Adenosine - American Association of Nurse Anesthetists

Adenosine: Novel antiarrhythmic therapy for
supraventricular tachycardia
JOHN J. NAGELHOUT, CRNA, PhD
Detroit,Michigan
Adenosine (Adenocard®) is a unique new
agentfor the acute treatment of paroxysmal
supraventriculartachycardia(PSVT).
Administered by intravenous bolus, it has an
onset and duration measured in seconds and
greaterthan 90% efficacy. Its primary effect is
to slow atrioventricularnodal conduction, thus
converting reentrantforms of PSVT to normal
sinus rhythm. Side effects quickly dissipate
without treatment because of the short
duration of action. Other uses include
diagnosis of broador wide QRS complex
tachycardiasand controlled intraoperative
hypotension. Its short duration and high
efficacy in convertingselectforms of PSVT
make adenosine an excellent alternative to
verapamilin patients with compromised
hemodynamics. This article will review the
clinical use and anesthetic implicationsfor the
administrationof this drug.
Key words: Adenosine, antiarrhythmic,
arrhythmia, supraventricular, tachycardia.
Introduction
Adenosine is an endogenous nucleoside found
throughout the body which participates in a number of physiologic processes (Table I). Reports dating back to 1929 noted adenosine's possible therapeutic potential, yet only recently has its true
clinical value become evident.' Interest in adenosine's antiarrhythmic effect derives from its ability
June 1992/ Vol. 60/No. 3
to slow sinoatrial (SA) node and, more importantly,
atrioventricular (AV) nodal conduction, thereby
terminating PSVT. 2 Verapamil is currently the
drug of choice for acute treatment of PSVT, but
adenosine exhibits a similar efficacy and a safer
adverse reaction profile.
Adenosine can also serve as a valuable diagnostic tool in differentiating the origin (supraventricular or ventricular) of broad QRS complex
tachycardia. 3 When combined with electrocardiographic analysis, it has a 92% predictive accuracy
rate in differentiating the source of these arrhythmias.
Chemistry and pharmacokinetics
The chemical structure of adenosine is shown
Table I
Physiologic effects of adenosine
Regulation of coronary, cerebral, and systemic
vascular tone
Inhibition of platelet aggregation
Stimulation of gastric secretion
Modulation of neurotransmission
Modulation of lymphocytes
Reduction of renal blood flow and renin release
Bronchoconstriction
Inhibition of lipolysis
Promotion of prostaglandin release
Depression of cerebral and cardiac electrical activity
287
in Figure 1. It is an endogenous adenine nucleoside (6-amino-9-B-D-ribofluranosyl-9H-purine)
with a molecular weight of 267. The onset of action
of adenosine is 10-20 seconds, and its duration is
approximately 1 minute. Its in vitro beta half-life
is 10 seconds. 4, 5 After intravenous (IV) administration, adenosine is rapidly removed from the
plasma by cellular uptake. Once inside the cell, it
is phosphorylated to adenosine monophosphate. 6
Figure 2
Biotransformation of adenosine
Adenosini
Adenosine deaminase
Inosine
Purine nucleoside
phosphorylase
Figure 1
Chemical structure of adenosine
Hypoxanthine
i
NH2
Xanthine
oxidase
Xanthine
_ jXanthine
]i
oxidase
Uric acid
ATP
AMP-Adenosine monophosphate
ADP-Adenosine diphosphate
ATP-Adenosine triphosphate
Figure 3
Classification and function of purinergic receptors
ATP
sensitive
At higher concentrations, intracellular conversion
to inosine, hypoxanthine, and, finally, uric acid
can occur.7 The biotransformation of adenosine is
shown in Figure 2.
Because of adenosine's rapid plasma clearance,
standard pharmacokinetic variables such as volume of distribution, protein binding, and elimination constants have not been determined. No dosing adjustments for renal or hepatic dysfunction
are required, since adenosine's clearance from
plasma is by cellular uptake.
Pharmacodynamics
The effects of adenosine are produced by an
agonist action on cell surface Al purinergic
receptors. 8 The classification and function of
purinergic receptors are shown in Figure 3.9
1
Inhibits
adenyl
cyclase
*A2
1
Activates
adenyl
cyclase
Produces:
Slowing of sinoatrial
and atrioventricular
nodal conduction
Bronchoconstriction
Dilation of cerebral and coronary
vessels
Constriction of renal vessels
Modulation of neurotransmitter
release
Found ingastrointes
tinal tract, vascular
endothelium and other
areas. Not methylxan
thine sensitive.
* A2 receptors are further subdivided into A2a (low affinity) and
A2b (high affinity).
10 En-
dogenous secretion of adenosine produces coronary vasodilation. Another messenger system
which mediates adenosine receptor function is cyclic adenosine monophosphate (cAmp). 9 Adeno-
288
Al
sine receptors are differentiated in part by their
ability to inhibit (Ai) or activate (A 2) the cAmpproducing enzyme complex adenyl cyclase. Ultimately, a cAmp-mediated decrease in calcium con-
Journalof the American Association of Nurse Anesthetists
Treatment
Nonpharmacologic approaches are usually attempted first. Maneuvers which increase vagal
tone, such as carotid massage, valsalva, gagging, or
ice water to the face (diving reflex), are occasion-
duction probably accounts for the pharmacologic
effect of the drug."
Pretreatment with atropine does not alter the
electrophysiologic effects of adenosine in humans.
As a result, muscarinic actions do not appear to
contribute to the inhibitory effects of adenosine on
the heart.2
5,
ally effective. 16
The drug of choice for acute termination of
PSVT is intravenous verapamil in a dose of 5-10
mg. It is effective within about 10 minutes approximately 93% of the time.' 7 18Although verapamil is
generally safe, it has some limitations. Profound
hypotension resulting from its negative inotropic
action may occur in patients with congestive heart
failure, reduced left ventricular function, or in
those on concomitant beta-blocker therapy.1 2 Precipitation of atrial fibrillation, ventricular fibrillation, and sudden death, have also been re21
ported. '23
Additive myocardial depression should also
be expected when verapamil is given with cardiodepressant anesthetic agents. 24 When problems do
occur, the relatively long duration of action of
verapamil (2-4 hours) may be a problem. 24
The use of edrophonium and Neo-Synephrine® (phenylephrine) for acute therapy of SVT
has been abandoned because of the high percentage of adverse outcomes.
Chronic therapy for prevention of recurrence
may include digitalis, propranolol, verapamil,
quinidine, procainamide, disopyramide, diltiazem,
and amiodarone.' 3
Adenosine. The efficacy of adenosine compared
to verapamil was studied in a prospective nonrandomized comparative trail in patients undergoing
invasive cardiac diagnostic studies." Adenosine
0.125 mg/kg (mean dose) was compared to verapamil 0.145 mg/kg (mean dose). Success was determined by termination of tachycardia, absence of
significant arrhythmia after conversion, and ability to unmask latent preexcitation. Adenosine terminated SVT in 20 out of 20 patients. Verapamil
terminated tachycardia in 19 out of 20 patients.
Clinical implications
PSVT is characterized by the sudden onset of
tachycardia with a QRS complex of supraventricular origin and rates in the range of 150-250 beats
per minute. 2 Rates of 180-200 are most common in
adults; however, they may exceed 250, especially in
children. Because of these rapid rates, P waves are
usually buried in the QRS complex. The QRS
complex is generally of normal size and duration,
however, broad QRS complex tachycardias may
occur." Broad or wide complex tachycardias indicate a QRS interval of greater than 1.2 seconds.
The term "paroxysmal" is used to indicate a tachycardia of sudden onset, changing from sinus
rhythm to tachycardia in one beat, i.e., a premature atrial complex which initiates supraventricular tachycardia (SVT) (Figure 4).
There are several types of SVT, which are delineated by the arrhythmia circuit pathway 14 (Figure 5). The most common SVTs include the AV
node in the aberrant circuit. (See Figure 5: A, B, C,
D.) Adenosine will convert more than 95% of these
arrhythmias. SVT, which does not directly include
the AV node, will usually not convert them. (See
Figure 5: E, F, G, H.) However, the dose-dependent
AV block produced by adenosine will slow ventricular response and may unmask atrial deflections
in the ECG, which aids in arrhythmia diagnosis.
The symptoms of SVT frequently include palpitations, anxiety, angina, syncope, and, in severe
cases, shock. SVT-induced hypotension may result
from a decrease in left ventricular end diastolic
volume and stroke volume as the atrial contribution to ventricular filling is lost. 12
Figure 4
Premature atrial complex (J) initiates a supraventricular tachycardia probably due to atrioventricular nodal reentry
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Figure 5
Schematic representation of supraventricular
tachycardias
AVNode
AP
His
Ventriclde
RA
ECG
-
LA
J-
A f
-AVN/
-AVN
VApV
A. AV nodal reentry B. AV reentry
C.AVreentry
(orthodromic) (antidromic)
Atrium
A
AVNode
His
Ventrc
RA -4----
ECG
----
A
,
API
Av
E. Atrial reentry
(Tachycardia,
flutter)
F.Atrial
automatic
I
G. Twoaccessory
pathways
H. Atrial through
AP (innocent
bystander)
Types A, B, C, and D have the atrioventricular node (AVN)
as part of their circuitry and therefore are adenosine-
atrial reentrant tachycardia, atrial fibrillation or
flutter, SA nodal reentry, or automatic atrial tachycardia (17 patients). Overholt et al demonstrated
similar results with adenosine in pediatric patients
6 hours to 17 years old. 26
Adenosine is also useful in the diagnosis of
broad complex tachycardias. Differentiating ventricular tachycardia (VT) from SVT is often difficult in emergency management of these arrhythmias. SVT is frequently the presumptive, and
erroneous, diagnosis. 27 If the complex is VT and
verapamil is given, the direct myocardial depression may lead to deleterious hemodynamic effects.
