Flumazenil: A specific benzodiazepine antagonist BRIAN J. KASSON, CRNA, MHS Cincinnati,Ohio

Flumazenil is a specific benzodiazepine (BZD) antagonist which inhibits the effects of BZD agonists by competing for the receptor site in the centralnervous system. It has completed clinical trials in the United States and received final approvalfrom the U.S. Foodand Drug Administrationfor release in January 1992. Following intravenous injection, clinically apparentarousalusually occurs within 1 to 5 minutes and is maintainedfor approximately 2 hours in patients either anesthetized or sedated with BZDs. This illustratesthe potential for resedation and the importance of careful monitoringfollowing administration. Flumazenil does not possess clinically significant intrinsicpharmacologicactivity. Because of its specificity for the BZD receptor, it has no effect on the actions of other non-BZD sedatives and anesthetics. Its efficacy has been establishednot only in conscious sedation and generalanesthesiabut also in the differential diagnosisof unknown/suspected BZD intoxication. To date, it has been well tolerated in most patients, with few reported side effects and has no effect on the pharmacokineticprofiles of coadministereddrugs. Flumazenil is a promising, effective, and short-actingBZD antagonistthat should provide an additionaldegree of safety whenever the undesirableeffects of BZD agonists occur. Key words: Benzodiazepine antagonist, flumazenil, midazolam reversal.

472

Introduction The compound flumazenil (Ro 15-1788) is a 1,4-imidazobenzodiazepine that is a potent specific antagonist of the central effects of benzodiazepines (BZD). Flumazenil antagonizes BZDs by competitively binding to the BZD receptor in the central nervous system following either parenteral or oral administration. It was synthesized and described in 1980 by Hunkeler and colleagues, and since that time it has received enormous attention in the fields of anesthesia and pharmacology.' The availability of 2,500 papers in 2 years after its introduction illustrates its potential impact on the medical community. 2 Flumazenil's unique site of action at the central BZD receptor is what sets it apart from other pharmacological agents that have been implicated in reversing the effects of BZI)s. For example, the centrally acting cholinesterase inhibitor physostigmine has been reported to reduce the somnolence and disorientation caused not only by diazepam, but also by ketamine, narcotics, and halothane.' In practice, physostigmine's effectiveness in reversing BZDs is unreliable. Because these agents have different proposed mechanisms of action, the effect of physostigmine can be described as nonspecific physiologic antagonism.' The need for a specific and reliable reversal agent was underscored by the introduction of the BZD agonist midazolam, which has been used not only for conscious sedation but also for the induction and maintenance of general anesthesia. It has an affinity twice that of diazepam for the BZI) receptor, resulting in a diazepam/midazolam potency

Journal of the American Association of Nurse Anesthetists

ratio of 1:2." It possesses clinically significant hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnestic properties. 7 However, all BZDs-including midazolam are known to possess respiratory depressant properties mediated by the central nervous system. The slope of the ventilatory response curve to carbon dioxide is decreased, not shifted to the right, as is observed with respiratory depression induced by narcotics." This indicates an impairment of central carbon dioxide chemoreceptor sensitivity. It has been noted that elderly patients are more susceptible to the effects of midazolam because of alternations in clearance and volume of distribution. In the same report it was found that in a trial of 74 patients of all ages, eight had prolonged elimination half-lives of greater than 10 hours. 9 After its release in May 1986, numerous fatalities were reported as a result of excessive respiratory depression and resultant cardiac arrest."' Despite U.S. Food and Drug Administration mandated reductions in recommended dose and widespread safety warnings, a total of 66 deaths had been reported by January 1988.' 0 There is no doubt that midazolam can be employed safely for conscious sedation if the correct dosage is used, allowance is made for the patient's age, and appropriate precautions are taken. However, as is the case with other potent central nervous system depressants, relative overdosage is a risk. Flumazenil offers an added degree of safety and security for the practitioner when these untoward effects occur. This article will address the spectrum of pharmacodynamic and pharmacokinetic effects of flumazenil. In addition, its mechanism of action, side effects, and potential interactions will be discussed in detail. Chemistry and structure Flumazenil belongs to the imidazobenzodiazepine ring system (Figure 1). It is both less lipophilic and water soluable when compared to midazolam but still sufficient to produce an injectable aqueous solution. Commercial ampules have a pH of about 4.2 It causes little, if any, local irritation after intravenous injection. Mechanism of action Gamma aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the central nervous system, and it exerts its main effect via a GABAa receptor located on the Cl- ion channel in the postsynaptic membrane." According to theory, there is a BZD receptor in close prox-

October 1992/Vol. 60/No. 5

Figure 1 This structural formula of the specific

benzodiazepine antagonist flumazenil (Ro 15-1788) belongs to the same benzodiazepine ring system as

midazolam. ^

1

COOC 2H5

F

CH3

0

I

I

imity to the GABAa receptor forming a complex. As a result of this proximity, activation of the BZD receptor modulates the function of GABAa receptors in several ways. BZDs increase the affinity of GABA for its receptor sites, as well as increasing the coupling of GABA receptors to the Cl" channel. When the channel is opened, Cl- diffuses inside, down its concentration gradient, and hyperpolarizes the cell membrane.' 2 This hyperpolarized membrane is then more resistant to neuronal excitation. There appear to be at least three groups of BZD receptor ligands (Figure 2). In the first group are the classical agonists, which produce the characFigure 2 This illustration is a simplified diagrammatic representation of the binding mechanism of a typical benzodiazepine agonist and competitive antagonist and the benzodiazepam/gamma aminobutyric acid (BZD/GABA) receptor complex. Antagonist Flumazenil

Agonist Midazolam

K?

