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Nitrates (Systemic)

This monograph includes information on the following:

1) Isosorbide Dinitrate
2) Isosorbide Mononitrate
3) Nitroglycerin

VA CLASSIFICATION
Isosorbide dinitrate
Primary: CV250
Secondary: CV900

Isosorbide mononitrate
Primary: CV250

Nitroglycerin
Primary: CV250
Secondary: CV402; CV900


Commonly used brand name(s): Apo-ISDN1; Cedocard-SR1; Coradur1; Coronex1; Deponit3; Dilatrate-SR1; IMDUR2; ISDN1; ISMO2; Isordil1; Isordil Tembids1; Isordil Titradose1; Minitran3; Monoket2; Nitro-Bid3; Nitro-Bid IV3; Nitro-Dur3; Nitro-par3; Nitro-time3; Nitrocot3; Nitrodisc3; Nitrogard3; Nitroglyn E-R3; Nitroject3; Nitrol3; Nitrolingual3; Nitrong SR3; Nitrostat3; Sorbitrate1; Transderm-Nitro3; Tridil3.

Another commonly used name is:
Glyceryl trinitrate —Nitroglycerin
.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:

Note: All of the nitrates have similar pharmacologic actions; however, clinical uses among specific agents may vary because of actual pharmacokinetic differences, availability of specific testing, and/or availability of clinical-use data.



Antianginal—Isosorbide Dinitrate; Isosorbide Mononitrate; Nitroglycerin;

Antihypertensive—Nitroglycerin Injection;

Vasodilator, congestive heart failure—Isosorbide Dinitrate; Nitroglycerin;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Table 1. Indications




 
Legend:
I=Angina pectoris, acute
(treatment)
II=Angina pectoris, acute
(prophylaxis)
III=Angina pectoris, chronic
(treatment)


IV=Hypertension (treatment); or Hypotension, controlled
V=Myocardial infarction (treatment adjunct)
VI=Congestive heart failure (treatment)

  I
 
II
 
III
 
IV
 
V
 
VI
 
Isosorbide dinitrate:
           
Oral
Tablets, regular
   
  [] 1
[] 1
Extended-release capsules or tablets
   
     
Chewable tablets



  []
[]
Sublingual
1


  [] 1
[] 1
Isosorbide mononitrate:
           
Oral
Tablets, regular
   
     
Nitroglycerin :
           
Buccal, extended-release
1


     
Lingual, aerosol

1
    [] 1
[] 1
Oral, extended-release
   
     
Parenteral
   



Sublingual


    [] 1
[] 1
Topical
Ointment
   

 
[] 1

[] 1
Transdermal systems
   
  []
[]
1 Not commercially available in Canada.Not included in Canadian product labeling

Accepted

Angina pectoris, acute (treatment)—The sublingual, lingual, and extended-release buccal1 dosage forms of nitroglycerin and the sublingual1 and chewable dosage forms of isosorbide dinitrate are indicated for the relief of pain of an acute episode of angina pectoris due to coronary artery disease. Sublingual or lingual nitroglycerin is preferred; isosorbide dinitrate should be used in patients intolerant of or unresponsive to nitroglycerin. Sublingual isosorbide dinitrate1 or sublingual or lingual nitroglycerin may be administered to relieve acute anginal attacks that may occur while the patient is on oral prophylactic therapy.

Angina pectoris, acute (prophylaxis)—The sublingual, lingual1 , and extended-release buccal dosage forms of nitroglycerin and the sublingual or chewable dosage forms of isosorbide dinitrate are indicated for prophylaxis of acute angina attacks in situations (such as stress or exertion) likely to provoke such attacks.

Angina pectoris, chronic (treatment)—The regular, chewable, sublingual, and extended-release oral dosage forms of isosorbide dinitrate; the regular and extended-release oral dosage forms of isosorbide mononitrate; and the extended-release oral and buccal dosage forms of nitroglycerin are indicated for the prophylaxis and long-term treatment of angina pectoris due to coronary artery disease, but not in the treatment of acute anginal attacks (except for chewable isosorbide dinitrate and buccal nitroglycerin). Rapid first-pass hepatic destruction of nitroglycerin may increase the dosage requirements {09} of the oral extended-release capsules and tablets in the prophylaxis and treatment of angina.
—Nitroglycerin injection is indicated in the treatment of unstable angina pectoris in patients who have not responded to recommended doses of other organic nitrates and/or a beta-blocker.
—Nitroglycerin ointment and nitroglycerin transdermal systems are indicated for the prophylaxis and long-term treatment of angina pectoris but are not indicated for the relief of an acute angina episode.

Hypertension (treatment) or
Hypotension, controlled—Nitroglycerin injection is indicated for blood pressure control during certain surgical procedures and for controlled hypotension during surgery to reduce bleeding into the surgical field.

Myocardial infarction (treatment adjunct) or
Congestive heart failure (treatment)—Nitroglycerin injection is indicated in the adjunctive therapy for congestive heart failure associated or not associated with acute myocardial infarction. (Treatment of congestive heart failure not associated with acute myocardial infarction is not included in Canadian product labeling.) [ Sublingual]1 , [ lingual]1 , and [ topical]1 nitroglycerin and; [ regular oral]1 , [chewable] , and [sublingual]1 isosorbide dinitrate are also being used for treatment of congestive heart failure, whether or not it is associated with acute myocardial infarction. In general, the oral extended-release dosage forms are not recommended because the effects are difficult to terminate if excessive hypotension or tachycardia develops, although these dosage forms may be acceptable once the patient is stabilized {09}.

[Anal fissures, chronic (treatment) ]1—Topical nitroglycerin is indicated for the treatment of chronic anal fissures.{57}{58}{59}{60}{61}{62}{63}{64}{65}{66}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Isosorbide dinitrate: 236.14
    Isosorbide mononitrate: 191.14 {51}
    Nitroglycerin: 227.09

Mechanism of action/Effect:

Antianginal or cardiac load–reducing agent—Not specifically known but thought to cause a reduction of myocardial oxygen demand. This is attributed to a reduction in left ventricular preload and afterload because of venous (predominantly) and arterial dilation with a more efficient redistribution of blood flow within the myocardium.

Antihypertensive—Peripheral vasodilation.

Absorption:

Isosorbide dinitrate—Bioavailability is 59% after sublingual administration and 22% after oral administration {15} {16} {17} {18} {19}.