Griffith et al administered adenosine to 26 patients
with broad complex tachycardia. 3 Eight of nine patients with SVT converted to sinus rhythm or narrow complex SVT. Only one of 17 patients with VT
converted to sinus rhythm; however, no adverse
hemodynamic effects were observed, leading researchers to conclude that adenosine was useful in
diagnosis and treatment of broad complex tachycardia.
Finally, it has been suggested that adenosine
may be the agent of choice for treatment of SVT
during pregnancy, although it has yet to be approved for this use. 28 Its short half-life would make
placental transfer highly unlikely and minimize
potential fetal effects.
terminable. In types E and F,the AV node only determines
the ventricular response; therefore, the only effect of
adenosine will be a transient decrease inthe ventricular
rate without affecting the tachycardia. Types G and H are
rare; the AVN is not part of their mechanism and adenosine
will not modify them in any way. (Reprinted with permission
from Pinski SL, Maloney JD.14)
AP -Accessory pathway
AVN -Atrioventricular node
LA
-Left atrium
NV -Nodoventricular
RA -Right atrium
However, two patients treated with verapamil experienced subsequent symptomatic arrhythmias
(preexcitation atrial flutter in one and atrial tachycardia in the other). Adenosine unmasked intermittent or latent preexcitation in all instances,
while verapamil identified preexcitation in only
25% of the patients. The investigators concluded
that, overall, adenosine was satisfactory in 100% of
the patients and verapamil in 70% (P< 0.05).
DiMarco et al, studied 46 patients with supraventricular tachyarrhythmias. 25 Adenosine in increments of 37.5 g/kg IV restored sinus rhythm
within 20 seconds of administration in patients
whose SVT involved the AV node (29 of 29). It did
not restore sinus rhythm in patients with intra-
290
Dosage and administration
Adenosine (Adenocard®) is distributed in 2
mL vials containing 3 mg/mL (6 mg total). Rapid
IV administration of a 6-mg bolus given in 1 or 2
seconds and immediately followed by a 10-mL saline flush is recommended. 29 Use of a central IV
line (if available) rather than a peripheral one is
preferred because of its closer deposition to the
heart. If administered slowly in a peripheral line,
adenosine may undergo cellular uptake and degradation before it reaches the heart. Slow, continuous infusion may result in systemic vasodilation,
hypotension, and undesirable reflex tachycardia,
so this method of administration is not recommended for treating SVT. If the arrhythmia persists after 2 minutes, a second bolus of 12 mg is
recommended. The 12-mg dose can be repeated
after 2 minutes. Single doses exceeding 12 mg are
not recommended.
Adverse effects, precautions, and
contraindications
The most common adverse effects of adenosine are flushing (15-20%), dyspnea (12-20%), and
chest pain (7-20%).
28 29
Headache, nausea, cough-
ing, and malaise have also been reported. 30 Many
short-lived arrhythmias, such as sinus arrest, sinus
Journalof the American Association of Nurse Anesthetists
exit block, sinus pause, and ventricular and junctional escape beats, may occur during conversion. 7' 28 Since all of these reactions are brief, usually lasting less than 1 minute, no intervention is
required.
Prolonged sinus pause in patients with SA
nodal dysfunction and an increase in ventricular
response to PSVT in patients with certain types of
Wolff-Parkinson-White syndrome have been reported. 25 Caution is advised when administering
adenosine to patients with these disorders.
Adenosine may induce bronchoconstriction0o
and although no formal studies are available, it
would appear prudent to use it with caution, if at
all, in asthmatic patients. No absolute contraindications have been reported.
Drug interactions
Several drug interactions are of interest. Adenosine should not be used in patients receiving
methylxanthine therapy, i.e., theophylline and
caffeine. 25 Methylxanthines are competitive antagonists of adenosine at cell surface adenosine receptors and completely block the drug's electrophysiologic effects. No data is available regarding the
effect of beverages containing xanthine, such as coffee, tea, or cola, on the efficacy of adenosine. 14
Dipyridamole (Persantine®, etc.) competitively inhibits the transport of adenosine into cells,
thereby preventing its subsequent deamination to
inosine. 31 This blockade of uptake and metabolism
by dipyridamole results in a potentiation of adenosine's clinical effects. 32 To avoid potentially severe
bradycardias, initial doses of adenosine should not
exceed 1 mg in patients receiving dipyridamole.
Other bradycardia-producing drugs, such as calcium channel blockers, beta receptor blockers, and
digitalis, may potentiate the negative chronotropic
and dromotropic effect of adenosine, 28 therefore,
dosage reductions would appear prudent.
Preliminary data suggests that diazepam and
possibly other benzodiazepines may also inhibit
cellular uptake of adenosine, thereby potentiating
its effect. 30
Anesthetic implications
The use of adenosine for termination of PSVT
during anesthesia has not been reported. Discussion of the use of any antiarrhythmic agent during
anesthesia should be preceded by three cautionary
statements:
1. The etiology of the arrhythmia should be
explored prior to instituting any treatment. Adequacy of ventilation, depth of anesthesia, acid-base,
and fluid and electrolyte balance should be verified before appropriate therapy can be formulated.
June 1992/Vol. 60/No. 3
2. The multiple drug administration which
constitutes modern anesthesia practice may result
in unexpected drug interactions.
3. Analysis of complex arrhythmias with the
commonly used 3- or 5-lead ECG system during a
surgical procedure is a less than ideal setting for
proper diagnosis and treatment. Nonetheless,
rhythm disturbances which compromise hemodynamic stability or may progress to more severe dysfunction must be addressed. The rapid onset, short
duration, high efficacy, and safety of adenosine
would appear to make it an excellent option for
anesthetic use.
The use of adenosine infusion for controlled
hypotension, as compared to nitroprusside during
cerebral aneurysm surgery, has recently been
reported. 33 Hypotension was achieved with
252 ± 55.8 g/kg/min adenosine infusion. Unlike
nitroprusside, adenosine did not produce renin release and rebound hypertension after discontinuation of the infusion. Significant reductions in renal
blood flow and glomerular filtration rate, which
may be problematic in patients with impaired renal
function, were observed. Four of 15 patients developed AV conduction disturbances. One patient exhibited first-degree AV block, two had nodal
rhythms, and one had third-degree block followed
by atrial flutter. All reverted to normal rhythm
without treatment after adenosine was discontinued.
Sietz et al reported that adenosine produces a
49% reduction in halothane MAC in dogs. 34 Other
studies in animals have demonstrated sedative, analgesic, and anticonvulsant properties which may
be of interest to anesthesia practitioners.
5
36
Summary
Adenosine adds a unique new choice to the
list of drugs available for the treatment of SVT. Its
quick onset and ultrashort duration of action allow
for rapid control of reentrant forms of PSVT while
minimizing prolonged undesirable effects. Although reports on its intraoperative effects have
yet to emerge, it would appear to offer the benefit
of a high efficacy with little chance for prolonged
drug interactions with the anesthetic agents. Investigations into the sedative, hypotensive, and other
potentially useful actions of adenosine are continuing.
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1. Drury AN, Szent-Gyorgyi A. The physiological action of adenine
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heart. JPhysiol(Lond). 1929;68:213-218.
(2) Dimarco JP, Sellers TD, Berne RM, et al. Adenosine: Electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation. 1983;68:1254-1263,
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(3) Griffith MJ, Linker NJ, Ward DE, Camm AJ. Adenosine in the
diagnosis of broad complex tachycardia. Lancet. 1988;1:672-675.
(4) Moser GH, Schrader J, Deussen A. Turnover of adenosine in
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(5) DiMarco JP, Miles W, Akhtar M, et al. Adenosine for paroxysmal
supraventricular tachycardia. Dose ranging and comparison with verapamil. Ann Int Med. 1990;113:104-110.
(6) Schrader J, Berne RM, Rubio R. Uptake and metabolism of adenosine by human erythrocyte ghosts. Am ]Physiol. 1972;223:159-166.
(7) Klabunde RE. Dipyridamole inhibition of adenosine metabolism
in human blood. EurJPharmacol.1983;93:21-26.
(8) Stiles GL. Adenosine receptors and beyond: Molecular mechanism of physiologic regulation. Clin Invest. 1990;38:10-18.
(9) Burnstock G. Purinergic receptors in the heart. Circ Res.
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(10) Rall TW. Drugs used in the treatment of asthma. In: Goodman
LS, Gilman AG, et al. eds. The PharmacologicalBasis of Therapeutics. 8th
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(11) Schrader J, Rubio R, Berne RM. Inhibition of slow action potentials of guinea pig atrial muscle by adenosine: A possible effect of
calcium influx JMol Cell Cardiol.1975;7:427-433.