0

BZD receptor

L + GABA receptor

473

teristic antianxiety, anticonvulsant, and sedative effects and include drugs like diazepam and midazolam. A second group is the BZD antagonists, which competitively bind to the receptor and inhibit the pharmacologic effects. The third group is a poorly understood one known as inverse agonists and contains compounds that cause the opposite effects of BZD agonists. Interestingly, the convulsant effects of these drugs have been reversed by flumazenil, implying an identical receptor. 3

are generally minor and seem unlikely to detract from its use as an antagonist. 21 The cardiovascular effects of flumazenil alone have also been studied in patients with ischemic heart disease and found to be negligible. 22 23 Flumazenil alone appears to have no effect on ventilation. 24 Although the efficacy of flumazenil has been clearly established in reversing the sedative and hypnotic effects of BZD, some doubt exists as to its effectiveness in completely eliminating all aspects of the respiratory depression produced by BZD.25

Pharmacodynamics Midazolam has been widely used for the induction and maintenance of general anesthesia. Great individual variations have been reported in response to recommended doses, resulting in occasional delayed awakening or excessive postoperative sedation. In a double-blind study involving gynecologic ambulatory surgery patients who had anesthesia induced with midazolam, flumazenil given in the postoperative period was effective in improving psychodiagnostic tests of recovery, as well as pulse oxygen saturation and end-tidal carbon dioxide tension. 14 Flumazenil injected intravenously in individually titrated doses has been clearly superior to a placebo in reversing BZD anesthesia. 1 In a study by Lauven and associates in 1985, midazolam anesthesia was maintained by infusion.' 6 A single large dose of flumazenil caused the subjects to be fully oriented within 65 seconds and fully asleep again after 145 minutes. This illustrates the limited duration of action of flumazenil and the potential for resedation once the reversal has worn off. Flumazenil has been found to be effective in reversing midazolam sedation in elderly patients after regional anesthesia. 17 However, this improvement in alertness and recall started to diminish slowly after 5 to 15 minutes following flumazenil administration. If prolonged reversal is necessary, the use of continuous flumazenil infusions may prove useful.

Flumazenil has been found to be partially effective in reversing diazepam-induced depression of hypoxic ventilatory drive and central carbon dioxide chemoreceptor sensitivity. 26 This incomplete action has been related to either the shorter elimination half-life of flumazenil or a possible agonistic action at another site. 27 It remains to be seen if flumazenil is as effective in patients with chronic obstructive pulmonary disease, as they are the ones most likely to receive midazolam with sedation during regional anesthesia. Therefore, careful monitoring of ventilation into the postoperative Y period is still mandatory. 28 2

The possibility that flumazenil has its own pharmacologic effects has been investigated, and the results have been inconclusive.' 8 However, it does appear as if flumazenil possesses very weak intrinsic activity in several behavioral, neurological, and electrophysiological tests in man. 9 Depending on the dose, the basal clinical conditions, and experimental tests, flumazenil is reported to have both weak agonist-like and inverse agonistlike properties which might be explained by a modulation of GABAergic activity.20 These effects

474

Studies of small numbers of patients admitted to intensive care units and emergency rooms have shown that, after 5 minutes, patients suffering from pure BZD overdose are fully awakened. However, reports of seizures and arrhythmias have appeared following the reversal of mixed drug overdoses. In a combined BZD/tricyclic overdose, the rapid elimination of BZD has unmasked the seizureproducing effects of tricyclic antidepressants, resulting in sustained seizure activity." 3 ' The same applies to BZD/chloral hydrate overdose, where flumazenil unmasks the arrhythmogenic effects of chloral hydrate producing uncontrollable ventricular arrhythmias. 2 Despite inconclusive early studies, it has been established that flumazenil has no influence on psychomotor function in acute ethanol intoxication. 33 An area of use that has been investigated and shows some promise is the use of flumazenil in the treatment of hepatic encephalopathy. It is postulated that increased GABA-mediated neurotransmission contributes to the mediation of hepatic encephalopathy. Flumazenil induced variable and transient, but distinct, improvements in the mental status of 10 of 14 patients with advanced cirrhosis. These findings strongly favor a prominent role of increased GABAergic tone and suggest that a positive response to flumazenil may be of prognostic value. 34

Journalof the American Association of Nurse Anesthetists

Pharmacokinetics High-performance liquid chromatography and, more recently, gas-liquid chromatography with nitrogen-phosphorous detection have been used to quantify flumazenil in the blood,:" which is readily absorbed after an oral dose and reaches its peak plasma concentration in 20-90 minutes. However, it undergoes significant first-pass metabolism in the liver, so that only 16% of an oral dose reaches. the systemic circulation. Peak plasma concentration after intravenous administration is 6-10 minutes (Table I). Table I Pharmacokinetic parameters for flumazenil 17

Parameter

Range

Elimination half-life (hours)

0.7-1.3

Volume of distribution at steady state (L/kg)

0.6-1.6

Free fraction (%)

54-64

Plasma clearance (L/hr)

31-78

Flumazenil is extensively metabolized in the liver by hepatic microsomal oxidative mechanisms to an inactive free carboxylic acid and a corresponding glucuronide, with only 0.12% of a dose excreted unchanged in the urine. Three metabolites of flumazenil have been identified to date, and they are not known to possess any intrinsic pharmacologic activity.s36

37

The elimination half-life of between 49 and 58 minutes following both oral and intravenous administration results in a duration of action of 2 to 3 hours. This rapid hepatic elimination can be characterized both by the short half-life (0.7 to 1.3 hours) or better, by the high plasma clearance (0.5 to 1.3 L/min).' 7 By comparison, midazolam has an elimination half-life of 1.5 to 3.0 hours and a plasma clearance of 0.35 to 0.5 L/min. 2 The protein-bound fraction of flumazenil is approximately 40% to 50%, and its volume of distribution is 0.6 to 1.6 L/kg. 17 The pharmacokinetics of flumazenil are not significantly affected by age, gender, or renal failure. Mean total clearance is decreased 40% to 75% of normal in patients with moderate to severe hepatic dysfunction.3 8 Side effects and pharmacokinetic interactions In studies conducted to date, the usual therapeutic doses of flumazenil have been well tolerated by most patients, and there is little if any pain on injection. A review of side effects in more than 1,700 patients noted that nausea and/or vomiting only occurred in more than 1% of patients. 39 The incidence of side effects is significantly greater in

