Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1055
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Nitroglycerin In Dextrose (Injection)
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Nitroglycerin in 5%
Dextrose Injection is intended for intravenous administration using
sterile equipment. It should be administered only via an infusion pump
that can maintain a constant infusion rate. A container which has lost its vacuum, or one in which particulate matter is visible, should not be
used. Dosage is affected
by the type of infusion set used (see Warnings). Although the usual adult starting dose in
published studies has been 25 mcg/min or more, these studies used PVC
tubing, so the delivered doses were less than those reported. When nonabsorptive tubing is used, doses must be
reduced. Even using
nonabsorptive tubing, the dose necessary to achieve a given response
will vary greatly from patient to patient. Patients with normal or low
left-ventricular filling pressure (e.g., patients with uncomplicated
angina pectoris) may respond fully to as little as 5 mcg/min, while
other patients may require a dose that is one or even two orders of
magnitude higher. Continuous monitoring of blood pressure and heart rate
is necessary in all patients receiving this medication; in many cases,
invasive monitoring of pulmonary capillary wedge pressure will also be
indicated. Lower
concentrations of Nitroglycerin in 5% Dextrose Injection increase the
potential precision of dosing, but these concentrations increase the
total fluid volume that must be delivered to the patient. Total fluid
load may be a dominant consideration in patients with compromised
function of the heart, liver, and/or kidneys. The necessary flow rates
to achieve various dose rates with the available concentrations are
shown in the following table. Using nonabsorptive
tubing, the initial adult dosage of Nitroglycerin in 5% Dextrose
Injection should be 5 mcg/min. Subsequent titration must be guided by
the clinical results, with dose increments becoming more cautious as
partial response is seen. Initial titration should be in 5 mcg/min
increments at intervals of 3 to 5 minutes. If no response is seen at 20
mcg/min, increments of 10 and even 20 mcg/min can be used.Once some
hemodynamic response is observed, dosage increments should be smaller
and less frequent. When the
concentration is changed, the tubing must be disconnected from the
patient and flushed with the new solution before therapy is continued.
If this precaution is not taken, then depending upon the tubing, pump,
and flow rate used, it might be several hours before nitroglycerin is
delivered at the desired rate. Parenteral drug
products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container
permit. Do not add
supplementary medication to Nitroglycerin in 5% Dextrose Injection.
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Nitroglycerin is
1,2,3-propanetriol trinitrate, an organic nitrate whose structural
formula is whose empiric
formula is CHNO, and
whose molecular weight is 227.09. The organic nitrates are vasodilators,
active on both arteries and veins. Dextrose (Dextrose
Hydrous, USP) is D-glucose monohydrate, a hexose sugar whose structural
formula is whose empiric
formula is CHO���HO,
and whose molecular weight is 198.17. Nitroglycerin in 5%
Dextrose Injection is a sterile, nonpyrogenic solution of nitroglycerin
and dextrose in water for injection. The solution is clear and
practically colorless. Each 100 mL contains 10 mg, 20 mg, or 40 mg
nitroglycerin (added as Diluted Nitroglycerin, USP with propylene
glycol); 5 g Dextrose Hydrous, USP; 0.84 mL Alcohol, USP (added as a
dissolution aid); and 105 mg Citric Acid Hydrous, USP (added as a buffer). The pH of the solution is adjusted with sodium hydroxide and,
if necessary, hydrochloric acid. Although dry
nitroglycerin is explosive, nitroglycerin in 5% dextrose is not. Composition,
osmolarity and pH are given in Table 1.
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The principal
pharmacological action of nitroglycerin is relaxation of vascular smooth
muscle and consequent dilatation of peripheral arteries and veins,
especially the latter. Dilatation of the veins promotes peripheral
pooling of blood and decreases venous return to the heart, thereby
reducing left ventricular end-diastolic pressure and pulmonary capillary
wedge pressure (preload). Arteriolar relaxation reduces systemic
vascular resistance, systolic arterial pressure, and mean arterial
pressure (afterload). Dilatation of the coronary arteries also occurs.
The relative importance of preload reduction, afterload reduction, and
coronary dilatation remains undefined. Dosing regimens for
most chronically used drugs are designed to provide plasma
concentrations that are continuously greater than a minimally effective
concentration. This strategy is inappropriate for organic nitrates.