(12) Akhtar M. Supraventricular tachycardias. Electrophysiologic
mechanisms, diagnosis and pharmacologic therapy. In: Josephson ME,
Wellens HJ, eds. Tachycardias: Mechanisms, Diagnosis, Treatment. Philadelphia: Lea and Febiger. 1984:137-159.
(13) Zipes DP. Specific arrhythmias: Diagnosis and treatment. In:
Braunwald E, ed. Heart Disease. 3rd ed. Philadelphia, Pennsylvania:
W.B. Saunders. 1988:660-662.
(14) Pinski SL, Maloney JD. Adenosine: A new drug for acute termination of supraventricular tachycardia. Cleve Clin J Med. 1990;57:383388.
(15) Waxman MB, Sharma AB, Cameron DA, et al. Reflex mechanisms responsible for early spontaneous termination of paroxysmal
supraventricular tachycardia. Am ]JCardiol. 1982;49:259-263.
(16) Tavsanoglu S, Ozenel E. Ice water washcloth rather than facial
emersion (diving reflex) for supraventricular tachycardia in adults. Am
J Cardiol. 1985;56:1003.
(17) Garratt C. Comparison of adenosine and verapamil for termination of paroxysmal junctional tachycardia. Am J Cardiol. 1989;64:13101316.
(18) Sung RJ, Elser B, McAllister RG. Intravenous verapamil for termination of re-entrant supraventricular tachycardias. Ann Intern Med.
1980;8:55-57.
(19) Chew CY, Hecht HS, Collett JT, et al. Influence of severity of
ventricular dysfunction on hemodynamic responses to intravenously
administered verapamil in ischemic heart disease. Am J Cardiol.
1981;47:917-922.
(20) Kieval J, Kirstein EB, Kessler KM, et al. The effects of intravenous verapamil on hemodynamic status of patients with coronary artery disease receiving propranolol. Circulation. 1982;65:653-659.
(21) Belhassen B, Viskin S, Laniado S. Sustained atrial fibrillation
after conversion of paroxysmal reciprocating junctional tachycardia by
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(22) Jacob AS. Fatal ventricular fibrillation following verapamil in
Wolff-Parkinson-White syndrome and atrial fibrillation. Ann Emerg
Med. 1985;14:159-162.
(23) Klein GJ, et al. Ventricular fibrillation in the Wolff-ParkinsonWhite syndrome. NEngJMed. 1979;301:1080-1085.
(24) Nagelhout JJ. Cardiac pharmacology: Calcium antagonists.
AANA Journal.1988;56:367-374.
(25) DiMarco JP, Sellers TD, Lerman BB, Greenberg ML, Berne RM,
Belardinelli L. Diagnostic and therapeutic use of adenosine in patients
with supraventricular tachyarrhythmias. J Am Coil Cardiol. 1985;6:417425.
(26) Overholt ED, Rheuban KS, Gutgesell HP, et al. Usefulness of
adenosine for arrhythmias in infants and children. Am J Cardiol.
1988;61:336-340.
(27) Rankin AC, Rae RP, Cobbne SM. Misuse of verapamil in patients
with ventricular tachycardia. Lancet. 1987;2:472-474.
(28) Porter SR. Adenosine: Supplementary considerations about activity and use. Clin Pharm. 1990;9:271-274.
(29) Lypho Med, Inc. Adenocard package insert. Rosemont, Illinois.
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(30) Parker RB, McCollum PL. Adenosine in the episodic treatment
of paroxysmal supraventricular tachycardia. Clin Pharm. 1990;9:261-271.
(31) Watt AH, Bernard MS, Webster J, et al. Intravenous adenosine in
the treatment of supraventricular tachycardia: A dose ranging study
and interaction with dipyridamole. BrJClinPharmacol.1986;21:227-230.
(32) Lerman BB, Wesley RC, Belardinelli L. Electrophysiologic effects of dipyridamole on atrioventricular nodal conduction and supraventricular tachycardia. Role of endogenous adenosine. Circulation.
1989;80:1536-1543.
(33) Zall S, Eden E, Winso I, Volkmann R, Sollevi A, Ricksten SE.
Controlled hypotension with adenosine or sodium nitroprusside during cerebral aneurysm surgery: Effects on renal hemodynamics excretory functions, and renin release. Anesth Analg. 1990;71:631-636.
(34) Seitz PA, Mennoter R, Rush W, Merrell WJ. Adenosine decreases
the minimum alveolar concentration of halothane in dogs. Anesthesiology. 1990;73:990-994.
(35) Williams M. Purine receptors in mammalian tissues: Pharmacology and functional significance. Ann Rev Pharmacol Toxicol. 1987;27:
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(36) Daly JW. Adenosine receptors: Targets for future drugs. J Med
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AUTHOR
John Nagelhout, CRNA, PhD, is an assistant professor of Anesthesia and Pharmaceutical Sciences, College of Pharmacy and Allied
Health, Wayne State University, Detroit, Michigan, and a staff anesthetist at Detroit Receiving Hospital in Detroit.
ACKNOWLEDGMENTS
The author would like to thank Valdor Haglund, CRNA, MS, for
his assistance with the electrocardiology concepts and Gail Partee for
preparation of this manuscript.
Journalof the American Association of Nurse Anesthetists
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elyevaluated.
These
orwhen
2Sg/g
In onfornlnduction
whenaunprereedicated
55yearfag~e and
ASA
IorllIrequiren2.0to
changerenoset,
intensity
Nljection does
notcauseuaclinicallysirgecant
effectsotIPRMANInjecton.
DIP~RAIN
and
rardinrespiratoty
tbetitrated
(apprxmately
sril hennsdiazepines
or intramuscular
opeaid&
For
DWR AN Injectionshould
prmdctdwith
odple
(ng,
usedneurmusclarbocking agenits
40mgevery
10seconds)against
theresponstofthe
patient
untithecinicalsigns showethe
onsetstfanesthesia.
Aswth
sedative ordurationatfactiontheracommonly
anesthesia
orsedatione(including
aranhge
interacis wthacomonlyaused
premsdicatiuosor
Nosignificaeteadverse
premedication
wilinfluence
theresponse
to
hypootic
agents,
theamount
oplold
and/orhbenzodizepne
ohserved.
Cwaurlegeuml,
andlocalanesthetic
agerhave heen
agents,
analgesic
agents,
muscle
reaxants,
andexperienced
withthentraenoususe DIPR~IANhInecion
Itis mportattohbetfamilarwith
aninduiondose DIPRMWIAinjection.
ir n dliwliveaninral
nothbeen
promdwith repeisl.
M kur55hpstkIoi5dMetF5IIUIT.AJimTal
aCI~lIstudies have
D~ueto
thereduced
clearance
andhigherbloodleves most
hetometruahing
elderty,
andASAIII or hIpatients.
Sarsonehasp)
mtation
icludedthe
Ames
(using
p .
mutapenicly
anshw
poentil fr muageridtyb
nject fr inducion
accorinmg
20mguevery
10seconds)atfDlPRtVW
15mnglrg(apprraamately
studies
in
a mouse
conversion
using
Sa~cerycexcwevisiae,invitrocytogenetic
thelkelhood
cardiornspiratory test,gene
tothir condition
andresponses.
Arapidholus
shoulddnotbe
used
asthiswdllmcrease
(6
themaximum
human
infemale
ratsatintravenous
doses
upto15mg/kg/day
test.Studios
(See
DOSAGE
ANDADMINISTRATION.)micronucleus
spots,
arway
ohstruction
and/or
oxygen
desaturation.
depression
including
hypotension,
affected
didnot showlImpaired
fertlity. Malefertiliy inratswassnot
to dayl7atfgestation
adminiering
DPPt N
by infusion
orintermttentIVhbolus inductiondoe for2weeksbeforepregnancy
Malnusnesd Aesthulia:
Aesthesia
caobe maintainedby
for5days.
Pregnaney
Cuesy 3:Reproductionestudluries
inadominant
lethal
studyatintravenousodoses
upto 15reg/hg/day
andfrequency
otincrereental
injetos When
wildeterninentheinftusion
rateor theuamount
Thepatientsclinical
response
the
humorinduction
dose)nod
doses 15mg/kig/day
(6
heenperformed
in ratsandrabbits
atlintravenous
pumpsorvolumetricpumpomustbeusedto providecontrolledinfusionrates.
admnirngDPRWMNlInjection by infusn,
Propefol,
hitwever,
hashernshown
tocause
fertilityorharmto
thefetussdue
topropofol.
have
revealed
noevidencedtimpaired
oxide
variable
ratelinfusson
with60%-70% nitrous
Continuous
ltunlue: DIPAt'AN
Injection
100 to200iag/k/mnnadministeredrina
(or
periodindamsotreated
with15mg/kg/day
ratsandrabbits
anddecreased
pap
survival
duringthelactating
matereal
deathsoin
should
general
surgery.
Mantenance
hyinfusion
atDIPRPAN
Injection
andoxygen
provides
anesthesia
for patients
undergoing
activty (anesthesia)afthe
drugonthe motherisprobatily
6itimesthe recommended
humaninductiondone).Thepharmascological
orcontinuous
anesthesia
during induction
phs.
immediatulyhfolow induction
done
in order
toprovide
satisfactory
in pregnant
arehowever,
noadequate
andwell-controlledstudies
effects
seenintheoffspring.