October 1992/ Vol. 60/No. 5

those who receive flumazenil for BZD intoxication. The most frequent occurrence was agitation (6.5%), followed by unspecified discomfort (4.6%), tearfulness (4.2%), and anxiety (4.2%).18 Flumazenil has

no influence on the pharmacokinetic parameters of coadministered BZDs or alcohol. 7 Conclusions Flumazenil is a unique member of the BZD class of drugs that has been shown to possess the properties of a competitive antagonist, thereby reversing the central effects of other BZDs. Its baseline efficacy has been established in a wide range of clinical applications that have had a significant impact on the anesthesia community. The immediate onset of effect and the relatively short duration of action would seem to make flumazenil ideally suited for use in anesthesia. Clearly, flumazenil should not be used routinely; however, with its recent U. S. Food and Drug Administration approval, it should make a welcome addition to the armamentarium of drugs currently available to the anesthesia practitioner. REFERENCES (1) Hunkeler W, Mohler H, Pieri L, et al. Selective antagonists of benzodiazepines. Nature. 1981;290:514-516. (2) Amrein R, Hertzel W. Pharmacology of Dormicum® (midazolam) and Anexate® (flumazenil). Acta Anesthesiologica Scandinavica. 1990;suppl 92(34):6-15. (3) DiLiberti J, O'Brien ML, Turner T. The use of physostigmine as an antidote in accidental diazepam intoxication. J Pediatr. 1975;86: 106-107. (4) Hill GE, Stanley TH, Sentker TR. Physostigmine reversal of postoperative somnolence. Canadian Anaesthetists Society Journal. 1977;24: 707-711. (5) Freidman J. Reversal agents. In: Aldrete JA, Stanley TH, eds. Trends in Intravenous Anesthesia. Chicago, Illinois: Year Book Medical Publishers. 1980:310-321. (6) Whitwam JG, Al-Khudhairi D, McCloy RF Comparison of midazolam and diazepam in doses of comparable potency during gastroscopy. BrJAnaesth. 1983;55:773-777. (7) Frye-Kryder S. Midazolam: A new benzodiazepine. AANA Journal 1987;55:121-125. (8) Forster A, Gardaz J, Suter P, Gemperie M. Respiratory depression by midazolam and diazepam. Anesthesiology. 1980;53:494-497. (9) Harper KW, Collier PS. Dundee JW, Elliot P, Halliday NJ, Lowry KG. Age and nature of operation influence the pharmacokinetics of midazolam. BrJAnaesth. 1985;57:866-871. (10) Midazolam- Is antagonism justified? Lancet. 1988;2(8603):140-142. (11) Olsen RW. Drug interactions at the GABA receptor ionophore complex. Annu Rev PharmacolToxicol. 1982;22:245-277. (12) Watkins WD, DeBruijn NP, Leslie JB. Pharmacodynamic principles. In: Miller RD, ed. Anesthesia. New York, New York: Churchill Livingstone, 1986:55-72. (13) Nutt DJ, Cowen PJ, Little HJ. Unusual reactions of benzodiazepine receptor antagonists. Nature. 1981;295:436. (14) Philip BK, Simpson TH, Hauch MA, Mallampati SR. Flumazenil reverses sedation after midazolam induced general anesthesia in ambulatory surgery patients. Anesth Analg. 1991;71:371-376. (15) Jensen S, Kirkegaard L, Anderson BN. Randomized clinical investigation of Ro 15-1788, a benzodiazepine antagonist, in reversing the central effects of flunitrazepam. Eur/ AnaesthesioL 1987;4:113-118.

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(16) Lauven PM, Schwilden H, Steockel H, Greenblat DJ. The effects of a benzodiazepine antagonist (Ro 15-1788) in the presence of stable concentrations of midazolam. Anesthesiology. 1985;63:61-64. (17) Katz JA, Fragen RJ, Dunn KL. Flumazenil reversal of midazolam sedation in the elderly. RegionalAnesthesia. 1991;16:247-252. (18) Higgit A, Lader M, Fonagy P. The effects of the benzodiazepine antagonist Ro 15-1788 on psychophysiological performance and subjective measure in normal subjects. Psychopharmacology. 1986;89:395-403. (19) Darragh A. Lambe R. O'Boyle C. Kenny M, Brick I. Absence of central effects in man of the benzodiazepine antagonist Ro 15-1788. Psychopharmacology. 1983;80:192-195. (20) Klotz U, Kanto J. Pharmacokinetics and clinical use of flumazenil (Ro 15-1788). Clin Pharmacokinet.1988;14:1-12. (21) Brogden RN, Goa KL. Flumazenil-A preliminary review of its benzodiazepine antagonist properties, intrinsic activity and therapeutic use. Drugs. 1988;35:448-467. (22) Croughwell, ND, Reves JG, Will CJ, Kasson BJ, Goodman DK. Safety of flumazenil in patients with ischemic heart disease. Anesth Analg. 1990;70:S450. (23) Croughwell ND, Reves JG, Will CJ, Kasson BJ, Goodman DK. Safety of rapid administration of flumazenil in patients with ischemic heart disease. Acta Anesthesiologica Scandinavica. 1990; suppl 92(34):55-58. (24) Halim B. The use of midazolam and flumazenil in locoregional anesthesia: An overview. Acta Anesthesiologica Scandinavica. 1990;suppl 92(34):42-46. (25) Whitwam JG. The use of midazolam and flumazenil in short surgical and diagnostic procedures. Acta Anesthesiologica Scandinavica. 1990;suppl92(34):16-20. (26) Barakat T, Lechat JP, Laurent P, Fletcher D, Clerque F, Viars P. Ventilatory effects of flumazenil on midazolam induced sedation. Anesthesiology. 1988;69(3A):A817. Abstract. (27) Mora C. Torjman M. White P. Effects of diazepam and flumazenil on sedation and hypoxic ventilatory response. Anesth Analg. 1989;68: 473-478. (28) Dailland P, Lirzin JD, Jugan E, Jacquinot P, Jorrot JC, Conseiller C. Effect of Ro 15-1788 (flumazenil) on the CO 2 responsiveness after midazolam-fentanyl anesthesia. Anesthesiology. 1988;69(3A):A815. Abstract. (29) Carter AS, Bell GD, Coady T, Lee J, Mordan A. Speed of reversal of midazolam induced respiratory depression by flumazenil-A study in patients undergoing upper G.I. endoscopy. Acta Anesthesiologica Scandinavica. 1990;suppl 92(34): 59-64.