Isosorbide mononitrate—Nearly 100%. {50} {33}

Protein binding:

Nitroglycerin—Moderate (60%) {24}.

Isosorbide mononitrate—Very low (< 4%). {50} {33}

Biotransformation:

Hepatic (very rapid and nearly complete) and in blood (enzymatically). Oral dosage forms undergo extensive first-pass metabolism.

Half-life:


Isosorbide dinitrate:

Sublingual: 60 minutes {15} {16} {17} {18} {19}.

Oral: 4 hours {15} {16} {17} {18} {19}.



Isosorbide mononitrate:

5 hours. {50} {33}



Nitroglycerin:

1 to 4 minutes.


Onset of action:

Note: Although information is limited {04}, pharmacokinetics of sublingual tablets administered buccally are probably similar to those after sublingual administration.



Isosorbide dinitrate:

Oral tablets: 15 to 40 minutes.

Chewable tablets: 2 to 5 minutes.

Extended-release capsules and tablets: 30 minutes.

Sublingual tablets: 2 to 5 minutes.



Isosorbide mononitrate:

Oral tablets: 1 hour. {50}



Nitroglycerin:

Buccal tablets: 3 minutes.

Lingual aerosol: 2 to 4 minutes.

Intravenous infusion: Immediate.

Sublingual tablets: 1 to 3 minutes.

Ointment: Within 30 minutes.

Transdermal systems: Within 30 minutes.


Duration of action:

Note: Although information is limited {04}, pharmacokinetics of sublingual tablets administered buccally are probably similar to those after sublingual administration.



Isosorbide dinitrate:

Oral tablets: 4 to 6 hours.

Chewable tablets: 1 to 2 hours.

Extended-release capsules and tablets: 12 hours.

Sublingual tablets: 1 to 2 hours.



Nitroglycerin:

Buccal extended-release tablets: Approximately 5 hours.

Extended-release capsules and tablets: 8 to 12 hours.

Intravenous infusion: Several minutes (dose-dependent).

Sublingual tablets: 30 to 60 minutes.

Ointment: 4 to 8 hours.

Transdermal systems: 8 to 24 {03} hours.


Elimination:
    Renal (after nearly total metabolism).


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one nitrate may be sensitive to other nitrates also, although the reaction is rare.

Patients sensitive to nitrites may be sensitive to nitrates also, although the reaction is rare.

Carcinogenicity

Studies with isosorbide dinitrate or nitroglycerin have not been done {15} {16} {17} {18} {19} {22}. Studies in mice given oral isosorbide mononitrate at doses of up to 900 mg per kg of body weight (mg/kg) per day (102 times the human exposure comparing body surface area) did not reveal evidence of carcinogenicity. {50}

Pregnancy/Reproduction
Fertility—
Isosorbide dinitrate: Studies in rats given isosorbide dinitrate at doses of 25 or 100 mg/kg per day found no impairment of fertility {15} {16} {17} {18} {19}.

Isosorbide mononitrate: No adverse effect on fertility was observed in male and female rats given isosorbide mononitrate at doses of up to 500 mg/kg per day (125 times the human exposure comparing body surface area). {50}

Pregnancy—
Adequate and well-controlled studies in humans have not been done.

Studies in rabbits given isosorbide dinitrate in oral doses of 35 and 150 times the maximum daily recommended human dose have shown a dose-related increase in embryotoxicity. Administration of isosorbide mononitrate to rats at doses of 500 mg/kg per day (125 times the human exposure comparing body surface area) was associated with increased rates of prolonged gestation, prolonged parturition, stillbirths and neonatal death, and decreases in birth weight, live litter size, and pup survival. {50} No evidence of developmental abnormalities, fetal abnormalities, or other effects on reproductive performance was observed in rats and rabbits given isosorbide mononitrate at doses of 250 mg/kg per day. {50}

FDA Pregnancy Category C.

Breast-feeding

It is not known whether nitrates are distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of nitrates have not been performed in the pediatric population.


Geriatrics


Appropriate studies on the relationship of age to the effects of nitrates have not been performed in the geriatric population. However, elderly patients may be more sensitive to the hypotensive effects of nitrates. In addition, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving nitrates.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetylcholine or
Histamine or
Norepinephrine (levarterenol)    (effects of these medications may be decreased when they are used concurrently with nitrates)


» Alcohol, moderate or excessive amounts or
» Antihypertensives or
Hypotension-producing medications, other (see Appendix II ) or
Opioid (narcotic) analgesics or
» Vasodilators, other    (concurrent use may intensify the orthostatic hypotensive effects of nitrates; dosage adjustments may be necessary)


Heparin    (the anticoagulant effect of heparin may be decreased in patients receiving nitroglycerin via intravenous infusion; adjustment of heparin dosage may be required to maintain the desired degree of anticoagulation during and following administration of a nitroglycerin infusion {16})


» Sildenafil{55}    (sildenafil can potentiate the hypotensive effects of nitrates and its use in patients who are concurrently using nitrates in any form is contraindicated {55}; deaths have been reported with concurrent use)


Sympathomimetics    (concurrent use may reduce the antianginal effects of nitrates)

    (nitrates may counteract the pressor effect of sympathomimetics, possibly resulting in hypotension)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Serum cholesterol determinations by the Zlatkis-Zak color reaction method    (may be falsely decreased)

With physiology/laboratory test values
Methemoglobin concentrations in blood    (may be increased by excessive doses of nitrates)


Urine catecholamine concentrations (epinephrine and norepinephrine) and
Urine vanillylmandelic acid (VMA) concentrations    (may be markedly increased by nitroglycerin)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:

For nitroglycerin injection only:
» Cerebral hemorrhage or
» Head trauma, recent    (nitroglycerin may increase cerebrospinal fluid pressure)


» Pericardial tamponade{24}
» Pericarditis, constrictive
Risk-benefit should be considered when the following medical problems exist

For all nitrates:
» Anemia, severe
» Cerebral hemorrhage or
» Head trauma, recent    (nitrates may increase cerebrospinal fluid pressure)


» Glaucoma    (nitrates may increase intraocular pressure)


Hepatic function impairment, severe    (increased risk of methemoglobinemia)


» Hyperthyroidism
Hypertrophic cardiomyopathy    (angina may be aggravated)


Hypotension, with low systolic pressure    (may be aggravated, accompanied by paradoxical bradycardia and increased angina pectoris)