Several well-controlled clinical trials have used exercise testing to
assess the anti-anginal efficacy of continuously-delivered nitrates. In
the large majority of these trials, active agents were indistinguishable
from placebo after 24 hours (or less) of continuous therapy. Attempts to
overcome nitrate tolerance by dose escalation, even to doses far in
excess of those used acutely, have consistently failed. Only after
nitrates have been absent from the body for several hours has their
anti-anginal efficacy been restored.<br/>Pharmacokinetics:: The volume
of distribution of nitroglycerin is about 3 L/kg, and
nitroglycerin is cleared from this volume at extremely rapid
rates, with a resulting serum half-life of about 3 minutes. The
observed clearance rates (close to 1 L/kg/min) greatly exceed
hepatic blood flow; known sites of extrahepatic metabolism
include red blood cells and vascular walls. The first
products in the metabolism of nitroglycerin are inorganic
nitrate and the 1,2-and 1,3- dinitroglycerols. The dinitrates
are less effective vasodilators than nitroglycerin, but they are
longer-lived in the serum, and their net contribution to the
overall effect of chronic nitroglycerin regimens is not known.
The dinitrates are further metabolized to (non-vasoactive)
mononitrates and, ultimately, to glycerol and carbon dioxide. To avoid
development of tolerance to nitroglycerin, drug-free intervals
of 10-12 hours are known to be sufficient; shorter intervals
have not been well studied. In one well-controlled clinical
trial, subjects receiving nitroglycerin appeared to exhibit a
rebound or withdrawal effect, so that their exercise tolerance
at the end of the daily drug-free interval was less than that
exhibited by the parallel group receiving placebo.<br/>Clinical Trials:: Blinded,
placebo-controlled trials of intravenous nitroglycerin have not
been reported, but multiple investigators have reported
open-label studies, and there are scattered reports of studies
in which intravenous nitroglycerin was tested in blinded fashion
against sodium nitroprusside. In each of
these studies, therapeutic doses of intravenous nitroglycerin
were found to reduce systolic and diastolic arterial blood
pressure. The heart rate was usually increased, presumably as a
reflexive response to the fall in blood pressure. Coronary
perfusion pressure was usually, but not always, maintained. Intravenous
nitroglycerin reduced central venous pressure (CVP), right
atrial pressure (RAP), pulmonary arterial pressure (PAP),
pulmonary-capillary wedge pressure (PCWP), pulmonary vascular
resistance (PVR), and systemic vascular resistance (SVR). When
these parameters were elevated, reducing them toward normal
usually caused a rise in cardiac output. Conversely, intravenous
nitroglycerin usually reduced cardiac output when it was given
to patients whose CVP, RAP, PAP, PCWP, PVR, and SVR were all
normal. Most
clinical trials of intravenous nitroglycerin have been brief;
they have typically followed hemodynamic parameters during a
single surgical procedure. In one careful study, one of the few
that lasted more than a few hours, continuous intravenous
nitroglycerin had lost almost all of its hemodynamic effect
after 48 hours. In the same study, patients who received
nitroglycerin infusions for only 12 hours out of each 24
demonstrated no similar attenuation of effect. These results are
consistent with those seen in multiple large, double-blind,
placebo-controlled trials of other formulations of nitroglycerin
and other nitrates.
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Allergic reactions
to organic nitrates are extremely rare, but they do occur. Nitroglycerin
in 5% Dextrose Injection is contraindicated in patients who are allergic
to it. In patients with
pericardial tamponade, restrictive cardiomyopathy, or constrictive
pericarditis, cardiac output is dependent upon venous return.
Intravenous nitroglycerin is contraindicated in patients with these
conditions. Solutions
containing dextrose may be contraindicated in patients with known
allergy to corn or corn products.
