Nitrostat®
(nitroglycerin)
Tablets
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
Nitrostat is a stabilized sublingual nitroglycerin tablet manufactured by a patented process*
which prevents the migration of nitroglycerin by adding the nonvolatile fixing agent polyethylene
glycol 3350.This stabilized formulation has been shown to be more stable and more uniform
than conventional molded tablets. Nitrostat tablets contain 0.3 mg (1/200 grain), 0.4 mg (1/150
grain) and 0.6 mg (1/100 grain) nitroglycerin. Also contains lactose, NF; polyethylene glycol
3350, NF; sucrose, 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:
Relaxation of vascular smooth muscle is the principal pharmacologic action of nitroglycerin. The
mechanism by which nitroglycerin produces relaxation of smooth muscle is
unknown. Although venous effects predominate, nitroglycerin produces, in a dose-related
manner, dilation of both arterial and venous beds. Dilation of the postcapillary vessels,
including large veins, promotes peripheral pooling of blood and decreases venous return to
the heart, reducing left ventricular end-diastolic pressure (preload). Arteriolar relaxation
reduces systemic vascular resistance and arterial pressure (afterload). Myocardial oxygen
consumption or demand (as measured by the pressure-rate product, tension-time index and
stroke-work index) is decreased by both the arterial and venous effects of nitroglycerin, and
a more favorable supply-demand ratio can be achieved.
Nitroglycerin also dilates large epicardial coronary arteries; however, the extent to which this
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, pulmonary vascular
resistance and systemic vascular resistance are also reduced by nitroglycerin therapy. Heart
rate is usually slightly increased, presumably a reflex response to the fall in blood pressure.
Cardiac index may be increased, decreased or unchanged. Patients with elevated left
ventricular filling pressure and systemic vascular resistance values in conjunction with a
depressed cardiac index are likely to experience an improvement in cardiac index. On the
other hand, when filling pressures and cardiac index are normal, cardiac index may be
slightly reduced by intravenous nitroglycerin.
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. This eventually leads to dephosphorylation of the light chain of myosin, which
regulates the contractile state in smooth muscle, resulting in vasodilation.
Pharmacokineties and Metabolism
Nitroglycerin is rapidly absorbed following sublingual administration. Its onset of action is
approximately one to three minutes. Significant pharmacologic effects are present for 30 to
60 minutes following administration by the above route.
Nitroglycerin is rapidly metabolized to dinitrates and mononitrates, with a short half-life,
estimated at 1 to 4 minutes. A liver reductase enzyme is of primary importance in the
metabolism of nitroglycerin to glycerol nitrate metabolites and organic nitrate. Two active
major metabolites 1,2- and 1,3-dinitroglycerols are less potent vasodilators and have longer
half-lives than the parent compound. Dinitrates are metabolized to mononitrates and
ultimately glycerol. The monohydrate is not considered biologically active with respect to
cardiovascular effects.
At plasma concentrations of between 50 and 500 ng/mL, the binding of nitroglycerin to
plasma proteins is approximately 60%, while that of 1,2 dinitroglycerin and 1,3 dinitroglycerin
is 60% and 30%, respectively. The activity and half-life of 1,2 dinitroglycerin and 1,3
dinitroglycerin are not well characterized. The mononitrate is not active.
Nitroglycerin is indicated for the acute relief of an attack or prophylaxis of angina pectoris
due to coronary artery disease.
Sublingual nitroglycerin therapy is contraindicated in patients with early myocardial
infraction, severe anemia, increased intracranial pressure and those with a known
hypersensitivity to nitroglycerin.
The use of nitroglycerin during the early course of acute myocardial infarction requires
particular attention to hemodynamic monitoring and clinical status.
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. Nitrostat tablets are
intended for sublingual or buccal administration and should not be swallowed.
Severe hypotension, particularly with upright posture, may occur even with small doses of
nitroglycerin. The drug should be used cautiously in patients with volume depletion or low
systolic blood pressure.
Paradoxical bradycardia and increased angina pectoris may accompany nitroglycerin-induced
hypotension.
Nitrate therapy may aggravate angina caused by hypertrophic cardiomyopathy.
Tolerance to the vascular and antianginal effects of nitroglycerin and cross-tolerance to other
nitrates and nitrites may occur.
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 Nitrostat
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.
Nitroglycerin should be kept in the original glass container, tightly capped. The cotton should
be discarded once the bottle is opened.
Drug Interactions: Concomitant use of nitrates and alcohol may cause hypotension.
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. Dose adjustment of either class of agent may be necessary.
Aspirin may decrease the clearance and enhance the hemodynamic effects of sublingual
nitroglycerin.
A decrease in the 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: No long-term studies in animals
were performed to evaluate the carcinogenic potential of nitroglycerin.
Pregnancy Category C: Animal reproduction studies have not been conducted with
nitroglycerin. It is also not known whether nitroglycerin can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. Nitroglycerin should
be given to a pregnant woman only if clearly needed.
Nursing Mother: it is not known whether nitroglycerin is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised when intravenous
nitroglycerin is administered to a nursing woman.
Pediatric Use: The safety and effectiveness of nitroglycerin in children have not been
established.
Headache which may be severe and persistent may occur immediately after use. Vertigo,
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 vasodilation has been
reported. Flushing, drug rash, and exfoliative dermatitis have been reported in patients
receiving nitrate therapy.
Nitrate overdose may result in: severe hypotenslon, tachycardia, bradycardia, heart block,
palpitation, death due to circulatory collapse, syncope, persistent throbbing headache,
vertigo, visual disturbance, increased intracranial pressure, paralysis and coma followed by
convulsions, flushing and diaphoresis, nausea and vomiting, colic and diarrhea, dyspnea
and methemoglobinemia.
Since hypotension from nitroglycerin overdosage results from venodilation and arterial
hypovolemia, therapy should be directed toward central volume expansion. Elevation of
extremities may be sufficient, but intravenous infusion may also be necessary. Use of arterial
vasoconstrictors may do more harm than good. Management of nitroglycerin overdose in
patients with renal disease or congestive heart failure may require invasive monitoring.
If methemoglobinemia is present, intravenous administration of methylene blue 1-2 mg/kg of
body weight may be required.
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 five 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. Nitrostat 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.
Nitrostat is supplied in three strengths in bottles containing 100 tablets each, with
color-coded labels, and in color-coded Patient Convenience Packages of four bottles of 25
tablets each.
0.3 mg (1/200 grain): N 0071-0569-24 -- Bottle of 100 tablets
0.4 mg (1/150 grain): N 0071-0570-13 -- Convenience Package
N 0071-0570-24 -- Bottle of 100 tablets
0.6 mg (1/100 grain): N 0071-0571-24 -- Bottle of 100 tablets
Store at controlled room temperature 15°- 30°C (59°- 86°F). Protect from moisture.
*US Patent No. 3,789,119
Caution Federal law prohibits dispensing without prescription.
1995, Warner-Lambert co.
Revised June 1995
PARKE-DAVIS
Div of Warner-Lambert Co
Morris Plains, NJ 07950 USA