» Myocardial infarction, recent    (risk of hypotension and tachycardia, which may aggravate ischemia)


Renal function impairment, severe{24}
Sensitivity to the nitrate prescribed{15}
For oral dosage forms only (in addition to the above):
Gastrointestinal hypermotility or
Malabsorption syndrome    (use of extended-release dosage forms should be avoided because they may not dissolve and may be excreted intact)


For nitroglycerin injection only (in addition to the above):
» Hypovolemia    (risk of producing severe hypotension and shock; should be corrected prior to use of nitroglycerin)


» Normal or low pulmonary capillary wedge pressure    (patients may be unusually sensitive to hypotensive effects {24})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure determinations and
Heart rate determinations{24}    (recommended at periodic intervals in patients using nitrates regularly to aid in dosage adjustment)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Blurred vision
    
dryness of mouth
    
headache, severe or prolonged
    
skin rash



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
—dose-related    
Flushing of face and neck
    
headache
    
nausea or vomiting
    
orthostatic hypotension (dizziness or lightheadedness, especially when getting up from a lying or sitting position)
    
restlessness
    
tachycardia (fast heartbeat)

Incidence less frequent
    
Sore, reddened skin —topical nitroglycerin dosage forms





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Signs and symptoms of overdose (in order of occurrence)
    
Bluish-colored lips, fingernails, or palms of hands
    
dizziness, extreme, or fainting
    
feeling of extreme pressure in head
    
shortness of breath
    
unusual tiredness or weakness
    
weak and fast heartbeat
    
fever
    
convulsions

Note: Cyanosis may occur at blood methemoglobin concentrations of 1.5 grams per 100 mL. More pronounced signs of methemoglobinemia (pressure in head, tiredness or weakness, shortness of breath) occur at concentrations of 20 to 50 grams per 100 mL. {02}



Treatment of overdose
Any remaining nitroglycerin should be removed (e.g., ointment, transdermal system). Buccal or sublingual tablets should be removed and the gum wiped clean at the site of insertion.

If excessive hypotension occurs, elevate the legs to aid venous return.

The rapid metabolism of nitroglycerin usually makes additional measures unnecessary. However, if additional correction of severe hypotension is required, administration of an intravenous alpha-adrenergic agonist such as methoxamine or phenylephrine may be considered; epinephrine should be avoided since it aggravates the shock-like reaction.

Methemoglobin concentrations in blood should be monitored and methemoglobinemia treated with high-flow oxygen and intravenous methylene blue.


Patient Consultation

Table 2. Patient Consultation



As an aid to patient consultation, refer to Advice for the Patient, Nitrates—Lingual Aerosol (Systemic) , Nitrates—Oral (Systemic) , Nitrates—Sublingual, Chewable, or Buccal (Systemic) , or Nitrates—Topical (Systemic) .

Consider advising the patient on the following:
Buccal
Lingual
Oral
Sublingual
Topical
Legend:
I=Extended-
release nitroglycerin

II=Aerosol nitroglycerin

III=Regular
IV=Chewable
V=Extended-
release
VI=Isosorbide
dinitrate
VII=Nitrogly-
cerin
VIII=Nitroglycerin ointment
IX=Transdermal nitroglycerin
I
 
II
 
III
 
IV
 
V
 
VI
 
VII
 
VIII
 
IX
 
Before using this medication
 
                 
» Conditions affecting use, especially:
Sensitivity to the nitrate prescribed









Use in the elderly—May have increased sensitivity to hypotensive effects









Other medications, especially antihypertensives, moderate or excessive amounts of alcohol, other vasodilators, or sildenafil









Other medical problems, especially cerebral hemorrhage, constrictive pericarditis, glaucoma, hyperthyroidism, hypovolemia, normal or low pulmonary capillary wedge pressure, pericardial tamponade, recent head trauma, or recent myocardial infarction









Proper use of this medication
» Compliance with therapy









» Reading patient instructions carefully
 
         

Proper administration:
                 
» Regular tablet or extended-release capsule or tablet—Taking with full glass of water on empty stomach
   
 
       
» Buccal—
                 
Placing under upper lip (above incisors) against gum or between cheek and upper gum; placing between upper lip (above incisors) and gum if food or drink to be taken within 3 to 5 hours; patients with dentures may place anywhere between cheek and gum

       

   
Touching with tongue or drinking hot liquids may increase rate of dissolution

       

   
Bedtime use not recommended because of risk of aspiration

       

   
Replacing tablet if inadvertently swallowed

       

   
Not using chewing tobacco while tablet in place

               
» Chewable tablet—Chewing well and holding in mouth for approximately 2 minutes
     
         
» Lingual aerosol—
                 
Removing plastic cover; not shaking container
 
             
Holding container vertically and spraying onto or under tongue; not inhaling spray
 
             
Closing mouth after each spray; not swallowing immediately
 
             
» Sublingual tablet—Placing under the tongue; avoiding eating, drinking, smoking, or using chewing tobacco while tablet is dissolving
         

   
» Ointment—Cleansing skin before applying; measuring; using applicator; spreading evenly over same size of skin area in each application; not rubbing into skin; applying to skin free of hair, in different areas; proper application of occlusive dressing, if ordered
             
 
Transdermal—Not trimming or cutting patch; applying to clean, dry skin free of hair, scars, cuts, or irritation (after removal of previous system); replacing systems that have loosened or fallen off; alternating application sites
               
» Not chewing, crushing, or swallowing

       

   
» Not breaking, crushing, or chewing before swallowing
       
       
For use in treating acute angina attacks
 
                 
» Sitting down and using medication at first sign of angina attack; caution if dizziness or faintness occurs


 
 

   
Remaining calm until medicine has opportunity to work


 
 

   
» Relief usually occurs within 5 minutes—


 
 

   
Dose may be repeated if pain not relieved in 5 to 10 minutes; calling physician or going to emergency room if angina pain not relieved by 3 doses in 15 minutes
 
 
 

   
Not repeating dose; using sublingual nitroglycerin and calling physician or going to emergency room if angina pain not relieved in 15 minutes

               
For use in preventing angina
 
                 
» This dosage form does not relieve angina attacks but rather prevents them (exceptions are chewable and sublingual isosorbide dinitrate)
   


   

Using 5 to 10 minutes prior to anticipated stress to prevent attack


 
 

   
Missed dose:
                 