There
fortheadverse
aregeneralyrequired
(150
to200pg/g/nm) torthetfrsti1D
followingtheinduction
dosehigher
ratesatintuson
thisinitalperiod
thsdrip shouldhbeused
duderengnac
arenotdalways
predctveaothuman
responses,
wen.rBecause
animal
reprdction studies
50%duringth hal-hur
Changes
invital
to15miniuten.
Infusion
rates
should
suhsequentyhbedecreased
30%omtetrlc.icuding
cesareansectin
dlveis
aud
tnjection
isonot
recommrendedfbro
only
ifcdearly
needed.
aber
aresponse
to surgical
stimulation
or
signs(increases
in poise
rate,
bloodpressure,
sweating
and/or
tearing)
thatindicate
atDIPRIVAN
Injection
anesthetic
agents,
theadministration
crosses
theplacenta,
andas othergeneral
DIPRIVAN
Injection
25mrg
(2SmL)to50mg (.0 ret)incremental
houses
by theadiniotration
atDIPRIVAN
Injection
anesthesia
mayhecontrolled
depression.
NeagMlhers: DIPOTAN
Injectionsnot
foruse
in nursing
mothers
mayb
hassociated
withneonatal
asanopinid,
Ifvital signchanges
arenot
controled
ateratfieminute
period,
otherrmeesssuch
and/or
bymicreasing infusion
rate.
oralabsorption
amountsofpropofol
DIPRIVAN
hashbeen
tobe
humanmilkandtheeffectsuof
because
procedures
(ie,
tocontroldthese
Forrereor
surgical
vasodilator
orlinhalation
agent
therapy
shouldheinitiated
hariturate,
patients
because
safety
and
effectiveness
DIPRIVAN
isnnot
pediatric
are
not
known.
Pediticen:
rateDIPRIVAN
Infusion
toprovide
satisfactory
anesthesia.
nitrous
maide
canhecominedwithavarahle
hody
surtace)
60D%-70%
derved
fromcontrolled talsandworldwide
ADVERSE
REA OS:vese event
informations
have
nottibeotetaished.
prcedures
(leintr-adominal)suppementation
wth analgesic
agents
shouldbe
considered
to prvide
Withmoeshinatingsurgical
clinical
study
helow,
rates themorecommon
events
US/Cunadian
marheting
experience.
Inthedescription
isotprovided,
administration
rate(s)atofMW~A
profieWhen
supplementiaion
withnitrusradide
asatistactory
anesthetic
andrecovery
8 millon
patents;
threre
areinsufficlent
publicatosoand
marketing
esperence
inover
frequent
events
arederived
principallyfrome
Less
Intuslon
rates
should
alwaysnbe
titrated
downward
Injection
and/or
opinlds
shouldheincreased
in order
toproideadequate
anesthesia.
profile
trom
150 patients
Inthe
esti'mate
thein
incidence
rates.
The
adverse
experience
unaccurate
clmnical
signsatlfght
anesthesia
untilamild
response
tosurgical
stmulation
isobtalned
inorder
toaold administration datatosupport
intheahsenceat
(seebeow).
withDIPRFAN
Injection
during
anesthesia
trialsissimilar
totheprofileestalished
MAC
sedationcinical
Generally,
rates 50to100 g/tinnshould heachieveddBuring US/Canadian
atrates
higher
thanarecinicallyonecessary.
ofDIPRtVAN
Inection
hypseentilation,
events
incladedcough,upperairwayobstruction,upota,
slgnificantrespiratory
DuringMACsedationclinicalhials,
maintenance
in order
tooptimize
luhrnelonM
slos: IncrereentsaotDPRWN
Injection
25mg(2SmL)hi50mg(58
Injectionhfor
in more
than3% patients
recevng
events
which
occurred
and
dyspoea.
Themostcommonradverse
patients
undergong
general
surgery.
Theincrementalhboluses
shouldbe
adninistered
mL)meayheadrministered
withnitrousmuxdelin
events
ndinjection
sitepanorhotes. The
estimatesatfadverse
MAC
sedation
included
hypotension,
nausea,
headache,
DIPRVAN
tnection
hasheen
used
with
whenchanges
invitalsigns
indicate
a
tosurgical
stimulation
orlightanesthesia.
studies.
These
studiesereconducted
Injectionare
derivedlfrmmreportsaot
2588patients
includedin
theUS/Canadian
forODIPOPAN
and
suchasatropine,
scopolamine,
glycoyrrsati ddrazepam,
depolarizing
a
coreonl usedin anesthesia
andvaidousnother
anestheticisedative
agents.
varyng
lengthssurgical/dlagnestic
procedures
aswithinhalational
andregional
unesthetic
agents.
Intheelderly,
usingavariety premedicants,
nondepolanazng
muscle
andopioid
analgesics,
aswell
adverse
eventswerereportedIn
patients
treated
wth DPRVA Injection.
Mostadverseeventsewere
milduand
transient.
Thefollowng
should
notbe
used
asthiswillincrease
cadiorespiratoey
effects
incluiding
hypotension,
apoea,
airwayohstruction
rapid
bolusdoses
1%-Alt mvess
regardles
Theyarepresentedwithineachbiodysysteme
in srder
ofdecreasinghrequency.
InciddsceGuntuethas
healthy
adults(<
55
Most
elderty
patients a
cftherecommended
maintenance ratesor
and/or
oxygen
desaturation.
Candloveseelu: IHypotenson'
(see
alsoCLINICAL
oftcasalty, derived re.clmical trials.Bedy as a Whole: Fever.
Injection
isadministered
fursedation,
rates
yeurs)
to5 to100pi
re/in
(3to6 mg/hg/h).
MAC
SEDATION:
When
DIPRIVAN
tte ratesocIlPRtstN
Injection
admrinstration
toclinicalresponse.
In rnostpatients
admooitrationshouldheiindhtidualized
andtitrated
B ragcida,
) bitnpAdmnlCapng
Hypertension,
Arhythmia.
CmaNrvsmSsemu:
aSl:Pi'wuin/tnrg
Movement',Headache,
epse
itcoughg
initiationMAC
sedation,
slowlatusion
or
used
furrmalntenance
general
anesthesia.
During
will heappoimately 2% ofthone
events
is 1%-3%;
*3% to
d Apnd,:Rash. Incidence
atunmarked
(netalsoCLINICAL
PHARMACLOGY).Shius
Cough
rateinfusion
Duringmaintenance
sedation,avariable
techniquesarepreterabile
over rapidbolusadministration.
sow rjection
trIals.
(Adverse
events
1%-CometlRelatioskibp
Pruhable,
deiheud
9%;,"10% orgreater.
IncidenceLameihas
In elderly
deiltatedandASA
Ill orP/patients,
rapid
(singleor
is preferable
over intermittent
bhidandose
adninltration.
Pain,Awareness,
Disorder,
Extremelties
in theliterature,
notnseen
Inclinica rials,areXmt) BodyaaWhele: Peritatal
UInad55hMb
sedation.
(SeeWARNINGS)
Arapidbelme juentlennnecall
holundose
adrinedtration
should
reot
heusedforMAC
Reaction.
Cardsvseular:
Drug
Effect,NeckRigldiy/Siffess, Trank Palo.
ChestPain,Increased
apnom
ep ar lwy obstrucionus
sdlurmwn iatneulun. lltlatuutdMAC
cwrdlermplealedpron
Inluidng
Depression,
AtrialContractions,
AbneormralECG,
Segment
Premature
Ventricular
Contractions.
Syncope,
Premature
w dcotelymonitoung
cardorespnatory Tachycardia,
injection
method
maybe
utlized
asedation,
eitheranifsinoa slow
Satit: forthionho
Celtnl
Block,Second A-VBlock.
Mycardial
Infarction,
Heart
Block,Atrloventrlcular
Bundle
Branchok, Extrasystole,
sedation
maybe intiated
hyrfusing
DWRFAN
Injection
at100
telo
150/hg/mn (6tofi g/g/)
function.W/Ohtheinuion method,
Chils/Shivering,
Somnolence,
CbiMclon~ ic Movement,
Hypertonla/Dystonla,
Nervum
Swlus: Btclng/JeringlThrashing,
Witho
andhttrating
to desired
levelofsedation
whiecosely
moritoing
torapeoofa3 to5minutes
Meaning,
Rigidity,
Combtativeness,
Tremor,
Agtation,
Confusion,
Detrin, Paresthesia,
Ahorha Dreamo,
Euphoria,
will require
gk admrinistered
over 3 to5 minutesandtitratedto clinical
injectionmethodfor inithation,patients
Il
stt S au:rigNuretiess, Coldness,
Depression.
DIusWMmHypemsalhoation,
Dry Mouth,Swanowing,
Enlarged
Parotid.
sedated
and
the
patientsuwill
headequately
WhenDIPROWN
Injection
isadinisteredslwyoe3 to ides, most
Discomfort,
Phebitis,
Hives/tchinp,
Rerdness/Olscoloration.
Mtheltliirtloml yefpma ucleeea:Mrda
athighpasma
levels.
Intheelderty
cardinespiratory
effects
occurring
while
minimizing
peak
drugeftect
canheachieved
Wheezing,
Dyspota,
Hypoventia
ior,
Upper
Al Otistruction,
PHARMACOLOGY),
Replrsry: Apea((seeasoCLINICAL
notbe
used
forMACsedation.