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(30) Burr W, Sandham P, Judd A. Death after flumazenil. British MedicalJournal.1989;298:1713. (31) Marchant B, Wray R, Leach A, Nama M. Flumazenil causing convulsions and ventricular tachycardia. British Medical Journal 1989;299: 860. (32) Short T, Maling T, Galletly D. Ventricular arrhythmia precipitated by flumazenil. British MedicalJournal 1988;296:1070-1071. (33) Clausen TJ, Wolff J, Carl P, Theilgaard A. The effect of the benzodiazepine antagonist, flumazenil, on psychometric performance in acute ethenol intoxication in man. EurJClin Pharmacol.1990;38:233-236. (34) Bansky G, Meier PJ, Riederer E, Walser H, Zeigler WH, Schmid M. Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. Gastroenterology.1989;97:744-750. (35) Abernathy DR, Arendt RM, Lauven PM, Greenblat DJ. Determination of Ro 15-1788, a benzodiazepine antagonist, in human plasma by gas liquid chromatography with nitrogen-phosphorous detecton. Pharmacology.1983;26:285-289. (36) Hunkeler W. Preclinical research findings with flumazenil: Chemistry. EurJAnaesthesiol 1988:suppl 2:37-62. (37) Zell M, Timm U. Highly sensitive assay of a benzodiazepine antagonist in plasma by capillary gas chromatography with nitrogen selective detection. J Chromatogr 1986;382:175-188. (38) Product information. Mazicon® (flumazenil). Roche Laboratories, Hoffman-La Roche Inc. Nutley, New Jersey. October 1991. (39) Amrein R, Leishman B, Bentzinger C, Roncari G. Flumazenil in benzodiazepine antagonism: Actions and clinical use in intoxications and anesthesiology. Medical Toxicology. 1987;2:411-429.

AUTHOR Brian J. Kasson, CRNA, MHS, received his nursing degree from Ohio State University College of Nursing, Columbus, Ohio, in 1986, and worked for three years in the cardiothroacic intensive care unit at Duke University Medical Center, Durham, North Carolina. He graduated from the Medical University of South Carolina's Anesthesia for Nurses Program in August of 1991 with a master in Health Sciences degree/certificate in Anesthesia. Mr. Kasson is currently a staff nurse anesthetist for Anesthesia Associates of Cincinnati, practicing at Christ Hospital, Cincinnati, Ohio.

Journal of the American Association of Nurse Anesthetists

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Brief Summary

Enlon-Plus® (edrophonium chloride, USP and atropine sulfate, USP) Injection DESCRIPTION Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection, for intravenous use, is a sterile, nonpyrogenic, nondepolarizing neuromuscular relaxant antagonist. Enlon-Plus is a combination drug containing a rapid acting acetylcholinesterase inhibitor edrophonium chloride, and an anticholinergic, atropine sulfate. Enlon-Plus contains in each mL of sterile solution: 5 mL Ampuls: 10 mg edrophonium chloride and 0.14 mg atropine sulfate compounded with 2.0 mg sodium sulfite as a preservative and buffered with sodium citrate and citric acid. The pH is adjusted in the range of 4.4-4.6. 15 mL Multidose Vials: 10 mg edrophonium chloride and 014 mg atropine sulfate compounded with 2.0 mg sodium sulfite and 4.5 mg phenol as a preservative and buffered with sodium citrate and citric acid. The pH is adjusted in the range of 4.4-4.6. INDICATIONS AND USAGE Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection is recommended as a reversal agent or antagonist of nondepolarizing neuromuscular blocking agents. It is not effective against depolarizing neuromuscular blocking agents. It is also useful if used adjunctively in the treatment of respiratory depression caused by curare overdosage. The appropriateness of the specific fixed ratio of edrophonium and atropine contained in Enlon-Plus has not been evaluated in myasthenia gravia Therefore, EnlonPlus is not recommended for use in the differential diagnosis of this condition.

CONTRAINDICATIONS Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection is not to be used in patients with known hypersensitivity to either of the components, or in patients with intestinal or urinary obstruction of mechanical type Atropine sulfate is contraindicated in the presence of acute glaucoma, adhesions (synechiae) between the iris and lens of the eye, and pyloric stenosis.

WARNINGS Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection should be used with caution in patients with bronchial asthma or cardiac arrhythmias. Cardiac arrest has been reported to occur in digitalized patients as well as in jaundiced subjects receiving cholinesterase inhibitors. In patients with cardiovascular disease, given anesthesia with narcotic and nitrous oxide without a potent inhalational agent, there is increased risk for clinically significant bradycarda. In patients receiving beta-adrenergic blocking agents there is increased risk for excessive bradycardia from unopposed parasympathetic vagal tone. Such patients should receive atropine sulfate alone prior to Enlon-Plus. Isolated instances of respiratory arrest have also been reported following the administration of edrophonium chloride. Additional atropine sulfate (1 mg) should be available for immediate use to counteract severe cholinergic reaction which may occur in hypersensitive individuals when Enlon-Plus is used. Enlon-Plus contains sodium sulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. There is a potential for tissue irritation by extravascular injection.

PRECAUTIONS GENERAL: As with any antagonist of nondepolarizing muscle relaxants, adequate recovery of voluntary respiration and neuromuscular transmission must be obtained prior to the discontinuation of respiratory assistance. Should a patient develop "anticholinesterase insensitivity" for brief or prolonged periods, the patient should be carefully monitored and the dosage of anticholinesterase drugs reduced or withheld until the patient again becomes sensitive to them. Use with caution in patients with prostatic hypertrophy and in debilitated patients with chronic lung disease. When used in therapeutic doses, atropine can cause dryness of the mouth. This effect is additive when the product is administered with other drugs that can cause dryness of the mouth. Since atropine sulfate slows gastric emptying and gastrointestinal motility, it may interfere with the absorption of other medications. The effect of atropine on dryness of the mouth may be increased if it is given with other drugs that have anticholinergic action (tricyclic antidepressants, antipsychotics some antihistamines, and antiparkinsonism drugs). DRUG INTERACTIONS: Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection should not be administered prior to the administration of any nondepolarizing muscle relaxants. It should be administered with caution to patients with symptoms of myasthenic weakness who are also on anticholinesterase drugs. Anticholinesterase overdosage (cholinergic crisis)

symptoms may mimic underdosage (myasthenic weaknes), so the use of this drug may women the condition of these patients (see OVERDOSAGE section for reatment). Narcotic analgesics, except when combined with potent inhaled anesthetics, appear to potentiate the effect of edrophonium on the sinus node and conduction system, increasing both the frequency and duration of

due to paralysis of the medullary centers. In the clinical studies performed with Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection, there were no reported overdoees and therefore no clinical information is available regarding overdosing with Enlon-Plus.

bradycardia. In patients with cardiovascular disease, given

DOSAGE AND ADMINISTRATION

anesthesia with narcotic and nitrous oxide without a potent inhalational agent, there is increased risk for clinically significant bradycardia. In patients receiving beta-adrenergic blocking agents there is increased risk for excessive bradycardia from unopposed parasympathetic vagal tone. Such patients should receive atropine sulfate alone prior to Enlon-Plus. Compared to muscle relaxants with some vagolytic activity, muscle relaxants with no vagolytic effects, i.e. vecuronium, may be associated with a slightly higher incidence of vagotonic effects such as bradycardia and first-degree heart block when reversed with Enlon-Plus.