Taking/using as soon as possible unless next scheduled dose is within:
               
—2 hours (exception is oral extended-release);

 

 


 
—6 hours (for oral extended-release);
       
       
Returning to regular dosing schedule; not doubling doses

 






» Proper storage









Protecting from freezing
 
             
Not puncturing, breaking, or burning aerosol container
 
             
Storing in cool place, tightly closed
             
 
Lack of reliability of flushing or headache as test of potency
           
   
» Keeping sublingual nitroglycerin in original glass, screw-cap bottle (unless using special nitroglycerin container) with cotton plug removed; avoiding handling tablets; capping quickly and tightly after each use; not storing in same container as other medications; not carrying close to body or in auto glove compartment; not storing in refrigerator or bathroom medicine cabinet
           
   
Precautions while using this medication
 
                 
» Not taking sildenafil while taking this medication because excessive hypotension and possibly death can occur









» Checking with physician before discontinuing medication; gradual dosage reduction may be needed









» Caution when getting up suddenly from a lying or sitting position









» Caution in using alcohol, while standing for long periods or exercising, and during hot weather because of enhanced orthostatic hypotensive effects









» Headache as a common effect; should decrease with continuing therapy; checking with physician if continuing or severe









Notifying physician if undigested extended-release tablets are found in stools (for isosorbide dinitrate only)
       
       
Side/adverse effects
Signs of potential side effects, especially blurred vision, dryness of mouth, severe or prolonged headache, and skin rash











General Dosing Information
Dosage must be adjusted to the needs and tolerance of the individual patient. Dosage requirements may be increased by a worsening of the patient's condition or a loss of medication potency.

Tolerance to the pharmacologic and therapeutic effects of nitrate medications may occur. {52} {53} {54} Nitrate tolerance manifests as a decrease in patient response to the nitrate or as a need for progressively higher doses to maintain therapeutic effect. {53} The development of nitrate tolerance may occur with any nitrate dosage form that maintains continuous medication blood levels. {53} Tolerance can be managed by adjustments in dosing strategy. Intermittent nitrate therapy appears to be effective. {52} {53} {54} An optimal nitrate-free period of at least 8 to 12 hours appears to be effective in preventing attenuation of nitrate effect. {52} {53} Careful monitoring is recommended to make sure that the desired therapeutic effect is being maintained.

Nitrate therapy should be discontinued if blurred vision or dry mouth continues or is severe {09}.

When this medication is to be discontinued following high-dose or long-term administration, dosage should be reduced gradually to prevent possible withdrawal rebound angina.

For oral dosage forms only
There have been reports of patients finding intact or partially dissolved extended-release isosorbide dinitrate tablets in the stool. Some patients may benefit by a change from the extended-release tablet to the extended-release capsule or the regular oral tablet and an increase in dosage to an effective level for each individual patient.

For buccal extended-release nitroglycerin tablets or sublingual tablets administered buccally only
The tablet should be placed between upper lip and gum (above the incisors) or between cheek and upper gum, and allowed to dissolve in place. Tablet placement sites may be alternated as patient desires.

The dissolution time of the buccal extended-release tablet may vary from 3 to 5 hours in most patients. The dissolution rate is increased when the tablet is touched with the tongue or the patient drinks hot liquids. The buccal extended-release tablet utilizes an inert polymer vehicle which enables a metered nitroglycerin release not affected by pH, food, or drink (placement is suggested behind the upper lip if food and drink are to be taken during dosing).

Use at bedtime is not recommended because of the risk of aspiration.

Sublingual isosorbide dinitrate and nitroglycerin tablets may also be administered buccally. Although information is limited, onset and duration of action are probably similar to sublingual dosing.

Diet/Nutrition
The regular oral dosage forms of this medication should preferably be taken with a glass of water on an empty stomach (either 1 hour before or 2 hours after meals) for faster absorption.

ISOSORBIDE DINITRATE


Oral Dosage Forms

ISOSORBIDE DINITRATE EXTENDED-RELEASE CAPSULES USP

Usual adult dose
Antianginal
Oral, 40 to 80 mg every eight to twelve hours.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


40 mg (Rx) [Dilatrate-SR] [Isordil Tembids][Generic]{48}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Stability:
Loss of potency is accelerated by exposure to heat and moisture.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Swallow capsules whole.
   • Store in a cool, dry place.


ISOSORBIDE DINITRATE TABLETS USP

Usual adult dose
Antianginal
Oral, 5 to 20 mg every six hours, the dosage being adjusted as needed and tolerated. The dosage range is 5 to 40 mg four times a day, with the usual dosage range being 20 to 40 {09} mg four times a day.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


2.5 mg (Rx)[Generic]


5 mg (Rx) [ISDN] [Isordil Titradose] [Sorbitrate][Generic]{48}


10 mg (Rx) [ISDN] [Isordil Titradose] [Sorbitrate][Generic]{48}


20 mg (Rx) [ISDN] [Isordil Titradose] [Sorbitrate][Generic]{48}


30 mg (Rx) [Isordil Titradose] [Sorbitrate][Generic]{48}


40 mg (Rx) [Isordil Titradose] [Sorbitrate][Generic]{48}

Canada—


10 mg (Rx) [Apo-ISDN] [Coronex] [Isordil Titradose]{56}[Generic]


30 mg (Rx) [Apo-ISDN] [Coronex] [Isordil Titradose]{56}[Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Stability:
Loss of potency is accelerated by exposure to heat and moisture.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Store in a cool, dry place.


ISOSORBIDE DINITRATE CHEWABLE TABLETS USP

Usual adult dose
Antianginal
Oral, 5 mg chewed well every two to three hours, the dosage being adjusted as needed and tolerated.


Note: Chewed tablet is to be held in mouth for one or two minutes to allow time for absorption through buccal tissues.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


5 mg (Rx) [Sorbitrate]{48}


10 mg (Rx) [Sorbitrate]{48}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Stability:
Loss of potency is accelerated by exposure to heat and moisture.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Chew well before swallowing.
   • Store in a cool, dry place.

Note: Chewable tablets up to 10 mg each are exempt from child-resistant container regulations.



ISOSORBIDE DINITRATE EXTENDED-RELEASE TABLETS USP

Usual adult dose
Antianginal
Oral, 20 to 80 mg every eight to twelve hours.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


40 mg (Rx) [Isordil Tembids][Generic]{48}

Canada—


20 mg (Rx) [Cedocard-SR] [Coradur]{56}[Generic]


40 mg (Rx) [Cedocard-SR]{56}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Stability:
Loss of potency is accelerated by exposure to heat and moisture.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Swallow tablets whole.
   • Store in a cool, dry place.