(See
(singe
or
hlsdodse
adiunistration
should
debiltated,
and
ASAIbmorlV
patients,
rapid
Hyperventilation,
ypoxia,
Pharyngitis.
SkisseudApedg: Flushing,
Buring
in
Snetting,
Tachypoes,
Bronchou
pasm,
and
the
dosage
at
DIPROSAnfecrio
should
he
reduced
to
WARNINGS)
Therateatadninedration
shouldheover3-5
Uregeelisl:hona
Urine
Diplopiu,
Taste
Perversion,
EyePain,ilnthas.
Urticaria,
Pruritus.
Special
Sousu:
Aretiyopia,
invitalsigns.
(See
patients
according
to condition,
andchanges
approximate
80%attheadultdosage
in these
cl.inl trials.(Adverse
events
Icidece Lesthan
1%- Caal Relatleehlp
Unknuws,
dervedfrom
Retention,
GeenUrine.
in
atsedation,
avariable
rateinfusion
method
Maluisuance
d MAC
Sdutieu:
Formaintenance
DOSAGE
AND MINISTRATION.)
Blgemry
are
las WhelAuisMfid.Cudlsueeelu'J/hrlal~hilation,
intheltieratur,
in
requiremaintenance
generally
prferabileoer an rtereittent
holes
donemethod.Withthevarablerateinfusionmethod,
les:
Emotional
SeprawinhriciTuhcardi,
Mocwt
isieena.
Hemmorrhage,
Edema,
\tintricutarFibhellaton,
ratesshould
sedation
maintenance.
Infusion
(1.5to4.5mg/hg/h)
during
thefirst10to 15
rates 25to75 jag/hg/nan
atl, flaiii
tlldrarc
Seizures,
C
Insomia, Genealieeldand
Localized
Anety
to
effect,
allow
andadjusted
tocinical
Intitrating
overtimeto25to50 jag/hgmn
suhsequentyhbe
decreased
R I
Metis N set:Hypeehalemia
Diarhra.
yrrpaifkCogulaionDisorder
Adnorna
atclinical
rates
should
always
hetitrated
downward
inthe
ahsence
2 minutes
foronsetofpeak
drugeftect.
Infusion
apprioreatlehy
Ear
Pain,
Urgelta:
L
andAppendam hDaoresis,
C
Hyeei. Speial Senee:
Larynpoxpusre.
Skhn
administrationaotDIPRIVAN
Injection
areotined inonterto
avoid
sedative
until rid responses
totimulation
signsof
light
sedation
o
trarhretirg
hashbeen
as
arest
mg
those
adverseevents
lstd
oloigadveseevent
atDIPRIVaAN
Injection 10
Oh uri. Inadditionto
Ofthe
intermittent
botlandose
method
isused,increments
atrates
higher
than
areclinically
necessary
shouldhbeindividualized
and
AND
ADMINISTRATION:
Dosege
andratedfadministration
experience:
amorous
hehavior.
DOSAGE
edation
Wth the
intermittenthbolus
methodatn
andtitrated
todesired
levelatnsedation.
canheadministered
(1.rel) or20mg(2.0Dm1)
age,ASA
concomitant
medications,
tclincallyreevant factorsncludingpreinduchiouand
tothedesiredffect
accordng
transiet
increases
in sedation
depth,
and/or
prolongation
ofrecovery. titrated
maintenance
there
isthepotential
forrespiratory
depression,
Theisllswlegleasbhnnvlatsdduunssgso
saladniiaturslIdresli
physical
classification
and
thepatient.
admnarstration
should
nothbe
used
forMAC
ASAIIIorIVpatients,
rapid
(single
or
housrdose
Intheuelderfy,
debiitated,
and
Pltois
dmnlamrtg
DIPRMN
Injet
nnIis
which
iseolyleiseaded
gue
lIthe
Injettle.
0%
should
hereduced
toappesxdmatehy
tedosageaofIPRWNInjection
ratedfadministration
and
sedation.
(See
WARNINGS)The
Imr~ea
sl
alndheaus lutu
l etfwith thespeclis
dssgeuandisskts nnmeibsdsllld
AND
responses,
andcharges
Invitalsigns.(SeeDOSAGE
patients
according
totheircondition,
of adultdosage
in
ledvdalalsetfDagsoo ee le theeldehly,
du~lblod andASA
II
Vpattents,
InaiheCONICAL
PHARMACDLDYofMAC
sedation
duringuriatigntc
adminstered
assthesole
agent
formaintenance
DIPRPAN
Injecion
canbe
AOMINISTRADO)N)
rapidhlus
doem
should
eathesmadithe mehodesdndfslsatslu.
dasenlhed
beow. (Se MIRNINB&)
increase
the
wthoproid
and/or
herzodiazepree
medications, agents
procedures.
WhenDIPRIVA
sedation
insupplemented
Drag nteractions)
a shower
recoveryprotfe.(SeePRECAUTIONS
andrespiratoryneffects
atDPRPANandmayalsoresufltin
sedative
at
furhothreduction
and/or
maintenunce
Injection
is anIVaesthetic
agent
that
canheused
INDICATIONS
AND
UGAE:DIPRIVAN
Dosage
shouldheindividualized
and
Induction
Injection,when
administered Aneths
fr inpatient
andoutpatient
surgery.
DIPRFAN
spart
anesthetic
technique
anesthesia
Adltn: Mosopatients
require
2.0to2.5rmg/kg
(approximately
40mevery 10secondnsuntillinduction
during
diagnostic
pscedures.
DIPRTAN
anesthesia
care(MAC)
sedation
initiate
andreaintain
monitored
IVasdirected,
canheusedto
onset.
in patients
andergoing
surgical
procedures.
reconjunction
withlocal/reglonal
anesthesia
Injection
may
alsoheused
forMAC
sedation
1.On 1.5mg/hg(approximately
EderlyDehbllalmdasad
ASAIIIuorIV Patloeui:Most patientsrequire
increased
intracranial
pressuoreor
atths timein
patientsuwith
isnotrecomemended
fornuse
DIPRIVAN
Injection
(SeePREAUIONS.)
20mgawery
10seconds
untilinduction
onset).
patients.
in nursing
mothers,
andin pediaric
in obistetrics
including
cesarean
section
deliveries,
impaired
ceretiral
Forcomplete
dosage
Information,
seeCLINICAL
PHARMACOLOGYIndividualization
ofDosage.
tsDPRIVAN
Into orois
inpatitstith aknonrhypersensitivity
DIPRIVANtIinjection
iscontraindicated
CONTRAINDICATIONS:
clinicaleffect.
Variable
rateInhaler-titrated tothedesired
Maintenance
rlisre dunsllad
M IN1SS
Fouws l sssssu
orsedationaecontraiedicated.
comeponent,
orwhen
gral anesthesia
100to 200 ja/kg/rein
(0 to 12mg/hg/h).
Anstheia: stausionAdults':Most
eiansndlhulu
Inlieaislnlshlnatmn
hesadmnuesd
sulpbysesm
sedatisn,
PRflINleuidlnuhud
can(MAC)
Elderty,
and AM Ill enIV Patiens: Most patients require 50 to 100 jag/hg/rein
sadaiittie
Putlel sdheeuntinuoumlyusunllosud
ry
L al epeueduet
andat luvolvud
ilutheundstd
(3to6 mg/hg/h).
nmethbeheudsluly
sutelinst
at ilvt Iseynsssist/
WM
'sadutwun
da pin
br mshdnmaaes
notheused
during
bolusadmmintration
should
rapid
(single
or
and
ASAhII
or I patients,
In elderly,
sealtabla
Maintnance
of
Increments25mgto50mgusneeded.
hypotension,
apnea,
aneway Anesthesia:
cardrespratry depresion
including
order
tominimiaze
undesirale
anesthesia
orMAC
sedationn
general
PHARMACOLOGYdosage
information,
seeCLINICAL
Forcomplete
Involved
theconduct
monitoredhypersonisnot
MACsedation
patients
shouldhecontinuiously
obstructionand/oroxygendesatsration.
Bolan
Individualization
Dosage.
Interreltteut
should
heimmeiteyavalatile andpovidedwhereclnically
ofthesurgicalordiagnosticprocedure,oxygensupplementation
hoindividualized.
Ieltiatonef
Dosage
andrateshould
montored
for early
signsothypotension,
hecontinuously
inallpatients.
Patientsushould
should
hemontored
andoxygen
saturation
Slow
infusion
orslowinjection
techniques
arepreferable
overrapidholus
administration.
Most
followngrapidinitiation
MACSedatius
Adults':
eftectsamorelielytooccur
These
cardinrespiratory
oiygen
desaturation.
airreayotistructionand/or
apnea,
of0.5mg/hg
150jag/kg/rein
(61t09
mg/kg/h)
ora slowinjection
patients
aninfusion
of10010o
IVpatients.