Dosages of Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection range from 0.0-0.1 mlJkg given slowly over 45 seconds to 1 minute at a point of at least 5% recovery of twitch response to neuromuscular stimulation (96% block). The dosage delivered is 0.-1.0 mg/kg of edrophonium chloride and 0.007-0.014 mg/kg of atropine sulfate. A total dosage of 1.0 mg/kg of edrophonium chloride should rarely be exceeded. Response should be monitored carefully and assisted or controlled ventilation secured. Satisfactory reversal permits adequate voluntary respiration and neuromuscular transmission (as tested with a peripheral nerve stimulator). Recurarization has not been reported after satisfactory reversal has been attained.

PREGNANCY CATEOORY C: Animal reproduction studies have not been conducted with Enlon-Plus. It is also not known whether Enlon-Plus can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Enlon-Plus should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. LABOR AND DELIVERY: The effect of Enlon-Plus on the mother and fetus, on the duration of labor or delivery, in the possibility that a forceps delivery or other intervention or resuscitation of the newborn will be necessary, is not known. The effect of the combination drug on the later growth, development and functional maturation of the child is also unknown. NURSING MOTHERS: The safety of Enlon-Plus during lactation in humans has not been established. PEDIATRIC USE: Safety and effectiveness in children have not been established. Pediatric patients may have increased vagal tone. The effect of fixed ratios of edrophonium and atropine on heart rate in such patients has not been evaluated.

ADVERSE REACTIONS CARDIOVASCULAR: Arrhythmias Frequency >10%: junctional rhythm, bradycardia, tachycardia: Frequency 3-10%: first and second degree A-V block, P Wave changes, atrial premature contractions; Frequency 1-3%: third degree A-V block, ventricular premature contractions; Frequency less than 1%: 3 second R-R interval. Of the patients who experienced any arrhythmias, 85 % had the onset within two minutes, 74% no longer had any arrhythmias after 10 minutes. Arrhythmias related to increased vagal tone, bradycardia, second and third degree heart block respond to treatment with 0.2 - 0.4 mg of atropine I.V.(Bigeminy or ventricular ectopy may be treated with lidocaine 50 mg IV.). Adverse experiences reported for anticholinesterase agents such as edrophonium chloride, but not observed in the 235 patients studied with Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection: CARDIOVASCULAR: Nonspecific EKG changes, fall in cardiac output leading to hypotension; RESPIRATORY: Increased tracheobronchial secretions, laryngospasm, bronchiolar constriction and respiratory muscle paralysis; NEUROLOGIC: Convulsions, dysarthria, dysphonia, and dysphagia;

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

HOW SUPPLIED Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection should be stored between 15 o 26 °C (59 O - 78 °F). NDC 10019 - 195 - 05

5 mL ampuls, boxes of 10

NDC 10019 - 195 - 15

15 mL multidose vials

Caution: Federal (USA) law prohibits dispensing without prescription.

REFERENCES 1. Cronnelly R, Morris RB, Miller RD: Edrophonium: Duration of action and atropine requirement in humans during halothane anesthesia. Anesthesiology 1982;57:261-266. 2. Hinderling PH, Oundert-Remy U, Schmidlin O, Heinsel G: Integrated pharmacokinetics and pharmacodynamics of atropine in healthy humans. I: Pharmacokinetics; II: Pharmacodynamics. J Pharmaceutical Sci 1985;74:I-703-710; II-711-717. 3. Morris RB, Cronnelly R, Miller RD, Stanski DR, Fahey MR: Pharmacokinetics of edrophonium and neostigmine when antagonizing d-tubocurarine neuromuscular blockade in man. Anesthesiology 1981;54:399-402. 4. Morris RB, Cronnelly R, Miller RD, Stanski DR, Fahey MR: Pharmacokinetics of edrophonium in anephric and renal transplant patients Br J Anaesth 1981;53:1311-1313. 5. Fisher DM, Cronnelly R, Sharma M, Miller RD: Clinical pharmacology of edrophonium in infants and children. Anesthesiology 1984; 61:428-433. 6. Silverberg PA. Matteo RS, Ornstein E, Young WL, Diaz J: Pharmacokinetics and pharmacodynamics of edrophonium in the elderly. Anesth Analg 1986;66:8142 7 Virtanen R, Kanto J, lisalo E, lisalo EU, Salo M, Sjovall S: Pharmacokinetic studies on atropine with special reference to age. Acta Anaesthesiol Scand 1982;26:297-300. 14 8 Back DJ, Calvey TN: Excretion of C-edrophonium and its metabolites in bile: role of the liver cell and the peribiliary vascular plexus. Br J Pharmacol., 1972; 44:534 Mfd. for: Anaquest Inc. Liberty Corner, NJ 07938 A Subsidiary of BOC Health Care Inc By: Taylor Pharmacal Co., Decatur, IL 62525 400 -288 A-0628 11-91

GASTROINTESTINAL: Nausea, vomiting, increased peristalsis, increased gastric and intestinal secretions, diarrhea, abdominal cramps; MUSCULOSKELETAL: Weakness and fasciculations; MISCELLANEOUS: Increased urinary frequency, diaphoresis, increased lacrimation, pupillary constriction, diplopia, and conjunctival hyperemia. Untoward reactions to atropine sulfate generally are dose-related. Individual tolerance varies greatly but systemic doses of 0.5 to 10 mg are likely to produce the following effects, which were not observed in the 235 patients treated with Enlon-Plus:

NEUROLOGIC: Speech disturbances and restlessness with asthenia; DERMATOLOGIC: Flushed, dry skin, formation of a scarlatiniform rash; MISCELLANEOUS: Dryness of the nose and mouth, thirst, blurred vision, photophobia, slight mydriasis. Atropine may produce fever through inhibition of heat loss by evaporation.