Sublingual Dosage Forms

ISOSORBIDE DINITRATE SUBLINGUAL TABLETS USP

Usual adult dose
Antianginal
Sublingual or buccal, 2.5 to 5 mg every two to three hours as needed.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


2.5 mg (Rx) [Isordil] [Sorbitrate][Generic]{48}


5 mg (Rx) [Isordil] [Sorbitrate][Generic]{48}


10 mg (Rx) [Isordil][Generic]{48}

Canada—


5 mg (Rx) [Apo-ISDN] [Coronex] [Isordil]{56}[Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Stability:
Loss of potency is accelerated by exposure to heat and moisture.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Dissolve tablets under tongue.
   • Store in a cool, dry place.

Note: Do not dispense sublingual tablets in child-resistant containers. Sublingual tablets up to 10 mg each are exempt from child-resistant container regulations.



ISOSORBIDE MONONITRATE

Summary of Differences


Pharmacology/pharmacokinetics:
Protein binding—Very low.

Half-life—5 hours.



Oral Dosage Form

ISOSORBIDE MONONITRATE TABLETS

Usual adult dose
Antianginal
Oral, 20 mg two times a day, with the two doses given seven hours apart. {33} {50}

Note: An initial dose of 5 mg may be appropriate for patients of particularly small stature; the dosage being increased to at least 10 mg by the second or third day of therapy. {33}



Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


10 mg (Rx) [Monoket (scored)]{48}


20 mg (Rx) [ISMO] [Monoket (scored)]{48}

Canada—


20 mg (Rx) [ISMO]{56}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F) in a tight container, unless otherwise specified by manufacturer.

Stability:
Loss of potency is accelerated by exposure to heat and moisture.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Store in a cool, dry place.


ISOSORBIDE MONONITRATE EXTENDED-RELEASE TABLETS

Usual adult dose
Antianginal
Oral, 30 or 60 mg once a day, the dosage being increased after several days to 120 mg once a day, as needed and tolerated. Rarely, 240 mg once a day may be needed.


Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


30 mg (Rx) [IMDUR (scored)]{48}


60 mg (Rx) [IMDUR (scored)]{48}


120 mg (Rx) [IMDUR (scored)]{48}

Canada—


60 mg (Rx) [IMDUR (scored)]{56}

Packaging and storage:
Store between 2 and 30 °C (36 and 86 °F) in a tight container.

Stability:
Loss of potency is accelerated by exposure to heat and moisture.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Store in a cool, dry place.
   • Do not crush or chew.


NITROGLYCERIN

Summary of Differences


Category:
Antihypertensive; cardiac load–reducing agent.



Indications:
Hypertension (parenteral dosage form); hypotension, controlled (parenteral dosage form); acute myocardial infarction; congestive heart failure.



Pharmacology/pharmacokinetics:
Half-life—1 to 4 minutes.



Precautions:
Medical considerations/contraindications—Contraindicated in increased intracranial pressure, constrictive pericarditis (parenteral dosage form); caution needed in hypovolemia or severe hepatic or renal function impairment (parenteral dosage form).



Additional Dosing Information
See also General Dosing Information .

For sublingual tablets only
Judging the ability of a sublingual tablet to relieve angina by the presence of a tingling or burning sensation after a tablet has been dissolved under the tongue is not completely reliable since some patients may be unable to detect these effects. Newer, stabilized sublingual nitroglycerin tablets are making such potency testing less useful, since the stabilized tablets may be less likely to produce these detectable effects.

Nitroglycerin tablets should maintain their potency through the expiration date on the bottle, provided the cap is tightly replaced after each use and proper storage instructions are adhered to.

A supplementary stainless steel container has been developed and approved for temporary storage of small quantities of nitroglycerin tablets. The pendant-type container on a chain, which can be worn around the patient's neck, is intended to provide a convenient source of nitroglycerin for emergency use.

For intravenous infusion form only
Special nitroglycerin infusion sets made of non-PVC plastic cause minimal absorption; therefore, nearly all the calculated dose will be delivered to the patient. When these sets are used, dosage instructions should be followed with care, as changing from a standard set (PVC) to a special set (non-PVC) may result in excessive nitroglycerin dosage unless allowances are made for the difference in the amount of nitroglycerin actually delivered to the patient.

For ointment dosage form only
The dose should be individualized starting with 1/2 to 1 inch of ointment as squeezed from the tube and then increasing the dose by 1/2 inch at each application until the desired clinical effect and the greatest asymptomatic decrease in resting blood pressure {04} occur. The largest dose that does not cause symptomatic hypotension {04} is used as the patient's individualized dose.

The ointment is applied with the dose-measuring application papers supplied with the medicine. The ointment is squeezed onto the measuring scale printed on the paper. The paper is then used to spread the ointment onto the skin in a thin, even layer, covering an area (at least 2 by 3 inches) of the same size at each dose without rubbing or massage.

The site of ointment application may be the non-hairy skin of the chest, stomach, front of the thighs, or any other accessible area of clean, dry skin. Application to the chest is commonly preferred since the patient also benefits psychologically from applying medication to the area where the pain is experienced.

For transdermal dosage forms only
Application should preferably be made at the same time each day (after removal of the previous system) to areas of clean, dry, hairless skin on the chest, inner side of the upper arm, or shoulders; application to extremities below the knee or elbow should be avoided. Skin areas with extensive scarring, calluses, or irritation should also be avoided. Application sites should be varied to avoid causing skin irritation.

All available transdermal systems provide therapeutic effects within 30 minutes and sustain the required plasma concentration of nitroglycerin for 8 to 24 {09} hours.

The transdermal units should not be cut or trimmed in an attempt to adjust dosage.

A new dosage unit should be applied if the first becomes loosened or falls off.

Removal of the transdermal unit before defibrillation or cardioversion is recommended because of the potential for altered electrical conductivity and enhanced risk of arcing associated with use of defibrillators.