DIPRIVAN
debilitated
and
ASAlllIor
especially
intheelderly,
maintenancenboluses,
(hoading)
bousesorduringsupplemental
ownr
3
to
5
minutes.
coepatildy
has
not
been
estalished.
should
rot
be
coadmninistered
through
the
same
hIVcathieter
with
or
plasmahbecause
Inection
ASAII Patleuis:
Most
patients
requre
dosages
similar
toaduts,hotmust
Ederly,
Dsilleldsand
haveuoccurred
withblood/pasma/serum
oftheemulionvehicle
thatagregtesatfthe
goular comeponent
Invtr stshave
shown
orslowinjection
andnotasarapid
bolus.(Sen
WARNINGS.)
hegiverasaslowinfusion
hetitrated
toclinicaleffect.
Dosage
andrateshould
Pli11ngele
Maliteannes
mineqas (SeI e EANDADMINISTRATION,
HnigPeuudrtl luusisssaest)
preferable
overanintermittenttbolus
technique.
Most
patients
Adults:
Avaniable
rateinfusion
technqueoi
MACSedaton
ther
advesm
conaesu
Inetloneueplesand/ur
popdsrueusayesstin
emlcrobal
entadation cawidngfevsti
handlng
orincremental
holosidoses
of110
mgor
aninfusion25tol75jag/kg/rein
(1.5Sto
4.5mg/hg/h)
maintenance
rate
Alovr induction
doneandaslower
Genrul:
isIls-theuussuln
g Aitnes.PRIECAUIONS:
which
coudteed
E0mg.
PHARMACOLOGY-Indivrduahization
(SeeCLINICAL
debilitated
sodASAIIIxrIVpatients.
should
heusedinelderly,
adminstration
the
adult
dose.
Elderly,
Dehlltasdsend
AEA
IIlor
IV
Most
patients
a
20%
reduction
Treatment
may
hypotension
and/or
tradycardia.
signs significant
meonitored
forearly
shouldhecontinuously
ofDosage.)(Paients
A rapid(single
si
holus
doseshould
nothouned.
(SeeWARNINGS.)
Forcomplete
dosage
ofatropine.
useofpressor
agents,
oradministration
oflowe extremities,
therateofintavnousfluid,elevation
include
increasing
information,
seeCLINICAL
PHARMACOLOGY-Individualization
ofDosage.
IPRIaAN
mayherequred.
Because
Ventilatory
suppoxt
persist
forrmore
thant60seconds.
Induction
andmay
Aprn
occursduing
hprlipopionnnemia 'Adults-healthy,lessthan55yearsofage
lipid
metabiolismesuch
as pomary
wthdisordersof
caution
should
heenarcisedinpatients
Injection
osaromuiion,
institstion
areauestablishedhfnroach
surgery
fordischarge
frmthe recoveryday
The
clinica
criteia
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and
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diabetic
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of
classified
of
of
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of
Induction,
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ofanesthesia
oftundesirable
Increase
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resultiIn
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otintravenous
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mutaion/gene
Injection
injecton.
the
creaxants).
recommended
times
During
responsible
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DsOWe.OIPRVA
ightening
with
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ofsmall
reported
escreted-in
responses.
Injection
recommendedfornisein
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of
represent
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of
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the
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ot
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o
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rlV
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Pad"ui: require
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of
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I'.in
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rofl®
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for injection se'
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110
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W
CRCA
PAA
ETR
INSLCTN
fori icio
THE LOGICA CHOICE FOR NEUROMUSCULAR BLOCKADE
ORGANON INC.
N bc oA a r WESTORANGE
See following page for brief summary of prescribing information.
NEW JEY
0
Norcuron
(vecuronium bromide)forinjection
Before prescribing, please consult complete product information, a summary of whichfollows:
THIS DRUGSHOULDBEADMINISTERED
BYADEQUATELY
TRAINEDINDIVIDUALS FAMILIAR WITH
ITS ACTIONS,CHARACTERISTICS,
AND HAZARDS.
in patientsknownto havea hypersensitivity
to it.
CONTRAINDICATIONS:
Norcuron® is contraindicated
SHOULD
BEADMINISTERED
INCAREFULLY
ADJUSTED
DOSAGE
BYORUNDER
THESUPERVIWARNINGS:
NORCURON®
ANDTHEPOSSIBLE
COMPLICATIONS
THAT
SIONOF EXPERIENCED
CLINICIANS
WHOAREFAMILIAR
WITHITSACTIONS
MIGHTOCCURFOLLOWING
ITSUSETHEDRUGSHOULD
NOTBEADMINISTERED
UNLESSFACILITIES
FORINTUBATION,
THERAPY,
ANDREVERSAL
AGENTS
AREIMMEDIATELY
AVAILABLE.
THECLINICIAN
ARTIFICIAL
RESPIRATION,
OXYGEN
MUSTBEPREPARED
TOASSISTORCONTROL
RESPIRATION.
TOREDUCE
THEPOSSIBILITY
OF PROLONGED
NEUROMUSCULAR
BLOCKADE
ANDOTHERPOSSIBLE
COMPLICATIONS
THATMIGHT
OCCURFOLLOWING
LONG-TERM
USEIN
INCAREFULLY
THEICU,NORCURON®
ORANYOTHER
NEUROMUSCULAR
BLOCKING
AGENT
SHOULD
BEADMINISTERED
ADJUSTED
DOSESBYORUNDER
THESUPERVISION
OF EXPERIENCED
CLINICIANS
WHOAREFAMILIAR
WITHITS
ACTIONS
ANDWHOAREFAMILIAR
WITHAPPROPRIATE
PERIPHERAL
NERVE
STIMULATOR
MUSCLE
MONITORING
TECH(Eaton-Lambert)
NIQUES(see PRECAUTIONS).
Inpatientswhoareknownto havemyastheniagravisor the myasthenic
and use of a
syndrome, smalldoses ofNorcuron® mayhaveprofoundeffects.Insuch patients,a peripheralnervestimulator
ofmuscle relaxants.
smalltest dose maybe ofvaluein monitoringthe response to administration
PRECAUTIONS:
blockingeffectin
significantprolongation
ofneuromuscular
Renal Failure: Norcuron® iswelltoleratedwithoutclinically
conditionsin anephric
patients withrenalfailurewho havebeen optimallypreparedforsurgery bydialysis. Underemergency
if anephric patientscannot be preparedfornonofneuromuscular blockagemayoccur;therefore,
patients some prolongation
should be considered.
electivesurgery,a lowerinitialdose ofNorcuron®
associated withslowercirculation
timein cardiovasculardisease, old age,edematous
Altered Circulation Time: Conditions
states resultingin increased volumeofdistributionmaycontributeto a delayin onset time,thereforedosage should not be
increased.
experience in patientswithcirrhosis orcholestasis has revealedprolongedrecoverytimein keepHepatic Disease: Limited
ing withthe rolethe liverplays in Norcuron®
metabolism
and excretion.Datacurrentlyavailabledo not permitdosage
recommendations in patientswithimpairedliverfunction.
blockingdrugs to faciliLong-term Use in I.C.U.: In theintensivecareunit,in rarecases, long-termuse ofneuromuscular
tate mechanicalventilationmaybe associated withprolongedparalysis and/or skeletalmuscleweakness thatmaybe first noted
Typically,
such patientsreceiveotherdrugs such as broadspectrum
duringattempts to weansuch patients fromthe ventilator.
imbalanceand diseases whichleadto electrolyteimbalance,
antibiotics, narcotics and/or steroids and mayhaveelectrolyte
any ofwhichmayenhance theactions of a
hypoxicepisodes ofvaryingduration,acid-base imbalanceand extremedebilitation,
forextendedperiods frequently
developsymptomsconsistent
neuromuscular blockingagent. Additionally,
patientsimmobilized
withdisuse muscle atrophyTherecoverypicturemayvaryfromregainingmovementand strengthin allmuscles to initialrecovthen to the remaining
muscles. Inrarecases recoverymaybe
ery of movement
of the facialand smallmuscles ofthe extremities
Therefore,
whenthereisa needforlong-term
overan extendedperiodoftime and mayeven,onoccasion, involverehabilitation.
thebenefits-to-risk ratioofneuromuscular
blockademust be considered.Continuousinfusionorintermechanical ventilation,
mittentbolus dosing to support mechanical
ventilationhas notbeen studiedsufficiently
to support dosage recommendations.
NERVE
STIMULATOR
TO
INTHEINTENSIVE
CAREUNIT,APPROPRIATE
MONITORING,
WITHTHEUSEOFA PERIPHERAL
PROLONGABLOCKADE
ISRECOMMENDED
TOHELPPRECLUDE
POSSIBLE
ASSESSTHEDEGREE
OFNEUROMUSCULAR
TIONOF THEBLOCKADE
WHENEVER
THEUSEOFNORCURON®
ORANYNEUROMUSCULAR
BLOCKING
AGENT
IS
BEMONITORED
CONTINUTHATNEUROMUSCULAR
TRANSMISSION
CONTEMPLATED
INTHEICU,ITIS RECOMMENDED
STIMULATOR.
ADDITIONAL
DOSES
OF
ADMINISTRATION
ANDRECOVERY
WITHTHEHELPOFA NERVE
OUSLYDURING
NOTBEGIVEN
BEFORE
THERE
ISADEFINITE
ORANYOTHER
NEUROMUSCULAR
BLOCKING
AGENT
SHOULD
NORCURON®
SHOULD
BE DISIFNORESPONSE
IS ELICITED,
INFUSION
ADMINISTRATION
RESPONSE
TOT ORTOTHEFIRSTTWITCH.