Anaqurnt Anaquest Inc 110 Allen Road PO Box 804 Liberty Corner NJ 07938 0804

908 647 9200

800 ANA DRUG

OVERDOSAGE Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions and bradycardia) may appear with overdosage (cholinergic crisis) of Enlon-Plus (edrophonium chloride, USP and atropine sulfate, USP) Injection, but may be managed by the use of additional atropine sulfate. Obstruction of the airway by bronchial secretions can arise and may be managed with suction (especially if tracheostomy has been performed).

A Subsidiary of BOC Health Care Inc Form No 09-0109 01992 Anaquest Inc

Should edrophonium chloride overdosage occur: 1. Maintain respiratory exchange. 2. Monitor cardiac function. Appropriate measures should be taken if convulsions occur or shock is present. Principal manifestations of overdosage (poisoning) with atropine sulfate are delirium, tachycardia and fever. In the treatment of atropine poisoning, respiratory assistance and symptomatic support are indicated. Death is usually

A BOC Health Car Company Critical Care Wtorldwide

From Burroughs Wellcome Co. A Long-Acting Neuromuscular Blocker

Excellent CV Stability

NUROMAX NJECTION (doxacurium chloride) 1mg/mL Please see brief summary of full prescribing information.

A Long-Acting Neuromuscular Blocker

NUROMAX INJECTION

(doxacurium chloride)

Excellent CV Stability Cardiovascular stability comparable with vecuronium Change in MAP

(m m/Hg)

864-

2-20MAP

Change in HR

(beats/r in)

0

2

4I

4

I

I

6

8

I

1

10

Time after injection (min) 1

Emmott et a compared the hemodynamic effects of Nuromax 0.037 and 0.075 mg/kg with the effects of pancuronium 0.09 mg/kg and vecuronium 0.075 mg/kg in 36 CABG patients (9 patients, each group). Mean changes from baseline values of mean systemic arterial pressure (MAP) and heart rate (HR) at 1, 5 and 10 min after administration. All routine cardiac and vasoactive medications were continued up to the morning of surgery. -

doxacurium 0.037 mg/kg

. ... pancuronium 0.09 mg/kg

doxacurium 0.075 mg/kg

vecuronium 0.075 mg/kg

-A,

JL

h--l

r

"

Longer acting than "high-dose" vecuronium Clinically effective block (time to 25% recovery) ED9, (0.025 mg/kg) E-

60 minutes (range 9-145)

2xED 95 (0.05 mg/kg) _

_

_

_

_

_

_

_

_

_

NUROMAX

- 100 minutes

(range ran 39-232) 3xED 9 s (0.08 mg/kg )*

160 minutes or more (range 110-338)

3xEDs (0.2 mg/kg) ~_68 minutes (range 50-106) 5xEDs (0.3 mg/kg)

- 111 minutes

vecuronium2t

(range 62-208) 7xEDs (0.4 mg/kg) ~ 115 minutes (range 35-191)

*This dose should be reserved for instances in which a need for very prolonged neuromuscular block is anticipated. tNumbers shown are not directly comparable since these data have been compiled from different study populations.

* Cardiovascular stability comparable with normal saline

3

* Noncumulative * Ready-to-use solution * Vials stored at room temperature, no refrigeration required * Supplied as a 5 mL vial, 1 mg/mL

NUROMAX EO (doxacurium chloride) 1mg/mL Excellent for Long CV Procedures

Please see brief summary of full prescribing information.

NUROMAX® INJECTION (DOXACURIUM CHLORIDE) Brief Summary This drug should be administered only by adequately trained individuals familiar with its actions, characteristcs, and hazards. Individuallzation of Dosages: In elderlypatients or patients who have impaired renal function, the potential for a prolongation of blockmay be reduced by decreasing the initialNuromax dose and by titrating the dose to achieve the desired depth of block. In obese patients (patients weighing > 30% more than ideal body weight for height), the Nuromax dose should be determined using the patient's