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Nitroglycerin in 5%
Dextrose Injection is supplied in glass container as follows: Exposure of
pharmaceutical products to heat should be minimized. Avoid excessive
heat. Protect from freezing. It is recommended the product be stored at
room temperature (25��C). Brief exposure up to 40��C
does not adversely affect the product. Baxter Healthcare Corporation Deerfield, IL 60015 Printed in
USA
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General:: Severe
hypotension and shock may occur with even 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 effect
of sublingual nitroglycerin on exercise tolerance, although
still observable, is somewhat blunted. In
industrial workers who have long-term exposure to unknown
(presumably high) doses of organic nitrates, tolerance clearly
occurs. Chest pain, acute myocardial infarction, and even sudden
death have occurred during temporary withdrawal of nitrates from
these workers, demonstrating the existence of true physical
dependence. Some
clinical trials in angina patients have provided nitroglycerin
for about 12 continuous hours of every 24-hour day. During the
nitrate-free intervals in some of these trials, anginal attacks
have been more easily provoked than before treatment, and
patients have demonstrated hemodynamic rebound and decreased
exercise tolerance. The importance of these observations to the
routine, clinical use of intravenous nitroglycerin is not known. Lower
concentrations of Nitroglycerin in 5% Dextrose Injection
increase the potential precision of dosing, but these
concentrations increase the total fluid volume that must be
delivered to the patient. Total fluid load may be a dominant
consideration in patients with compromised function of the
heart, liver, and/or kidneys. Nitroglycerin in 5% Dextrose Injection should be administered
only via an infusion pump that can maintain a constant infusion
rate. Intracoronary injection of Nitroglycerin in 5% Dextrose
Injection has not been studied. Solutions
containing dextrose should be used with caution in patients with
known sub-clinical or overt diabetes mellitus. ]<br/>Laboratory Tests:: Because of
the propylene glycol content of intravenous nitroglycerin, serum
triglyceride assays that rely on glycerol oxidase may give
falsely elevated results in patients receiving this
medication.<br/>Drug Interactions:: The
vasodilating effects of nitroglycerin may be additive with those of other vasodilators. Marked
symptomatic orthostatic hypotension has been reported when
calcium channel blockers and organic nitrates were used in
combination. Intravenous
nitroglycerin interferes, at least in some patients, with the
anticoagulant effect of heparin. In patients receiving
intravenous nitroglycerin, concomitant heparin therapy should be
guided by frequent measurement of the activated partial
thromboplastin time. Administration of Nitroglycerin in 5% Dextrose Injection
through the same infusion set as blood can result in
pseudoagglutination and hemolysis. More generally, Nitroglycerin
in 5% Dextrose Injection should not be mixed with any other
medication of any kind.<br/>Carcinogenesis and
Mutagenesis and Impairment of Fertility:: Animal
carcinogenesis studies with injectable 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 both sexes were 52% vs. 0% in controls and
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
two 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, p.o., or in
in vitro cytogenetic
tests in rat and dog tissues. In a
three-generation reproduction study, rats received dietary
nitroglycerin at doses up to about 434 mg/kg/day for six months
prior to mating of the Fgeneration with treatment
continuing through successive Fand Fgenerations. 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 Fgeneration
was seen. Infertility noted in subsequent generations, however,
was attributed to increased interstitial cell tissue and
aspermatogenesis in the high-dose males. In this
three-generation study there was no clear evidence of
teratogenicity.<br/>Pregnancy Category
C:: Animal
teratology studies have not been conducted with nitroglycerin
injection. Teratology studies in rats and rabbits were conducted
with topically applied nitroglycerin ointment at doses up to 80
mg/kg/day and 240 mg/kg/day, respectively, and no toxic effects
on dams or fetuses were seen. There are no adequate and
well-controlled studies in pregnant women. Nitroglycerin should be given to a pregnant woman only if clearly needed.<br/>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.<br/>Pediatric Use:: 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.<br/>Geriatric Use:: Clinical
studies of Nitroglycerin 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. Do not use
unless vacuum is present and solution is clear.
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Hemodynamic
Effects:: The ill
effects of nitroglycerin overdose are generally the results of
nitroglycerin's capacity to induce vasodilation, venous pooling,
reduced cardiac output, and hypotension. These hemodynamic
changes may have protean manifestations, including increased
intracranial pressure, with any or all of persistent throbbing
headache, confusion, and moderate fever; vertigo; palpitations;
visual disturbances; nausea and vomiting (possibly with colic
and even bloody diarrhea); syncope (especially in the upright
posture); air hunger and dyspnea, later followed by reduced
ventilatory effort; diaphoresis, with the skin either flushed or
cold and clammy; heart block and bradycardia; paralysis; coma;
seizures; and death. Laboratory
determinations of serum levels of nitroglycerin and its
metabolites are not widely available, and such determinations
have, in any event, no established role in the management of
nitroglycerin overdose. No data are
available to suggest physiological maneuvers (e.g., maneuvers to
change the pH of the urine) that might accelerate elimination of
nitroglycerin and its active metabolites. Similarly, it is not
known which -if any-of these substances can usefully be removed
from the body by hemodialysis. No specific
antagonist to the vasodilator effects of nitroglycerin is known,
and no intervention has been subject to controlled study as a
therapy of nitroglycerin overdose. Because the hypotension
associated with nitroglycerin overdose is the result of
venodilatation and arterial hypovolemia, prudent therapy in this
situation should be directed toward increase in central fluid
volume. Passive elevation of the patient's legs may be
sufficient, but intravenous infusion of normalsaline or similar
fluid may also be necessary. The use of
epinephrine or other arterial vasoconstrictors in this setting
is likely to do more harm than good. In patients with renal disease or congestive heart failure, therapy
resulting in central volume expansion is not without hazard.