CONTINUED
UNTILA RESPONSE
RETURNS.
diseasemayposeairwayand/or
Severe Obesity or Neuromuscular Disease: Patientswithsevereobesityorneuromuscular
blockingagentssuchas Norcuron®.
specialcarebefore,duringand afterthe useofneuromuscular
ventilatory
problemsrequiring
Malignant Hyperthermia: Manydrugs used in anesthetic practicearesuspected ofbeingcapableoftriggeringa potentially
dataderivedfromscreening
Thereare insufficient
fatal hypermetabolism ofskeletalmuscleknownas malignanthyperthermia.
is capableoftriggeringmalignanthyperthermia.
in susceptible animals (swine)to establish whetherornot Norcuron®
mustbe accomC.N.S.: Norcuron*has no knowneffecton consciousness, the painthresholdorcerebration.Administration
panied byadequate anesthesia orsedation.
blockingeffectofNorcuron®
ofsuccinylcholine
mayenhance the neuromuscular
Drug Interactions: Prioradministration
the administration
of
is used beforeNorcuron®,
injectionand its durationofaction.Ifsuccinylcholine
(vecuroniumbromide)for
as the intubating
effectshows signs ofwearingoff.Withsuccinylcholine
Norcuron®should be delayeduntilthesuccinylcholine
blockwithclinito producecompleteneuromuscular
agent, initialdoses of 0.04-0.06 mg/kgof Norcuron"maybe administered
beforesuccinylcholine,
in orderto attenuatesomeofthe side
cal durationofactionof25-30 minutes.Theuse ofNorcuron®
has not beensufficiently
studied.
effectsofsuccinylcholine,
act in the
d-tubocurarine,
metocurine,and gallamine)
agents (pancuronium,
Other nondepolarizing
neuromuscular blocking
maymanifestan additiveeffectwhenusedtogether.
same fashionas does Norcuron®, thereforethese drugs and Norcuron®
musclerelaxantsin thesame patient.
and othercompetitive
Thereare insufficientdatato support concomitantuse ofNorcuron®
anesthetics such as enflurane,isoflurane,and halothanewith
Inhalational Anesthetics: Use ofvolatileinhalational
Withthe
blockade.Potentiation
is most prominent
withuse ofenfluraneand isoflurane.
Norcuron®
willenhance neuromuscular
anesthetichas
aboveagents the initialdose ofNorcuron'maybe the same as with balanced anesthesia unless the inhalational
been administeredfora sufficienttimeat a sufficientdose to havereachedclinicalequilibrium.
administration
ofhigh doses of certainantibioticsmayintensifyor produceneuroAntibiotics: Parenteral/intraperitoneal
antibiotics
havebeen associated withvariousdegrees ofparalysis:aminoglycosides
muscular blockon theirown.Thefollowing
polymyxin
bacitracin;
tetracyclines;
and dihydrostreptomycin);
kanamycin,gentamicin,
(such as neomycin,streptomycin,
® ,B;
are used inconjunctionwithNorcuron unexI these or othernewlyintroducedantibiotics
colistin;and sodium colistimethate.
a
possibility.
should
be
considered
ofneuromuscularblock
pected prolongation
of quinidineduringrecoveryfromuse ofothermusclerelaxantssuggest thatrecurrent
Other: Experienceconcerninginjection
blockadehas
paralysis mayoccur Thispossibility must also be consideredforNorcuron'. Norcuron"inducedneuromuscular
animals(cat) Electrolyte
imbalanceand diseases
been counteractedby alkalosisand enhanced byacidosis in experimental
havebeen shownto alterneuromuscular
blockade.
imbalance, such as adrenalcorticalinsufficiency,
whichleadto electrolyte
maybe expectedMagnesiumsalts, administered
Depending onthe natureof the imbalance,eitherenhancement or inhibition
blockade.
forthe management oftoxemiaof pregnancy,mayenhance the neuromuscular
Drug/laboratory test interactions: Noneknown
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-termstudies in animalshavenot beenperformedto
evaluatecarcinogenic ormutagenicpotentialor impairmentoffertility.
studies havenot been conductedwithNorcuron*It is also nol
Pregnancy: Pregnancy Category C:Animalreproduction
capacity
knownwhetherNorcuron'can cause fetalharmwhenadministeredto a pregnantwomanor can affectreproduction
Norcuron'"should be givento a pregnantwomanonlyit clearlyneeded.
Pediatric Use: Infantsunder1 yearofage but olderthan 7weeks,also testedunder halothaneanesthesia, are moderately
presently
more sensitiveto Norcuron"on a mg/kgbasis thanadults and takeabout 11'timesas longto recoverInformation
usage in neonates.
availabledoes not permitrecommendations for
blockingagents as a class consists ofan
Themost frequentadversereactionto nondepolarizing
ADVERSEREACTIONS:
actionbeyondthe timeperiodneeded.Thismayvaryfromskeletalmuscleweakness to
extension ofthe drug's pharmacological
orapnea.
profoundand prolongedskeletalmuscleparalysisresultingin respirationinsufficiency
as withallcurariorm drugs. Theseadverse
blockadeis possible withNorcuron*'
Inadequatereversalof the neuromuscular
untilrecoveryis judgedadequateLittleor no increasein intensity
reactions are managed bymanualor mechanicalventilation
narcoticanalgesics, nitrousoxide,or
of blockadeor durationofactionwithNorcuron is notedfromthe use ofthiobarbiturates,
fordiscussion ofotherdrugs used in anestheticpracticewhichalso cause respiratory
droperidolSee OVERDOSAGE
depression.
Prolongedto profoundextensions ofparalysis and/or muscleweakness as wellas muscleatrophyhavebeenreportedafter
long-termuse to support mechanical ventilationin theintensivecareunit(see PRECAUTIONS).
reactions(bronchospasm,
Theadministration
ofNorcuron*has beenassociated withrare instances ofhypersensitivity
sometimes associated withacuteurticariaor erythema).
hypotension and/or tachycardia,
muscletwitchresponse to
The possibility ofiatrogenicoverdosage can be minimizedbycarefullymonitoring
OVERDOSAGE:
peripheral nervestimulation
blockagebeyondthe
effects.Residualneuromuscular
Excessivedoses ofNorcuron*produceenhanced pharmacological
blockers.Thismaybe manifestedbyskeletalmustime periodneeded mayoccur with Norcuron*as withotherneuromuscular
cle weakness, decreased respiratoryreserve,lowtidalvolume,or apnea A peripheralnervestimulatormaybe usedto assess
the degree ofresidualneuromuscular blockadefromothercauses of decreased respiratoryreserve.
Respiratorydepression maybe dueeitherwhollyor in partto otherdrugs used duringtheconduct ofgeneralanesthesia
such as narcotics,thiobarbiturates and othercentralnervous systemdepressants. Undersuch circumstances, the primarytreatuntilcompleterecoveryofnormalrespirationis
mentis maintenance ofa patentairwayand manualormechanicalventilation
withatropineor glycopyrbromide)injection,neostigmine,oredrophonium,in conjunction
assured. Regonol (pyridostigmine
Satisfactoryreversalcan be judgedbyadequacy
rolatewillusuallyantagonizethe skeletalmusclerelaxantactionof Norcuron*.
mayalso be used to monitorrestorationof
A peripheralnervestimulator
ofskeletalmuscletone and byadequacy ofrespiration.
carcinomatosis,
twitchheight Failureofpromptreversal(within30minutes)mayoccur in thepresence ofextremedebilitation,
or anesthetic agents and otherdrugs whichenhanceneuroand withconcomitantuse ofcertain broadspectrum antibiotics,
isthesameas that
the management
depressionoftheirown Undersuchcircumstances
muscularblockadeorcauserespiratory
hasresumedcontrol
byartificial
meansuntilthepatient
blockade.
Ventilation
mustbesupported
of prolonged
neuromuscular
agent
shouldbe madeto thespecificpackageinsertofthereversal
of hisresration. Priortothe use reversalagents,reference
(vecinformation.
Norcuron®
pleaseconsultcompleteproduct
Beforeprescribing,
DOSAGE
ANDADMINISTRATION:
uroniumbromide)forinjectionisfor intravenoususe only This drugshould be administeredbyor underthesupervision of
in eachcase. The
blockingagents. Dosagemust be individualized
experienced clinicians familiarwiththeuse ofneuromuscular
dosage information
whichfollowsis derivedfromstudies based upon units ofdrug per unitof bodyweightand is intendedto
byvolatileanesthetics and
serve as a guideonly,especially regardingenhancement ofneuromuscular blockadeofNorcuron®
Interactions).
Parenteraldrugproducts shouldbe inspected visually
(see PRECAUTIONS/Drug
by prioruse ofsuccinylcholine
priorto administration
wheneversolutionand containerpermit.
forparticulate matter and discoloration
of muscle
and to minimizethepossibility ofoverdosage, themonitoring
To obtainmaximumclinicalbenefitsofNorcuron®
twitchresponse to peripheralnervestimulation
is advised.