formulae: according to the following ideal body weight (IBW), Men:IBWinkg = [106 + (6 x inches in height above 5 feet)/2.2 Women: IBWin kg = [100 + (5 x inches in height above 5 feet)/2.2 Dosage requirements for patients withsevere liverdisease are variable; some patients mayrequire a higher than normal initialNuromax dose to achieve clinically effective block. Once adequate block is duration of block may be prolonged in such patients relative to patients with established, the clinical normal liverfunction. As with pancuronium, metocurine, and vecuronium, resistance to Nuromax, manifested by a reduced intensity and/or shortened duration of block, must be considered when Nuromax is selected for use in patients receiving phenytoin or carbamazepine (see Drug Interactions subsection of PRECAUTIONS). As with other nondepolarizing neuromuscular blocking agents, a reduction indosage of Nuromax must be considered in cachectic or debilitated patients, in patients withneuromuscular diseases, severe electrolyte abnormalities, or carcinomatosis, and in other patients in whom potentiation of neuromuscular block or difficulty with reversal is anticipated. Increased doses of Nuromax may be required inbum patients (see PRECAUTIONS). INDICATIONS ANDUSAGE: Nuromax is a long-acting neuromuscular blocking agent, indicated as an adjunct to general anesthesia, to provide skeletal muscle relaxation during surgery. Nuromax can also be used to provide skeletal muscle relaxation for endotracheal intubation. in patients knownto havehypersensitivity to it. is contraindicated CONTRAINDICATIONS: Nuromax WARNINGS: NUROMAX SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED DOSAGE BY OR UNDERTHE SUPERVISION OF EXPERIENCED CLINICIANS WHO ARE FAMILIAR WITH THE DRUG'S ACTIONS AND THE POSSIBLE COMPLICATIONS OF ITS USE. THE DRUG SHOULD NOT BE ADMINISTERED UNLESS FACILITIES FOR INTUBATION, ARTIFICIAL RESPIRATION, OXYGEN THERAPY, AND AN ANTAGONIST ARE WITHIN IMMEDIATE REACH. IT IS RECOMMENDED THAT CLINICIANS ADMINISTERING LONG-ACTING NEUROMUSCULAR BLOCKING AGENTS SUCH AS NUROMAX EMPLOY A PERIPHERAL NERVE STIMULATOR TO MONITOR DRUG RESPONSE, NEED FORADDITIONAL RELAXANTS, AND ADEQUACY OF SPONTANEOUS RECOVERY OR ANTAGONISM. NUROMAX HAS NO KNOWN EFFECT ON CONSCIOUSNESS, PAIN THRESHOLD, OR CEREBRATION. TO AVOID DISTRESS TO THEPATIENT, NEUROMUSCULAR BLOCK SHOULD NOT BE INDUCED BEFORE UNCONSCIOUSNESS. NuromaxInjection isacidic(pH 3.9to 5.0) and maynot be compatible withalkalinesolutions havinga pHgreaterthan8.5 (e.g.,barbiturate solutions). NuromaxInjectioncontainsbenzylalcohol.In newbominfants,benzyl alcoholhas beenassociated withan increased incidence of neurological andothercomplications which are sometimes fatal.See Pediatric Usesubsection of PRECAUTIONS. PRECAUTIONS: General: Nuromax has no clinically significant effects on heart rate; therefore, Nuromax will not counteract the bradycardia produced by many anesthetic agents or by vagal stimulation. Neuromuscular blocking agents may have a profound effect in patients with neuromuscular diseases (e.g., myasthenia gravis and the myasthenic syndrome). In these and other conditions inwhich prolonged neuromuscular block is a possibility (e.g., carcinomatosis), the use of a peripheral nerve stimulator and a small test dose of Nuromax is recommended to assess the level of neuromuscular block and to monitor dosage requirements. Shorter acting muscle relaxants than Nuromax maybe more suitable for these patients. Resistance to nondepolarizing neuromuscular blocking agents may develop in patients with burns depending upon the time elapsed since the injuryand the size of the bum. Nuromax has not been studied in patients with bums. Acid-base and/or serum electrolyte abnormalities may potentiate or antagonize the action of neuromuscular blockingagents. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy. Nuromax has not been studied in patients with asthma. No data are available to support the use of Nuromax by intramuscular injection. Renal and Hepatic Disease: Nuromax has been studied in patients with end-stage kidney (n=8) or liver (n=7) disease undergoing transplantation procedures (see CLINICAL PHARMACOLOGY). The possibility of prolonged neuromuscular block in patients undergoing renal transplantation and the possibility of a variable onset and duration of neuromuscular blockin patients undergoing livertransplantation must be considered when Nuromax is used in such patients. Obesity: Administration of Nuromax on the basis of actual body weight is associated witha prolonged duration of action in obese patients (patients weighing 30% more than ideal body weight for height) (see CLINICAL PHARMACOLOGY). Therefore, the dose of Nuromax should be based upon ideal body weight inobese patients (see Individualization of Dosages subsection of CLINICAL PHARMACOLOGY). Malignant Hyperthermla (MH):In a study of MH-susceptible pigs, Nuromax did not trigger MH.Nuromax has not been studied in MH-susceptible patients. Since MHcan develop in the absence of established triggering agents, the clinician should be prepared to recognize and treat MH in any patient scheduled for general anesthesia. Long-Term Use In the Intensive Care Unit (ICU):No data are available on the long-term use of Nuromax in patients undergoing mechanical ventilation in the ICU. Drug Interactions: Prior administration of succinylcholine has no clinically important effect on the neuromuscular blocking action of Nuromax. The use of Nuromax before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on concomitant use of Nuromax and other nondepolarizing neuromuscular blocking agents. Isoflurane, enflurane and halothane decrease the EDso of Nuromax by 30% to 45%. These agents may also prolong the clinically effective duration of action by up to 25%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as Nuromax include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. As with some other nondepolarizing neuromuscular blocking agents, the time of onset of neuromuscular block induced by Nuromax is lengthened and the duration of block is shortened in patients receiving phenytoin or carbamazepine. Carcinogenesis, Mutagenesls, Impairment of Fertility: Carcinogenesis and fertilitystudies have not been performed. Nuromax was evaluated in a battery of four short-term mutagenicity tests. It was non-mutagenic in the Ames Salmonella assay, in the mouse lymphoma assay, and in the human lymphocyte assay. In the in vivo rat bone marrow cytogenetic assay, statistically significant increases in the incidence of structural abnormalities, relative to vehicle controls, were observed in male rats dosed with 0.1 mg/kg (0.625 2 mg/m ) Nuromax and sacrificed at 6 hours, but not at 24 or 48 hours, and in female rats dosed with 0.2 2 mg/kg (1.25 mg/m ) Nuromax and sacrificed at 24 hours, but not at 6 or 48 hours. There was no increase in structural abnormalities in either male or female rats given 0.3 mg/kg (1.875 mg/m 2) Nuromax and sacrificed at 6, 24, or 48 hours. Thus, the incidence of abnormalities in the in vivo rat bone marrow cytogenetic assay was not dose-dependent and, therefore, the likelihood that the observed abnormalities were treatment-related or clinicallysignificant is low. Pregnancy: Teratogenic Effects: Pregnancy Category C. Teratology testing in nonventilated, pregnant rats and mice treated subcutaneously withmaximum subparalyzing doses of Nuromax revealed no maternal or fetaltoxicity or teratogenic effects. There are no adequate and well-controlled studies of Nuromax in pregnant women. Because animal studies are not always predictive of human response and the doses used