Treatment of nitroglycerin overdose in these patients may be
subtle and difficult, and invasive monitoring may be
required.<br/>Methemoglobinemia:: Nitrate
ions liberated during metabolism of nitroglycerin can oxidize
hemoglobin into methemoglobin. Even in patients totally without
cytochrome breductase activity, however, and even
assuming that the nitrate moieties of nitroglycerin are
quantitatively applied to oxidation of hemoglobin, about 1 mg/kg
of nitroglycerin should be required before any of these patients
manifests clinically significant (���10%) methemoglobinemia. In
patients with normal reductase function, significant production
of methemoglobin should require even larger doses of
nitroglycerin. In one study in which 36 patients received 2-4
weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr,
the average methemoglobin level measured was 0.2%; this was
comparable to that observed in parallel patients who received
placebo. Notwithstanding these observations, there are case reports of
significant methemoglobinemia in association with moderate
overdoses of organic nitrates. None of the affected patients had
been thought to be unusually susceptible. Methemoglobin levels are available from most clinical
laboratories. The diagnosis should be suspected in patients who
exhibit signs of impaired oxygen delivery despite adequate
cardiac output and adequate arterial pO.
Classically, methemoglobinemic blood is described as chocolate
brown, without color change on exposure to air. When
methemoglobinemia is diagnosed, the treatment of choice is
methylene blue, 1-2 mg/kg intravenously.
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Nitroglycerin and Dextrose
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Nitroglycerin In Dextrose (Injection)
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Adverse reactions
to nitroglycerin are generally dose-related and almost all of these
reactions are the result of nitroglycerin's activity as a vasodilator.
Headache, which may be severe, is the most commonly reported side
effect. Headache may be recurrent with each daily dose, especially at
higher doses. Transient episodes of lightheadedness, occasionally related to blood pressure changes, may also occur. Hypotension occurs
infrequently, but in some patients it may be severe enough to warrant
discontinuation of therapy. Syncope, crescendo angina, and rebound
hypertension have been reported but are uncommon. Allergic reactions
to nitroglycerin are also uncommon, and the great majority of those
reported have been cases of contact dermatitis or fixed drug eruptions
in patients receiving nitroglycerin in ointments or patches. There have
been a few reports of genuine anaphylactoid reactions, and these
reactions can probably occur in patients receiving nitroglycerin by any
route. Extremely rarely,
ordinary doses of organic nitrates have caused methemoglobinemia in
normal-seeming patients. Methemoglobinemia is so infrequent at these
doses that further discussion of its diagnosis and treatment is deferred
(see Overdosage). Data are not
available to allow estimation of the frequency of adverse reactions
during treatment with Nitroglycerin in 5% Dextrose
Injection.
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Amplification of the vasodilatory effects of
Nitroglycerin by sildenafil can result in severe hypotension. The
time course and dose dependence of this interaction have not been
studied. Appropriate supportive care has not been studied, but it
seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion. Nitroglycerin
readily migrates into many plastics, including the polyvinyl chloride
(PVC) plastics commonly used for intravenous administration sets.
Nitroglycerin absorption by PVC tubing is increased when the tubing is
long, the flow rates are low, and the nitroglycerin concentration of the
solution is high. The delivered fraction of the solution's original
nitroglycerin content has been 20-60% in published studies using PVC
tubing; the fraction varies with time during a single infusion, and no
simple correction factor can be used. PVC tubing has been used in most
published studies of intravenous nitroglycerin, but the reported doses
have been calculated by simply multiplying the flow rate of the solution
by the solution's original concentration of nitroglycerin. The actual doses delivered have been less,
sometimes much less, than those reported. Relatively
non-absorptive intravenous administration sets are available. If intravenous nitroglycerin is administered
through non-absorptive tubing, doses based upon published reports
will generally be too high. Some in-line
intravenous filters also absorb nitroglycerin; these filters should be
avoided. Solutions
containing dextrose without electrolytes should not be administered
through the same administration set as blood, as this may result in
pseudoagglutination or hemolysis. The intravenous
administration of solutions may cause fluid overloading resulting in
dilution of serum electrolyte concentrations, overhydration and
congested states of pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of the
injections. The risk of solute overload causing congested states with
peripheraland pulmonary edema is directly proportional to the
electrolyte concentration of the injections.
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Nitroglycerin in 5%
Dextrose Injection is indicated for treatment of peri-operative
hypertension; for control of congestive heart failure in the setting of
acute myocardial infarction; for treatment of angina pectoris in
patients who have not responded to sublingual nitroglycerin and��-blockers; and for induction of intraoperative hypotension.
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Nitroglycerin In Dextrose
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