Document
DailyMed Label: Nitroglycerin
Title
DailyMed Label: Nitroglycerin
Date
2009
Document type
DailyMed Prescription
Name
Nitroglycerin
Generic name
Nitroglycerin
Manufacturer
Physicians Total Care, Inc.
Product information
NDC: 54868-6045
Product information
NDC: 54868-6045
Description
Nitroglycerin tablets are stabilized sublingual compressed
tablets that contain 0.3 mg (1/200 grain), 0.4 mg (1/150 grain), or 0.6 mg
(1/100 grain) nitroglycerin; as well as lactose monohydrate, NF; glyceryl
monostearate, NF; pregelatinized starch, NF; calcium stearate, NF powder; and
silicon dioxide, colloidal, NF.
Nitroglycerin, an organic nitrate, is a vasodilating agent. The chemical name
for nitroglycerin is 1, 2, 3 propanetriol trinitrate and the chemical structure
is:
C 3 H 5 N 3 0 9
Molecular weight: 227.09
image of chemical structure
Indications
Nitroglycerin is indicated for the acute relief of an attack or acute
prophylaxis of angina pectoris due to coronary artery disease.
Dosage
One tablet should be dissolved under the tongue or in the buccal
pouch at the first sign of an acute anginal attack. The dose may be repeated
approximately every 5 minutes, until relief is obtained. If the pain persists
after a total of 3 tablets in a 15-minute period, prompt medical attention is
recommended. Nitroglycerin tablets may be used prophylactically 5 to 10 minutes
prior to engaging in activities which might precipitate an acute attack.
During administration the patient should rest, preferably in the sitting
position.
No dosage adjustment is required in patients with renal failure.
Contraindications
Allergic reactions to organic nitrates are extremely rare, but
they do occur. Nitroglycerin is contraindicated in patients who are allergic to
it.
Sublingual nitroglycerin therapy is contraindicated in patients with early
myocardial infarction, severe anemia, increased intracranial pressure, and those
with a known hypersensitivity to nitroglycerin.
Administration of nitroglycerin tablets is contraindicated in patients who
are using sildenafil citrate since sildenafil citrate has been shown to
potentiate the hypotensive effects of organic nitrates.
Precautions
General Only the smallest dose required for effective relief of the acute
anginal attack should be used. Excessive use may lead to the development of
tolerance. Nitroglycerin tablets are intended for sublingual or buccal
administration and should not be swallowed.
Severe hypotension, particularly with upright posture, may occur with small
doses of nitroglycerin. This drug should therefore be used with caution in
patients who may be volume-depleted or who, for whatever reason, are already
hypotensive. Hypotension induced by nitroglycerin may be accompanied by
paradoxical bradycardia and increased angina pectoris.
Nitrate therapy may aggravate the angina caused by hypertrophic
cardiomyopathy.
As tolerance to other forms of nitroglycerin develops, the effects of
sublingual nitroglycerin on exercise tolerance, although still observable, is
blunted.
In industrial workers who have had long-term exposure to unknown (presumably
high) doses of organic nitrates, tolerance rarely occurs. Chest pain, acute
myocardial infraction, and even sudden death have occurred during temporary
withdrawal of nitrates from these workers, demonstrating the existence of true
physical dependence.
Several clinical trials of nitroglycerin patches or infusions in patients
with angina pectoris have evaluated regimens which incorporated a 10 to 12 hour
nitrate free interval. In some of these trials, an increase in the frequency of
anginal attacks during the nitrate free interval was observed in a small number
of patients. In one trial, patients had decreased exercise tolerance at the end
of the nitrate interval. Hemodynamic rebound has been observed only rarely; on
the other hand, few studies were so designed that rebound, if it had occurred,
would have been detected.
Nitrate tolerance as a result of sublingual nitroglycerin administration is
probably possible, but only in patients who maintain high continuous nitrate
levels for more than 10 or 12 hours daily. Such use of sublingual nitroglycerin
would entail administration of scores of tablets daily and is not
recommended.
The drug should be discontinued if blurring of vision or drying of the mouth
occurs. Excessive dosage of nitroglycerin may produce severe headaches.
Information for Patients If possible, patients should sit down when taking nitroglycerin
tablets. This eliminates the possibility of falling due to lightheadedness or
dizziness.
Nitroglycerin may produce a burning or tingling sensation when administered
sublingually; however, the ability to produce a burning or tingling sensation
should not be considered a reliable method for determining the potency of the
tablets.
Headaches can sometimes accompany treatment with nitroglycerin. In patients
who get these headaches, the headaches may be a marker of the activity of the
drug.
Treatment with nitroglycerin may be associated with lightheadedness on
standing, especially just after rising from a recumbent or seated position. This
effect may be more frequent in patients who have also consumed alcohol.
Nitroglycerin should be kept in the original glass container, tightly
capped.
Drug Interactions Patients receiving antihypertensive drugs, beta-adrenergic
blockers, or phenothiazines and nitrates should be observed for possible
additive hypotensive effects. Marked orthostatic hypotension has been reported
when calcium channel blockers and organic nitrates were used concomitantly.