Therecommended initialdose of Norcuronw
is0.08 to 0.10mg/kg(1.4to 1.75timesthe EDre)givenas an intravenousbolus
in 2.5 to 3 minutes
injection.Thisdose can be expected to produce good or excellentnon-emergency intubationconditions
blockadelasts approximately
25-30 minutes,with
afterinjection.Underbalanced anesthesia, clinicallyrequiredneuromuscular
25to 40 minutesafterinjectionand recoveryto 95%ofcontrolachieved
recoveryto 25%of controlachievedapproximately
blockingeffect
45-65 minutesafterinjection.Inthe presence ofpotentinhalationanesthetics, the neuromuscular
approximately
is enhanced. IfNorcuron®
isfirstadministeredmorethan5 minutesafterthe startofinhalation agent orwhen
of Norcuron®
15%,i.e.,0.060 to 0.085 mg/kg.
dose maybe reducedbyapproximately
steady state has been achieved,the initialNorcuron®
of succinylcholine
mayenhance theneuromuscular
blockingeffectand durationofactionofNorcuron®
Prioradministration
to 0.04-0.06 mg/kgwith inhalation
a reductionof initialdose of Norcuron®
If intubationis performedusing succinylcholine,
anesthesia and 0.05-0.06 mg/kgwith balanced anesthesia maybe required.
afterthe
are recommended;
Duringprolongedsurgicalprocedures, maintenance doses of0.010to 0.015mg/kgofNorcuron®
clinicalcriteinitialNorcuron®
injection,the firstmaintenancedose willgenerallybe requiredwithin25to 40 minutes.However,
cumulativeeffects,
doses. Since Norcuron®
lacksclinicallyimportant
ria should be used to determinethe needformaintenance
subsequent maintenance doses, if required,maybe administeredat relativelyregularintervalsforeachpatient,rangingapproximatelyfrom12to 15minutesunder balanced anesthesia, slightlylongerunder inhalationagents. (Iflessfrequentadministrationis desired,higher maintenance
doses maybe administered.)
Should therebe reason forthe selectionof largerdoses in individualpatients,initialdoses rangingfrom0.15mg/kgupto
system
0.28 mg/kg havebeen administeredduringsurgery underhalothaneanesthesia withoutilleffectsto the cardiovascular
beingnotedas longas ventilation
is properlymaintained.
dose of80-100jpg/kg,a continuousinfusionof1pg/kg/min canbe initiUse by Continuous Infusion: Afteran intubating
should be initiatedonlyafterearlyevidenceofspontaneous recovery
atedapproximately
20-40 min later.InfusionofNorcuron®
in the intensivecareunithas not been
fromthe bolus dose. Long-termintravenousinfusionto support mechanicalventilation
(see PRECAUTIONS).
to support dosage recommendations
studied sufficiently
shouldbe adjusted according
should be individualized
foreach patient.Therateofadministration
The infusionofNorcuron®
An initialrateof1pg/kg/min is recommended,
to the patient's twitchresponse as determinedbyperipheralnervestimulation.
infusionratesmay
withthe rateofthe infusionadjusted thereafterto maintaina 90% suppression of twitchresponse. Average
rangefrom0.8 to 1.2 pg/kg/min.
blockingactionofnonInhalationanesthetics, particularlyenfluraneand isofluranemayenhance the neuromuscular
it maybe necessary to
depolarizingmuscle relaxants.Inthe presence ofsteady-state concentrations ofenfluraneor isoflurane,
dose. Underhalothaneanesthesia it maynot be necreduce the rateofinfusion25-60 percent, 45-60 minafterthe intubating
essary to reducethe rateofinfusion.
discontinuation
ofNorcuron®
infusionmaybe
blockadefollowing
Spontaneous recoveryand reversalofneuromuscular
a singlebolus dose.
expected to proceed at ratescomparableto thatfollowing
can be preparedbymixingNorcuron®
withan appropriateinfusionsolutionsuch as 5%
Infusionsolutions ofNorcuron®
glucose in water,0.9% NaCI,5%glucose in saline, or LactatedRingers.Unusedportionsofinfusionsolutions should be
discarded.
table:
InfusionratesofNorcuron®
can be individualized
foreachpatientusing thefollowing
of
InfusionDeliveryRate(mL/kg/min)
0.1 mg/mL*
0.2 mg/mLt
DrugDeliveryRate(jLg/kg/min)
0.007
0.008
0.009
0.010
0.011
0.012
0.013
0.7
0.8
0.9
1.0
1.1
1.2
1.3
0.0035
0.0040
0.0045
0.0050
0.0055
0.0060
0.0065
in 100mLsolution
in 100mLsolution
t20 mg ofNorcuron®
*10mg ofNorcuron®
Thefollowing
table is a guidelineformt/min deliveryfora solutionof0.1 mg/mL(10mg in 100mL)withan infusionpump.
NORCURON®
INFUSION
RATE
- mL/MIN
AmountofDrug
jg/kg/min
40
50
60
0.7
0.8
0.9
1.0
1.1
1.2
1.3
0.28
0.32
0.36
0.40
0.44
0.48
0.52
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.42
0.48
0.54
0.60
0.66
0.72
0.78
PatientWeight- kg
70
80
0.49
0.56
0.63
0.70
0.77
0.84
0.91
0.56
0.64
0.72
0.80
0.88
0.96
1.04
90
100
0.63
0.72
0.81
0.90
0.99
1.08
1.17
0.70
0.80
0.90
1.00
1.10
1.20
1.30
of0.2 mg/mLis used (20mg in 100mL),therateshould be decreased byone-half.
NOTE:
Ifa concentration
(mg/kg)as
the same dosage requirements
Dosage in Children: Olderchildren(10to 17years ofage)haveapproximately
adults and maybe managed the same way.Youngerchildren(1to 10yearsofage) mayrequirea slightlyhigherinitialdose and
mayalso requiresupplementation slightlymoreoftenthan adults.Infantsunderone yearofage but olderthan 7weeksare
on a mg/kgbasis thanadultsand takeabout11,timesas longto recover.See also
moderatelymoresensitiveto Norcuron®
onusage in
presentlyavailabledoes not permitrecommendation
titledPediatricUse.Information
subsection ofPRECAUTIONS
neonates (see PRECAUTIONS).
Thereare insufficient
dataconcerningcontinuous infusionofvecuroniuminchildren,therefore,
nodosing recommendation
can be made.
is compatiblein solutionwith:
Norcuron®
COMPATIBILITY:
0.9% NaCIsolution
Sterilewaterforinjection
LactatedRingers
5% glucose in saline
5% glucose in water
Usewithin24 hours ofmixingwiththe abovesolutions.
priorto administration
whenParenteraldrug products should be inspected visuallyforparticulatematterand discoloration
eversolutionand containerpermit.
HOWSUPPLIED:
waterforinjection,USP).
10mLvials(10mg vecuronium
bromide)and 10mLprefilledsyringesofdiluent(bacteriostatic
Boxesof10
NDCNo.0052-0441-60
22 g 1V4"
needle.
USP).
10mLvials(10mg vecuroniumbromide)and 10mLvialsofdiluent(bacteriostatic
waterfor injection,
Boxesof10
NDCNo 0052-0441-17
NDCNo.0052-0441-15
NOTSUPPLIED. Boxesof10
10mLvials(10mg vecuroniumbromide)only;DILUENT
NDCNo.0052-0442-46
NOTSUPPLIED. Boxeso 10
on
bromide)only;DILUENT
bromide)
20 mLvials(20mg vecuronium
15°-30°C(59°-86°F). Protectfromlight.
STORAGE:
AFTERRECONSTITUTION:
WHICH
ISNOT
BENZYL
ALCOHOL,
* Whenreconstitutedwithsupplied bacteriostaticwaterforinjection:CONTAINS
or refrigerated.
INTENDED
FORUSEINNEWBORNS
Usewithin5 days.Maybe storedat roomtemperature
vial.Usewithin24 hours.
* Whenreconstitutedwithsterilewaterfor
injectionorothercompatibleIV.solutions:Refrigerate
Singleuse only Discardunused portion.
REVISED 1/92
Caution: Federallawprohibitsdispensing withoutprescription
References
1. GalloJA,CorkRC,PuchiP Comparisonofeffectsofatracuriumand vecuroniumin cardiacsurgicalpatients.Anesth Analg.
et al.Vecuronium
does not alterserumhistaminewithinthe clinicaldose
1988,67:161-165. 2. BastaSJ, SavareseJJ, AllHH,
®
JA,
bromide)for
injectionpackageinsert. 4. Kaufman
range.Anesthesiol. 1983,58(3):A2733. Norcuron (vecuronium
effectsofvecuronium:
A dose response studyJ ClinAnesth.
Dubois MY,ChenJC, LeaD.Pharmacodynamic
1989:1(6):434-439.5 Tracrium'Injection
(atracuriumbesylate)packageinsert. 6. ScottRPF,SavareseJJ, BastaSJ, et al.
histaminereleaseand attenuatingthe haemodynamic
response. BrJAnaesth.
AtracuriumClinicalstrategies forpreventing
1985,57:550-553
'Tracriumis a registeredtrademarkofBurroughsWellcomeCo.
Organon
ORGANON INC.
WESTORANGE
NEW JERSEY 07052
Manufactured for ORGANON INC.
By BEN VENUE LABORATORIES, INC. * BEDFORD, OHIO 44146
or by
ORGANON INC. * WEST ORANGE, NEW JERSEY07052
01992 ORGANON INC.
ORG-13842
PRINTED IN USA
FEBRUARY1992