z

were subparalyzing, Nuromaxshouldbe usedduringpregnancy onlyif the potentialbenefitjustifies thepotential riskto the fetus.Labor and Delivery: The use of Nuromax duringlabor,vaginaldelivery, or cesareansection has not beenstudied.It is not knownwhetherNuromaxadministered to the motherhasimmediateordelayedeffectsonthefetus.The durationof actionof Nuromaxexceedsthe usualdurationof operativeobstetrics (cesarean section).Therefore,Nuromax is notrecommended for usein patientsundergoing C-section. Nursing Mothers: it is notknownwhetherNuromaxis excreted in humanmilk. Because many drugs are excreted in humanmilk, caution should be exercised following Nuromax administration to a nursing woman.Pediatric Use: Nuromax has notbeenstudied in children below the age of 2 years. See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION for dinical experienceand recommendations for usein children2 to 12 yearsof age. Geriatric Use: Nuromaxhasbeen usedin elderlypatients,includingpatientswithsignificant cardiovascular disease.In elderlypatients the onsetof maximum blockis slowerand thedurationof neuromuscular blockproduced byNuromaxismorevariableand,in somecases,longerthan in young adult patients (seePharmacodynamlcs and Individualization of Dosages subsections of CLINICAL PHARMACOLOGY). ADVERSE REACTIONS: The mostfrequentadverseeffectof nondepolarizing blockingagentsas a class consists of an extension of the pharmacological action beyond thetimeneededforsurgeryand anesthesia.This effectmayvaryfromskeletalmuscleweaknessto profoundand prolonged skeletal muscleparalysis resultingin respiratory insufficiency and apnea which require manualor mechanical ventilation untilrecoveryisjudgedto be clinically adequate (see OVERDOSAGE). Inadequatereversal of neuromuscular block from Nuromaxis possible, as withall nondepolarizing agents.Prolonged neuromuscular blockand inadequatereversalmayleadto postoperative complications. Observed In Clinical Trials: Adverse experiences were uncommon among the 1034 surgical patients and volunteers who receivedNuromaxand otherdrugs in U.S. clinical studies in the courseof a wide varietyof proceduresconducted duringbalancedor inhalational anesthesia.The followingadverse expenences were reportedinpatientsadministered Nuromax (all eventsjudgedby investigators during theclinical trialsto have a possible causalrelationship): Incidence Greter than 1%- None Incidence Less than 1% Cardiovascular': hypotension,' flushing,ventricular fibrillation, myocardial infarction Respiratory: bronchospasm, wheezing Dermatological: urticaria, injection sitereaction SpecialSenses: diplopia Nonspecific: difficultneuromuscular blockreversal,prolonged drugeffect,fever * Reportsof ventricular fibrillation (n=1)and myocardial infarction (n=1)were limitedto ASA Class3-4 patients undergoing cardiacsurgery(n=142). ' 0.3% incidence. All otherreactions unmarked were< 0.1%. OVERDOSAGE: Overdosage withneuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway and controlled ventilation untilrecovery of normal neuromuscular function is assured. Once evidence of recovery from neuromuscular block is observed, further recovery may be facilitated by administration of an anticholinesterase agent (e.g., neostigmine, edrophonium) in conjunction withan appropriate anticholinergic agent (see Antagonism of Neuromuscular Block). Antagonism of Neuromuscular Block: ANTAGONISTS (SUCH AS NEOSTIGMINE) SHOULD NOT BE ADMINISTERED PRIOR TO THE DEMONSTRATION OF SOME SPONTANEOUS RECOVERY FROM NEUROMUSCULAR BLOCK. THE USE OF A NERVE STIMULATOR TO DOCUMENT RECOVERY AND ANTAGONISM OF NEUROMUSCULAR BLOCK IS RECOMMENDED. T4 /T, SHOULD BE > ZERO BEFORE ANTAGONISM IS ATTEMPTED. In an analysis of patients in whom antagonism of neuromuscular block was evaluated following administration of single doses of neostigmine averaging 0.06 mg/kg (range: 0.05 to 0.075) administered at approximately 25% T1 spontaneous recovery during balanced anesthesia, 71% of patients exhibited TJTi 0.7 before monitoring was discontinued. For these patients, the mean time to T4 /T1 0.7 was 19 minutes (range: 7 to 55). As with other long-acting nondepolarizing neuromuscular blocking agents, the time for recovery of neuromuscular function following administration of neostigmine is dependent upon the level of residual neuromuscular blockat the time of attempted reversal; longer recovery times than those cited above may be anticipated when neostigmine is administered at more profound levels of block (i.e., at < 25% T1 recovery). Patients should be evaluated for adequate clinical evidence of antagonism, e.g., 5-second head lift, and grip strength. Ventilation must be supported untilno longer required. As withother neuromuscular blocking agents, physicians should be alert to the possibility that the action of the drugs used to antagonize neuromuscular block may wear off before the effects of Nuromax on the neuromuscular junction have declined sufficiently. Antagonism may be delayed in the presence of debilitation, carcinomatosis, and the concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular block or separately cause respiratory depression (see Drug Interactions subsection of PRECAUTIONS). Under such circumstances the management is the same as that of prolonged neuromuscular block. In clinical trials, a dose of 1 mg/kg edrophonium was not as effective as a dose of 0.06 mg/kg neostigmine in antagonizing moderate to deep levels of neuromuscular block (i.e., < 60% Ti recovery). Therefore, the use of 1 mg/kg edrophonium is not recommended for reversal from moderate to deep levels ofblock. The use of pyndostigmine has not been studied. Adults: Initial Doses: When administered as a component of a thiopental/narcotic inductionintubation paradigm as well as for production of long-duration neuromuscular block during surgery, 0.05 mg/kg (2 x EDa) Nuromax produces good-to-excellent conditions for tracheal intubation in 5 minutes in approximately 90% of patients. Lower doses of Nuromax may result in a longer time for development of satisfactory intubation conditions. Clinically effective neuromuscular block may be expected to last approximately 100 minutes on average (range: 39 to 232) following 0.05 mg/kg Nuromax administered to patients receiving balanced anesthesia. An initial Nuromax dose of 0.08 mg/kg (3 x EDge)should be reserved for instances in which a need for very prolonged neuromuscular block is anticipated. In approximately 90% of patients, good-toexcellent intubation conditions may be expected in 4 minutes after this dose; however, clinically effective block may be expected to persist foras long as 160 minutes or more (range: 110 to 338) (see CLINICAL PHARMACOLOGY). STORAGE: Store Nuromax Injection at room temperature of 15" to 25°C (59° to 77"F). DO NOT FREEZE. U.S. Patent No. 4701460 March 1991

562004

1. Emmott RS, Bracey BJ, Goldhill DR, Yate PM, Flynn PJ. Cardiovascular effects of doxacurium, pancuronium and vecuronium in anaesthetized patients presenting for coronary artery bypass surgery. BrJ Anaesth. 1990;65:480-486. 2. Tullock WC, Diana P, Cook R, et al. Neuromuscular and cardiovascular effects of high-dose vecuronium Anesth Analg. 1990;70:86-90. 3. Stoops CM, Curtis CA, Kovach DA, et al. Hemodynamic effects of doxacurium chloride in patients receiving oxygen sufentanil anesthesia for coronary artery bypass grafting or valve replacement. Anesthesiology. 1988;69:365-370.

BurroughsWellcome Co.. 3030 Cornwallis Road, ResearchTriangle Park, NC 27709 WeoWmeCopr. Burroughs Wellcome Co.All rights reserved. NM-Y01326R

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3u oays vaca on wim pay. vppotunes ror wona iraveL Finally we give their careersroom to flourish, or even gain in responsibility We'll even help them get the education they need to get ahead. With that kind of care,it's no wonder they respond.For more information about

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