Concomitant use of nitrates and alcohol may cause hypotension.
The vasodilatory and hemodynamic effects of nitroglycerin may be enhanced by
concomitant administration of aspirin.
Intravenous administration of nitroglycerin decreases the thrombolytic effect
of alteplase. Therefore, caution should be observed in patients receiving
sublingual nitroglycerin during alteplase therapy.
Intravenous nitroglycerin reduces the anticoagulant effect of heparin and
activated partial thromboplastin times (APTT) should be monitored in patients
receiving heparin and intravenous nitroglycerin. It is not known if this effect
occurs following single sublingual nitroglycerin doses.
Tricyclic antidepressants (amitriptyline, desipramine, doxepin, others) and
anticholinergic drugs may cause dry mouth and diminished salivary secretions.
This may make dissolution of sublingual nitroglycerin difficult. Increasing
salivation with chewing gum or artificial saliva products may prove useful in
aiding dissolution of sublingual nitroglycerin.
Oral administration of nitroglycerin markedly decreases the first-pass
metabolism of dihydroergotamine and subsequently increases its oral
bioavailability. Ergotamine is known to precipitate angina pectoris. Therefore,
patients receiving sublingual nitroglycerin should avoid ergotamine and related
drugs or be monitored for symptoms of ergotism if this is not possible.
Administration of nitroglycerin is contraindicated in patients who are using
sildenafil citrate. Sildenafil citrate has been shown to potentiate the
hypotensive effects of organic nitrates.
A decrease in therapeutic effect of sublingual nitroglycerin may result from
use of long-acting nitrates.
Drug/Laboratory Test Interactions Nitrates may interfere with the Zlatkis-Zak color reaction
causing a false report of decreased serum cholesterol.
Carcinogenesis, Mutagenesis, Impairment of
Fertility Animal carcinogenesis studies with sublingually administered
nitroglycerin have not been performed.
Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years
developed dose-related fibrotic and neoplastic changes in liver, including
carcinomas, and interstitial cell tumors in testes. At high dose, the incidences
of hepatocellular carcinomas in males was 48% and in females was 33% compared to
0% in untreated controls. Incidences of testicular tumors were 52% vs 8% in
controls. Lifetime dietary administration of up to 1058 mg/kg/day of
nitroglycerin was not tumorigenic in mice.
Nitroglycerin was weakly mutagenic in Ames tests performed in 2 different
laboratories. Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with
doses up to about 363 mg/kg/day, PO, or in ex vivo
cytogenetic tests in rat and dog tissues.
In a 3-generation reproduction study, rats received dietary nitroglycerin at
doses up to about 434 mg/kg/day for 6 months prior to mating of the F 0 generation with treatment continuing through successive
F 1 and F 2 generations. The high
dose was associated with decreased feed intake and body weight gain in both
sexes at all matings. No specific effect on the fertility of the F 0 generation was seen. Infertility noted in subsequent
generations, however, was attributed to increased interstitial cell tissue and
aspermatogenesis in the high-dose males. In this 3-generation study there was no
clear evidence of teratogenicity.
Pregnancy Category C Animal reproduction and teratogenicity studies have not been
conducted with nitroglycerin sublingual tablets. Teratology studies in rats and
rabbits, however, were conducted with topically applied nitroglycerin ointment
at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on
dams or fetuses were seen at any dose tested.
There are no adequate and well-controlled studies in pregnant women.
Nitroglycerin should be given to a pregnant woman only if clearly needed.
Nursing Mothers It is not known whether nitroglycerin is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
nitroglycerin is administered to a nursing woman.
Pediatric Use The safety and effectiveness of nitroglycerin in pediatric
patients have not been established.
Geriatric Use Clinical studies of nitroglycerin tablets did not include
sufficient numbers of subjects aged 65 and over to determine whether they
respond differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
Adverse reactions
Headache which may be severe and persistent may occur immediately after use.
Vertigo, dizziness, weakness, palpitation, and other manifestations of postural
hypotension may develop occasionally, particularly in erect, immobile patients.
Marked sensitivity to the hypotensive effects of nitrates (manifested by nausea,
vomiting, weakness, diaphoresis, pallor, and collapse) may occur at therapeutic
doses. Syncope due to nitrate vasodilatation has been reported. Flushing, drug
rash, and exfoliative dermatitis have been reported in patients receiving
nitrate therapy.
How supplied
Nitroglycerin tablets are supplied as white, round, flat-faced
tablets in 0.4 mg strength in bottles containing 100
tablets each, with color-coded labels, and in color-coded Patient Convenience
Packages of 4 bottles of 25 tablets each.
0.4 mg (1/150 grain):
Coded "N" on one side and "4" on the other.
NDC 54868-6045-1 —Convenience Package
NDC 54868-6045-0 —Bottle of 100
tablets
Store at Controlled Room Temperature 20°–25°C (68°–77°F)
[see USP].