Buccal Dosage Forms

NITROGLYCERIN EXTENDED-RELEASE BUCCAL TABLETS

Usual adult dose
Antianginal
Buccal, 1 mg dissolved in place on the oral mucosa every five hours during waking hours, the dosage being increased by frequency and/or strength as required.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


1 mg (Rx) [Nitrogard]{48}


2 mg (Rx) [Nitrogard]{48}


2.5 mg (Rx) [Nitrogard]{48}


3 mg (Rx) [Nitrogard]{48}


5 mg (Rx) [Nitrogard]{48}

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a glass container with a tight screw cap.

Stability:
Loss of potency is accelerated by exposure to heat and moisture.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Dissolve tablet between lip or cheek and upper gum.
   • Do not chew or swallow.
   • Keep in original container, tightly closed.
   • Store in a cool, dry place.



Lingual Dosage Forms

NITROGLYCERIN LINGUAL AEROSOL

Usual adult dose
Antianginal
On or under the tongue, 1 or 2 metered doses (400 or 800 mcg [0.4 or 0.8 mg]) repeated at five-minute intervals as needed for relief of angina attack.


Note: If relief is not obtained after a total of 3 metered doses in a fifteen-minute period, the physician should be contacted or the patient taken to a hospital.


Usual adult prescribing limits
1.2 mg per day.

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


400 mcg (0.4 mg) per metered dose (Rx) (Rx) [Nitrolingual]{48}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • Do not shake.
   • Caution with alcoholic beverages.
   • Store in a cool place.



Oral Dosage Forms

NITROGLYCERIN EXTENDED-RELEASE CAPSULES

Usual adult dose
Antianginal
Oral, 2.5, 6.5, or 9 mg every twelve hours, the dosage being increased to every eight hours if needed and tolerated.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


2.5 mg (Rx) [Nitrocot] [Nitroglyn E-R] [Nitro-par] [Nitro-time][Generic]{48}


6.5 mg (Rx) [Nitroglyn E-R] [Nitro-par] [Nitro-time][Generic]{48}


9 mg (Rx) [Nitroglyn E-R] [Nitro-par] [Nitro-time][Generic]{48}

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a container with a tight screw cap.

Stability:
Loss of potency is accelerated by exposure to heat and moisture.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Swallow capsules whole.
   • Keep container tightly closed.
   • Store in a cool, dry place.


NITROGLYCERIN EXTENDED-RELEASE TABLETS

Usual adult dose
Antianginal
Oral, 2.6 or 6.5 mg every twelve hours, the dosage being increased to every eight hours as needed and tolerated.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


2.6 mg (Rx){48}[Generic]


6.5 mg (Rx){48}[Generic]

Canada—


2.6 mg (Rx) [Nitrong SR]{56}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a glass container with a tight screw cap.

Stability:
Loss of potency is accelerated by exposure to heat and moisture.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Swallow tablets whole.
   • Keep container tightly closed.
   • Store in a cool, dry place.



Parenteral Dosage Forms

NITROGLYCERIN INJECTION USP

Usual adult dose
Antianginal or
Antihypertensive or
Cardiac load–reducing agent
Intravenous infusion, initially administered at a rate of 5 mcg (0.005 mg) per minute, the dosage being increased by increments of 5 mcg per minute at three- to five-minute intervals until an effect is obtained or until the rate is 20 mcg (0.02 mg) per minute. If no effect is obtained at 20 mcg per minute, the dosage may be increased further by increments of 10 mcg (0.01 mg) per minute at the same time intervals, and later increased by increments of 20 mcg (0.02 mg) per minute if necessary to obtain an effect. The dosage increments should be reduced and the time interval between dosage increases lengthened when a partial effect is observed, to attain the desired response cautiously.


Note: Close attention must be given to manufacturers" instructions for dilution, dosage, and administration because concentrations and/or volume per vial of nitroglycerin may differ among the several products available from different manufacturers.
Stated dosage is based on use of special, non-polyvinylchloride (non-PVC) intravenous infusion sets. Dosage requirements may vary when standard infusion sets of polyvinyl chloride (PVC) are used. Continuous concurrent monitoring of blood pressure and heart rate in all patients must be performed to establish the correct effective dose.
To achieve optimal control of dosage and effects, it is recommended that nitroglycerin be administered intravenously by means of an infusion pump, a micro-drip regulator, or a similar device to allow precise adjustment of the flow rate.
Standard intravenous infusion sets made of PVC plastic may unpredictably absorb 40 to 80% of the nitroglycerin from a diluted solution for infusion.
Some intravenous filters may also absorb nitroglycerin, but the effect is variable; since nitroglycerin dosage is titrated according to response, no precaution is necessary {09}.Extra caution should be observed when non-PVC infusion sets are used to administer intravenous nitroglycerin. Some infusion pumps—

   • When turned off may not completely stop the flow of infusion solution with these non-PVC sets.
   • May not accurately deliver the infusion solution at low rates of flow.
   • Require extension sets and other connecting equipment made of PVC, thus partially negating the advantage of the non-PVC infusion set.
Close monitoring of patient hemodynamic response is required. All infusion pumps should be tested with the infusion set being used to ensure accurate delivery of nitroglycerin at low flow rates and complete interruption of flow when the set is turned off {24}.


Usual adult prescribing limits
No fixed maximum dose established. Dosage is titrated to individual patient response beginning with small doses (to which hypersensitive patients may respond).

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


5 mg per mL (Rx) [Nitro-Bid IV] [Tridil][Generic]{48}

Canada—


1 mg per mL (Rx) [Nitroject]


5 mg per mL (Rx) [Nitroject] [Tridil][Generic]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Preparation of dosage form:
   • Not for direct intravenous injection.
   • Must be diluted prior to infusion. Dilution may be in 5% dextrose injection or 0.9% sodium chloride injection, followed by thorough mixing. Dilution and storage of nitroglycerin injection should be made only in glass parenteral solution bottles, to avoid absorption of nitroglycerin into plastic containers {24}.
   • Must not be admixed with other medications.

Stability:
It is recommended that diluted solutions of nitroglycerin not be kept or used longer than 24 hours, unless otherwise specified by the manufacturer. Solution is not explosive either before or after dilution.

Note: Manufacturer's package information must be checked for dilution, administration, and dosage because of product differences.
Some products contain substantial amounts of propylene glycol or ethanol.




Sublingual Dosage Forms

NITROGLYCERIN TABLETS (SUBLINGUAL) USP

Usual adult dose
Antianginal
Sublingual or buccal, 300 to 600 mcg (0.3 to 0.6 mg) repeated at five-minute intervals as needed for relief of angina attack.


