had preexisting coronary artery disease. In patients with coronary artery disease that were not on nitrates, rosiglitazone therapy did not increase the risk of myocardial ischemia.
    Serdexmethylphenidate; Dexmethylphenidate: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by concurrent nitrates. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of procedure results.
    Sympathomimetics: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents or rapid-onset vasodilators, such as nitrates.
    Thiazide diuretics: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Treprostinil: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    Isosorbide dinitrate (ISDN) is classified as FDA pregnancy risk category C. Animal studies have shown no hazard at doses approximating usual human dosage. At oral doses 35 and 150 times the daily Maximum Recommended Human Dose (MRHD), isosorbide dinitrate has been shown to cause a dose related increase in embryotoxicity (increase in mummified pups) in rabbits. Human data are limited. Limited case reports exist of the successful use of nitrates for cardiac ischemia during pregnancy when necessary; these reports do not indicate the possibility of adverse effects resulting from the use of nitrates during pregnancy. Safety in pregnancy however, has not been established. For chronic anti-anginal therapy, other drugs (e.g., cardioselective beta-blockers) may also be considered. In making the decision to administer ISDN during pregnancy, the potential risks to the fetus must be weighed against the potential benefits to the mother.

    It is not known whether isosorbide dinitrate or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isosorbide dinitrate is administered to a woman who is breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Similar to other nitrites and organic nitrates, isosorbide dinitrate is converted in vitro to the active intermediate compound nitric oxide (NO), a reactive free radical. Nitric oxide is also formed endogenously and is believed to be endothelial-derived growth factor. Among other properties, NO is believed to produce vasodilation. Nitric oxide activates the enzyme guanylate cyclase, thereby stimulating the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP). This second messenger then activates a series of protein kinase-dependent phosphorylations in the smooth muscle cells, eventually resulting in the dephosphorylation of the myosin light chain of the smooth muscle fiber and the subsequent release, or extrusion, of calcium ions. The contractile state of smooth muscle is normally maintained by a phosphorylated myosin light chain (stimulated by an increase in calcium ions). Thus, the nitrite- or nitrate-induced dephosphorylation of the myosin light chain signals the cell to release calcium, thereby relaxing the smooth muscle cells and producing vasodilation.
     
    It is believed that nitrates correct myocardial oxygen imbalances by reducing systemic and pulmonary arterial pressure (afterload) and decreasing cardiac output secondary to peripheral dilation rather than coronary artery dilation. Nitrates therefore relax peripheral venous vessels, causing a pooling of venous blood and decreased venous return to the heart, which decreases preload. Nitrates reduce both arterial impedance and venous filling pressures, resulting in a reduction of the left ventricular systolic wall tension, thereby decreasing afterload. Thus, nitrate-induced vasodilation increases venous capacitance and decreases arteriole resistance, thereby reducing both the preload and afterload and lowering the cardiac oxygen demand.
     
    Total coronary blood flow may be increased by nitrites and nitrates in patients with normal hearts, but in patients with ischemia the drug does not increase total coronary blood flow but simply redistributes blood to ischemic areas. This effect is believed to be due to the drug's preferential dilation of the larger conductive vessels of the coronary circulation, which, in the presence of coronary atherosclerosis, redirects the distribution of the coronary blood supply to ischemic areas.
     
    Nitrates cause a transient reflex compensatory increase in heart rate and myocardial contractility that would normally increase myocardial oxygen consumption, yet the nitrate-induced decrease in ventricular wall tension results in a net decrease in myocardial oxygen demand and amelioration of the pain of angina pectoris. In addition, isosorbide relaxes all other types of smooth muscle including bronchial, biliary, GI, ureteral, and uterine. Nitrites and nitrates are functional antagonists of acetylcholine, norepinephrine, and histamine.
     
    In individuals who have little compensatory tachycardia response, syncope can result from the decrease in blood pressure that occurs following higher doses of nitrites and nitrates. Although this is not likely to occur with doses of nitrates that do not cause blood pressure reduction, patients should be sitting or lying down during and immediately after administration of isosorbide dinitrate.
     
    Continuous administration of nitrates can lead to the rapid development of tolerance. The mechanisms responsible for nitrate tolerance are not fully understood; however, proposed mechanisms include neurohormonal counterregulatory mechanisms including activation of reflex vasoconstriction, intravascular volume expansion, desensitization of guanylate cyclase, depletion of sulfhydryl groups in vascular smooth muscle, a decrease in nitroglycerin biotransformation, or nitrate-mediated vascular superoxide production. Nitrate tolerance is thought to occur as a result of several of these mechanisms. Using a dosing schedule with a nitrate-free interval is the most reliable and successful strategy in preventing nitrate tolerance during chronic administration.

    PHARMACOKINETICS

    Isosorbide dinitrate (ISDN) is administered orally. It is about 28% protein bound and the volume of distribution is 2—4 L/kg. Isosorbide distributes throughout the body tissues and is metabolized by denitration to isosorbide-2-mononitrate (15—25%) or isosorbide-5-mononitrate (75—85%), both of which are pharmacologically active and contribute to the efficacy of isosorbide dinitrate, especially isosorbide-5-mononitrate. ISDN is virtually completely metabolized, with minute portions of the parent drug and metabolites excreted renally. The half-life of the parent drug, isosorbide-5-mononitrate, and isosorbide-2-mononitrate in plasma is 1 hour, 5 hours, and 2 hours, respectively.

    Oral Route

    Orally administered isosorbide dinitrate is absorbed rapidly from the GI tract and undergoes extensive first-pass metabolism resulting in a variable bioavailability of roughly 25% (ranging from 10—90%); most studies have observed increases in bioavailability during chronic therapy. Sublingual administration bypasses the first-pass effect, resulting in a bioavailability of 45—59%. The bioavailability of sustained-release preparations of ISDN approach 75%. The sublingual and chewable preparations of the drug exert their effect within 5—20 minutes, while the onset of action of conventional oral forms of isosorbide begins in 7.5—45 minutes following administration. Extended-release capsules or tablets have an onset of action of 60—90 minutes. The duration of effect of the sublingual and chewable forms of the drug is 45 minutes to 2 hours, while that of the conventional oral forms is 2—6 hours. The duration of effect of the sustained-release oral preparations is 10—14 hours.