Clinical pharmacology
The principal pharmacological action of nitroglycerin is
relaxation of vascular smooth muscle. Although venous effects predominate,
nitroglycerin produces, in a dose-related manner, dilation of both arterial and
venous beds. Dilation of postcapillary vessels, including large veins, promotes
peripheral pooling of blood, decreases venous return to the heart, and reduces
left ventricular end-diastolic pressure (preload). Nitroglycerin also produces
arteriolar relaxation, thereby reducing peripheral vascular resistance and
arterial pressure (afterload), and dilates large epicardial coronary arteries;
however, the extent to which this latter effect contributes to the relief of
exertional angina is unclear.
Therapeutic doses of nitroglycerin may reduce systolic, diastolic, and mean
arterial blood pressure. Effective coronary perfusion pressure is usually
maintained, but can be compromised if blood pressure falls excessively or
increased heart rate decreases diastolic filling time.
Elevated central venous and pulmonary capillary wedge pressures, and
pulmonary and systemic vascular resistance are also reduced by nitroglycerin
therapy. Heart rate is usually slightly increased, presumably due to a
compensatory response to the fall in blood pressure. Cardiac index may be
increased, decreased, or unchanged. Myocardial oxygen consumption or demand (as
measured by the pressure-rate product, tension-time index, and stroke-work
index) is decreased and a more favorable supply-demand ratio can be achieved.
Patients with elevated left ventricular filling pressures and increased systemic
vascular resistance in association with a depressed cardiac index are likely to
experience an improvement in cardiac index. In contrast, when filling pressures
and cardiac index are normal, cardiac index may be slightly reduced following
nitroglycerin administration.
Mechanism of Action Nitroglycerin forms free radical nitric oxide (NO) which
activates guanylate cyclase, resulting in an increase of guanosine 3'5'
monophosphate (cyclic GMP) in smooth muscle and other tissues. These events lead
to dephosphorylation of myosin light chains, which regulate the contractile
state in smooth muscle, and result in vasodilatation.
Pharmacodynamics Consistent with the symptomatic relief of angina, digital
plethysmography indicates that onset of the vasodilatory effect occurs
approximately 1 to 3 minutes after sublingual nitroglycerin administration and
reaches a maximum by 5 minutes postdose. Effects persist for at least 25 minutes
following nitroglycerin administration.
Pharmacokinetics and Drug Metabolism Absorption Nitroglycerin is rapidly absorbed following sublingual
administration of nitroglycerin tablets. Mean peak nitroglycerin plasma
concentrations occur at a mean time of approximately 6 to 7 minutes postdose
(Table 1). Maximum plasma nitroglycerin concentrations (Cmax) and area under the
plasma concentration-time curves (AUC) increase dose-proportionally following
0.3 to 0.6 mg nitroglycerin tablets. The absolute bioavailability of
nitroglycerin from nitroglycerin tablets is approximately 40% but tends to be
variable due to factors influencing drug absorption such as sublingual hydration
and mucosal metabolism.
Table 1
Mean Nitroglycerin
(SD) Values
2 x 0.3 mg
1 x 0.6 mg
Parameter
Nitroglycerin Tablets
Nitroglycerin Tablets
Cmax, ng/mL
2.3 (1.7)
2.1 (1.5)
tmax, min
6.4 (2.5)
7.2 (3.2)
AUC(0–∞), min
14.9 (8.2)
14.9 (11.4)
t1/2, min
2.8 (1.1)
2.6 (0.6)
Distribution The volume of distribution (V Area ) of
nitroglycerin following intravenous administration is 3.3 L/kg. At plasma
concentrations between 50 and 500 ng/mL, the binding of nitroglycerin to plasma
proteins is approximately 60%, while that of 1,2- and 1,3-dinitroglycerin is 60%
and 30%, respectively.
Metabolism A liver reductase enzyme is of primary importance in the
metabolism of nitroglycerin to glycerol di- and mononitrate metabolites and
ultimately to glycerol and organic nitrate. Known sites of extrahepatic
metabolism include red blood cells and vascular walls. In addition to
nitroglycerin, 2 major metabolites 1,2- and 1,3-dinitroglycerin, are found in
plasma. Mean peak 1,2- and 1,3-dinitroglycerin plasma concentrations occur at
approximately 15 minutes postdose. The elimination half-life of 1,2- and
1,3-dinitroglycerin is 36 and 32 minutes, respectively. The 1,2- and 1,3
dinitroglycerin metabolites have been reported to possess approximately 2% and
10% of the pharmacological activity of nitroglycerin. Higher plasma
concentrations of the dinitro metabolites, along with their nearly 10-fold
longer elimination half-lives, may contribute significantly to the duration of
pharmacologic effect. Glycerol mononitrate metabolites of nitroglycerin are
biologically inactive.
Elimination Nitroglycerin plasma concentrations decrease rapidly with a mean
elimination half-life of 2 to 3 minutes. Half-life values range from 1.5 to 7.5
minutes. Clearance (13.6 L/min) greatly exceeds hepatic blood flow. Metabolism
is the primary route of drug elimination.
Package label
nitroglycerin
sublingual tablets, USP
0.4 mg (1/150 gr)
Rx only
image of 0.4 mg package label
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