Note: If relief is not obtained after a total of 3 tablets used over a fifteen-minute period, the physician should be contacted or the patient taken to a hospital.


Usual adult prescribing limits
10 mg per day.

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


300 mcg (0.3 mg) (Rx) [Nitrostat][Generic]{48}


400 mcg (0.4 mg) (Rx) [Nitrostat][Generic]{48}


600 mcg (0.6 mg) (Rx) [Nitrostat][Generic]{48}

Canada—


300 mcg (0.3 mg) (Rx) [Nitrostat][Generic]{56}


600 mcg (0.6 mg) (Rx) [Nitrostat][Generic]{56}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in original container with tight metal screw cap.

Stability:
Loss of potency through volatilization of nitroglycerin from tablets is accelerated by exposure to air, heat, and moisture. After the bottle is opened, stabilized tablets will maintain potency through the expiration date provided the bottle cap is replaced tightly after each use. {08}

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • Dissolve tablets under tongue.
   • Keep in original container, tightly closed.
   • Store in a cool, dry place.

Note: Do not dispense sublingual nitroglycerin tablets in child-resistant containers.
Suggest to the patient that the cotton be removed from the container before the tablets are required for angina attack.
USP requires that sublingual forms of nitroglycerin be dispensed in the original unopened manufacturer's container.
Sublingual nitroglycerin tablets should not be placed in containers with other medications.




Topical Dosage Forms

NITROGLYCERIN OINTMENT USP

Usual adult dose
Antianginal
Topical, to the skin, 15 to 30 mg of nitroglycerin (contained in 2.5 to 5 cm [1 to 2 inches] of ointment as squeezed from the tube) every eight hours during the day and at bedtime. If angina occurs between doses, frequency of application may be increased to every six hours {03}.

Note: Ointment is applied in a thin, even layer covering an area of the same size (measuring at least 2 by 3 inches) at each use, but is not to be rubbed or massaged into the skin.

[Chronic anal fissures (treatment)]1
Topical, twice daily.{57}{58}{59}{60}{61}{62}{63}{64}{65}{66}



Usual adult prescribing limits
75 mg of nitroglycerin (contained in 12.5 cm [5 inches] of ointment as squeezed from the tube) per application. Rarely, application as frequently as every four hours may be necessary {09}.

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


2% (Rx) [Nitro-Bid] [Nitrol][Generic]{48}

Canada—


2% (Rx) [Nitrol]{56}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • For external use only.
   • Store in a cool place.
   • Keep tightly closed.

Note: Dispense ointment in original manufacturer's tube together with patient instructions and dose-measuring papers.



NITROGLYCERIN TRANSDERMAL SYSTEM

Usual adult dose
Antianginal
Topical, to the intact skin, 1 transdermal dosage system, delivering the smallest available dose of nitroglycerin in its dosage series, every twenty-four hours. Dosage adjustments may be made by changing to the next larger dosage system in the series or to a combination of systems.


Note: To prevent tolerance, it is recommended that the patch be left on only 12 to 14 hours a day, with a patch-off period of 10 to 12 hours before the next daily patch is applied {45}.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—



Dose of nitroglycerin delivered per hour


0.1 mg (Rx) [Minitran{49}] [Nitro-Dur{32}] [Transderm-Nitro{46}]


0.2 mg (Rx) [Deponit{48}] [Minitran{49}] [Nitrodisc{48}] [Nitro-Dur{32}] [Transderm-Nitro{46}][Generic]


0.3 mg (Rx) [Nitrodisc{48}] [Nitro-Dur{32}]


0.4 mg (Rx) [Deponit{48}] [Minitran{49}] [Nitrodisc{48}] [Nitro-Dur{32}] [Transderm-Nitro{46}][Generic]


0.6 mg (Rx) [Minitran{49}] [Nitro-Dur{32}] [Transderm-Nitro{46}][Generic]


0.8 mg (Rx) [Nitro-Dur{32}] [Transderm-Nitro{46}][Generic]

Canada—



Dose of nitroglycerin delivered per hour


0.2 mg (Rx) [Minitran{01}] [Nitro-Dur{01}] [Transderm-Nitro{01}]


0.3 mg (Rx) [Nitro-Dur{01}]


0.4 mg (Rx) [Minitran{01}] [Nitro-Dur{01}] [Transderm-Nitro{01}]


0.6 mg (Rx) [Minitran{01}] [Nitro-Dur{01}] [Transderm-Nitro{01}]


0.8 mg (Rx) [Minitran{01}] [Nitro-Dur{01}] [Transderm-Nitro{01}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Caution with alcoholic beverages.
   • For external use only.
   • Store in a cool place.

Note: Include patient instructions when dispensing.




