Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2844
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Nitroglycerin in Dextrose (Injection, Solution)
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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 Table 1. 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 responseis 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. Do not use unless vacuum
is present and solution is clear.
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Nitroglycerin is 1,2,3-propanetriol trinitrate, an
organic nitrate whose structural formula is: whose molecular formula is CHNO, and whose molecular weight is
227.09. The organic nitrates are vasodilators, active on both arteries
and veins. Dextrose, USP is chemically designated
D-glucose monohydrate CHO���HO, a hexose sugar freely soluble in water whose structural
formula is: The 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 mL of 100 mcg/mL Nitroglycerin in 5% Dextrose
Injection contains nitroglycerin 100 mcg; propylene glycol 0.9 mg
and dextrose, hydrous 50 mg in water for injection. May contain nitric
acid for pH adjustment. The pH is 4.0 (3.0 to 6.5) and the calculated
osmolarity is 265 mOsmol/L.* Each mL of 200
mcg/mL Nitroglycerin in 5% Dextrose Injection contains nitroglycerin
200 mcg, propylene glycol 1.80 mg and dextrose, hydrous 50 mg
in water for injection. May contain nitric acid for pH adjustment.
The pH is 4.0 (3.0 to 6.5) and the calculated osmolarity is 277 mOsmol/L.* Each mL of 400 mcg/mL Nitroglycerin in 5% Dextrose Injection
contains nitroglycerin 400 mcg, propylene glycol 3.60 mg and
dextrose, hydrous 50 mg in water for injection. May contain nitric
acid for pH adjustment. The pH is 4.0 (3.0 to 6.5) and the calculated
osmolarity is 301 mOsmol/L.* *Normal physiologic
osmolarity range is approximately 280 to 310 mOsmol/L. Administration
of substantially hypertonic solutions (���600 mOsmol/L) may cause
vein damage. Although dry nitroglycerin is explosive,
nitroglycerin in 5% dextrose is not.
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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. 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 only12 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 large volume glass containers as follows: Store at 20 to 25��C (68 to 77��F). [See
USP Controlled Room Temperature.] Protect from freezing. Revised: October, 2005
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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 subclinical
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, Mutagenesis, 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:: 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:: Safety and effectiveness in pediatric patients have
not been established.<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.
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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 normal saline 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. 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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Nitroglyercin
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Nitroglycerin in Dextrose (Injection, Solution)
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| dailymed-instance:adverseRe... |
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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| dailymed-instance:warning |
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 inmost 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 nonabsorptive
intravenous administration sets are available. If intravenous nitroglycerin is administered through nonabsorptive
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
peripheral and 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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