Revised: 06/07/2002



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 31st ed. Ottawa: Canadian Pharmaceutical Association; 1997. p. 943-4, 1044-6, 1614-5.
  1. Harrison's principles of internal medicine. 7th ed. New York: McGraw-Hill; 1974. p. 1645.
  1. Federal Register 1986 Sep 3; 51: 31374.
  1. Panel comment, 1987 revision.
  1. Lahiri A, Piero Carboni G, Raftery EB. Buccal nitroglycerin tablets in heart failure. Ann Intern Med 1986; 105: 141.
  1. Lahiri A, Crawley JC, Sonecha TN, Raftery EB. Acute and chronic effects of sustained action buccal nitroglycerin in severe congestive heart failure. Int J Cardiol 1984; 5(1): 39-48.
  1. Adv Pharmacother 1982; 1: 73-97.
  1. Written communication, Parke-Davis 5/19/93.
  1. Panel comments, 1989 revision.
  1. Parker JO, Farrell B, Lahey KA, Moe G. Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N Engl J Med 1987; 316(23): 1440-4.
  1. Parker JO. Nitrate therapy in stable angina pectoris. N Engl J Med 1987; 316(26): 1635-42.
  1. May DC, Popma JJ, Black WH, Schaefer S, Lee HR, Levine BD, Hillis LD. In vivo induction and reversal of nitroglycerin tolerance in human coronary arteries. N Engl J Med 1987; 317(13): 805-9.
  1. Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med 1987; 317(13): 799-804.
  1. Nitroglycerin injection package insert (Abbott—US), 8/83.
  1. Isosorbide dinitrate package insert (Isordil, Wyeth—US), 6/9/87.
  1. Isosorbide dinitrate package insert (Sorbitrate, Stuart—US), 2/85.
  1. Isosorbide dinitrate package insert (Dilatrate-SR, Reed & Carnrick—US), 9/84.
  1. Isosorbide dinitrate package insert (Iso-Bid—US), 1/86.
  1. Isosorbide dinitrate package insert (Lederle—US), 9/85.
  1. Isosorbide dinitrate package insert (Vangard—US), 5/81.
  1. Nitroglycerin ointment package insert (Fougera—US), 3/85.
  1. Nitroglycerin E-R caps package insert (Lederle—US), 2/86.
  1. Nitroglycerin SL tablets package insert (Lilly—US), 8/21/85.
  1. Nitroglycerin injection package insert (LyphoMed—US), 5/85.
  1. Nitroglycerin package insert (Deponit, Wyeth—US), 12/2/85.
  1. Nitroglycerin package insert (Nitro-Bid E-R, Marion—US), 9/85.
  1. Nitroglycerin package insert (Nitro-Bid IV, Marion—US), 3/85.
  1. Nitroglycerin ointment package insert (Nitro-Bid, Marion—US), 1/85.
  1. Nitroglycerin caps package insert (Nitrocine E-R, Kremers-Urban—US), 4/87.
  1. Nitroglycerin transdermal package insert (Nitrocine, Kremers-Urban—US), 5/87.
  1. Nitroglycerin package insert (Nitrodisc, Searle—US), 12/20/85.
  1. Nitroglycerin package insert (Nitro-Dur, Key—US), 11/84; Rev 7/95.
  1. Isosorbide mononitrate package insert (Monoket, Schwarz Pharma—US), New 5/93, Rec 8/93.
  1. Nitroglycerin package insert (Nitroglyn, Key—US), 4/85.
  1. Nitroglycerin package insert (Nitrol IV, Kremers-Urban—US), 7/82.
  1. Nitroglycerin ointment package insert (Nitrol, Kremers-Urban—US), 4/85.
  1. Nitroglycerin package insert (Nitrolingual, Rorer—US), 11/85.
  1. Nitroglycerin tablets package insert (Nitrong E-R, Wharton—US), 9/84.
  1. Nitroglycerin ointment package insert (Nitrong, Wharton—US), 9/83.
  1. Nitroglycerin package insert (Nitrospan, USV—US), 1/86.
  1. Nitroglycerin package insert (Nitrostat, PD—US), 2/86.
  1. Nitroglycerin package insert (Nitrostat IV, PD—US), 7/84.
  1. Nitroglycerin ointment package insert (Nitrostat, PD—US), 7/83.
  1. Nitroglycerin package insert (NTS, Bolar—US), 3/86.
  1. Nitroglycerin package insert (Transderm-Nitro, CIBA—US), 11/85.
  1. Nitroglycerin package insert (Transderm-Nitro, Summit—US), 10/89; Rev 5/96.
  1. Nitroglycerin package insert (Tridil, American Critical Care—US), 12/82.
  1. Red book 1998. Montvale, NJ: Medical Economics Company; 1998.
  1. U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research, [Washington: Supt. of Docs., U.S. G.P.O.]. Approved drug products with therapeutic equivalence evaluations. 17th ed. 1997. chapter 3, p. 230.
  1. Isosorbide mononitrate package insert (ISMO, Wyeth-Ayerst—US), New 1/92, Rec 5/92.
  1. Fleeger CA, editor. USAN 1993. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1992. p. 347.
  1. Glasser SP, Arnett DK. Update on nitrate therapy: reexamination of tolerance issues and efficacy endpoints of long-acting products. Hosp Formul 1990; 25: 42-9.
  1. Amsterdam EA. Rationale for intermittent nitrate therapy. Am J Cardiol 1992; 70: 55G-60G.
  1. Parker JO, Farrell B, Lahey KA, Moe G. Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N Engl J Med 1987; 316: 1440-4.
  1. Sildenafil package insert (Viagra, Pfizer—US). Cited July 10, 1998. Available from: URL: http://www.viagra.com/hcp/prod_info_temp.htm.
  1. Health Canada Drug Product Database (DPD) [online database]. Cited June 23, 1998. Available from: URL: http://www.hc-sc.gc.ca/english/search.htm.
  1. Reviewers' consensus on ballot of 04/09/2002.
  1. Zuberi BF, Rajput MR, Abro H, Shaikh SA. A randomized trial of glyceryl trinitrate ointment and nitroglycerin patch in healing of anal fissures. Int J Colorectal Dis 2000 Aug;15(4):243-5
  1. Richard CS, Gregoire R, Plewes EA, et al. Internal sphincterotomy is superior to topical nitroglycerin in the treatment of chronic anal fissure: results of a randomized, controlled trial by the Canadian Colorectal Surgical Trials Group. Dis Colon Rectum 2000 Aug;43(8):1048-57; discussion 1057-8.
  1. Palazzo FF, Kapur S, Steward M J et al. Glyceryl trinitrate treatment of chronic fissure in ano: one year's experience with 0.5% GTN paste. R Coll Surg Edinb 2000 Jun; 45(3):168-70.
  1. Hasegawa H, Radley S, Morton DG et al. Audit of topical glyceryl trinitrate for treatment of fissure-in-ano. Ann R Coll Surg Engl 2000 Jan; 82(1):27-30.
  1. Kennedy ML, Sowter S, Nguyen H et al. Glyceryl trinitrate ointment for the treatment of chronic anal fissure: results of a placebo-controlled trial and long-term follow-up. Dis Colon Rectum 1999 Aug; 42(8):1000-6.
  1. Brisinda G, Maria G, Bentivoglio AR et al. A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. N Engl J Med 1999 Jul 8; 341(2):65-9.
  1. Carapeti EA, Kamm MA, McDonald PJ et al. Randomised controlled trial shows that glyceryl trinitrate heals anal fissures, higher doses are not more effective, and there is a high recurrence rate. Gut 1999 May; 44(5):727-30.
  1. Bacher H, Mischinger HJ, Werkgartner G et al. Local nitroglycerin for treatment of anal fissures: an alternative to lateral sphincterotomy? Dis Colon Rectum 1997 Jul; 40(7):840-5.
  1. Lund JN, Scholefield JH. Glyceryl trinitrate is an effective treatment for anal fissure. Dis Colon Rectum 1997 Apr; 40(4):468-70.
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