PRODUCT MONOGRAPH

ZEMURON(r)

Rocuronium Bromide Injection 10 mg/mL multiple dose vials (5 mL and 10 mL)

Non-depolarizing Skeletal Neuromuscular Blocking Agent

Organon Canada Ltd./Ltee. Date of Approval: February 4, 1993 200 Consilium Place, Suite 700 Date of Revision: January 8, 2002 Scarborough, Ontario M1H 3E4 Control# 072642

PRODUCT MONOGRAPH

ZEMURON(r)

Rocuronium Bromide Injection 10 mg/mL multiple dose vials (5 mL and 10 mL)

Non-depolarizing Skeletal Neuromuscular Blocking Agent

THIS DRUG SHOULD BE ADMINISTERED ONLY BY ADEQUATELY-TRAINED INDIVIDUALS FAMILIAR WITH ITS ACTIONS, CHARACTERISTICS, AND HAZARDS.

ACTIONS AND CLINICAL PHARMACOLOGY

ZEMURON(r) (rocuronium bromide) Injection is a non-depolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and an intermediate duration of action. The drug acts by binding competitively to cholinergic receptors at the motor end-plate to antagonize the action of acetylcholine, an effect which is reversible in the presence of acetylcholinesterase inhibitors, such as neostigmine and edrophonium. Pharmacodynamics: The ED95 (dose required to produce 95% suppression of the first [T1] mechanomyographic [MMG] response of the thumb to indirect supramaximal train-of-four stimulation of the ulnar nerve) is approximately 0.3 mg/kg (300 mcg/kg) in adults receiving opioid/N2O/O2 anesthesia. At equipotent doses, rocuronium has approximately the same clinically effective duration of action as vecuronium. However, the onset of action is approximately 40% shorter for rocuronium than for vecuronium at doses of 2 to 3 times the ED95. The median pharmacodynamic parameter values for ZEMURON(r) over a range of doses are presented in Tables 1 and 2: Table 1. Pharmacodynamic Parameter Values for the Initial Dose of ZEMURON(r) administered during Opioid/N2O/O2 Anesthesia (Adults) and Halothane Anesthesia (Children) Median [Range].

n= the number of patients who had Time to Maximum block recorded. Clinical duration= time until return to 25% of control T1.

Patients receiving doses of 0.45mg/kg who achieved less than 90% block (16% of these patients) had about 12 to 15 minutes to 25% recovery.

Table 2. Intubating Conditions in Patients with Intubation Initiated at 60 to 70 seconds. Percent, Median [Range]

Excludes patients undergoing cesarean section

Excellent Intubating Conditions = jaw relaxed, vocal cords apart & immobile, no diaphragmatic movement Good Intubating Conditions = jaw relaxed, vocal cords apart & immobile, some diaphragmatic movement

Intubation Conditions: (r)

A dose of 0.60 mg/kg (2 X ED ) ZEMURON

administered following the induction of thiopental/narcotic anesthesia in adults or halothane anesthesia in children generally produces good or excellent conditions for tracheal intubation initiated at 60-70 seconds post- administration (see Table 2). Intubating conditions were assessed in 230 patients in six clinical trials where anesthesia was induced with either thiopental (3-6 mg/kg) or propofol (1.5-2.5 mg/kg) in combination with either fentanyl (2-5 mcg/kg) or alfentanil (1mg). Most of the patients also received a premedication such as midazolam or temazepam. Most patients had intubation attempted within 60 to 90 seconds of administration of ZEMURON(r) (rocuronium bromide) Injection 0.6 mg/kg or succinylcholine 1-1.5 mg/kg. Excellent or good intubating conditions were achieved in 119/120 (99%[95% CI 95-99.9%]) patients receiving ZEMURON(r) and in 108/110 (98%[95% CI 94-99.8%]) patients receiving succinylcholine. The duration of action of ZEMURON(r) 0.6 mg/kg is longer than succinylcholine and at this dose is approximately equivalent to the duration of other intermediate acting neuromuscular blocking drugs. Maintenance Doses: In adult patients under opioid/N2O/O2 anesthesia, the median (range of individual values) clinical duration (time from injection of the maintenance dose at a T1 of 25% of control to a return to 25% of the control T1) of maintenance doses of 0.1, 0.15 and 0.2 mg/kg (100, 150 and 200 mcg/kg) of ZEMURON(r) is 12 minutes (range 2 - 31 minutes), 17 minutes (range 6 - 50 minutes), and 24 minutes (range 7 - 69 minutes), respectively. Repetitive maintenance dosing results in clinically insignificant median increases of 2 - 4 minutes in clinical duration between the first and fifth consecutive dose. The median (range) rate of spontaneous recovery of T1 from 25 to 75% (n = 182), following the final maintenance dose of ZEMURON(r), is 13 minutes (4 - 84 minutes). Anticholinesterase Antagonism: Once spontaneous recovery has started, the neuromuscular block produced by ZEMURON(r) is readily reversed with various anticholinesterase agents, e.g., edrophonium or neostigmine. The deeper the level of neuromuscular blockade at reversal, the longer the time required for recovery of neuromuscular function and the greater the dose of anticholinesterase agent required. Reversal data were analyzed for 320 patients who received neostigmine or edrophonium in the North American clinical trials. When neuromuscular block was reversed at a T1 of 22-28% in 36 adults, recovery to a T1 of 89(50-132)% and T4/T1 of 69(38-92)% was achieved within 5 minutes. Only five of the 320 adults reversed received an additional dose of reversal agent. The median (range) dose of neostigmine was 0.04 (0.01 to 0.09) mg/kg and the median (range) dose of edrophonium was 0.5 (0.3 to 1.0) mg/kg. In geriatric patients (n=51) reversed with neostigmine, the median T4/T1 increased from 40 to 88% in 5 minutes. Children (n=27) who received 0.5 mg/kg edrophonium had increases in the median T4/T1 from 37% at reversal to 93% after 2 minutes. Children (n=58) who received 1 mg/kg edrophonium had increases in the median T4/T1 from 72% at reversal to 100% after 2 minutes. Infants (n=10) who were reversed with 0.03 mg/kg neostigmine recovered from 25 to 75% T1 within 4 minutes. There were no reports of less than satisfactory clinical recovery of neuromuscular function. Inhalation Anesthetics: The duration of the neuromuscular blocking action of ZEMURON(r) may be enhanced by approximately 30% in the presence of potent inhalation anesthetics. The median clinical duration of a dose of 0.6 mg/kg was 30, 38, and 42 minutes under opioid/N2O/O2, enflurane and isoflurane maintenance anesthesia, respectively. During 1 - 2 hr of infusion, the infusion rate of ZEMURON(r) required to maintain about 95% block was decreased by as much as 40% under enflurane and isoflurane anesthesia (see the "Inhalation Anesthetics" subsection of PRECAUTIONS). Pediatrics: Children (1-13 yr) under halothane anesthesia are less sensitive to ZEMURON(r) (ED approximately 0.18 mg/kg [180 mcg/kg], ED95 0.35-0.4 mg/kg [350-400 mcg/kg]) than adults on a mg/kg (mcg/kg) basis. The onset time and duration of block are shorter in children (1-13 yr) than in adults (see Table 1). During halothane anesthesia, at doses of 0.6 mg/kg (600 mcg/kg) of ZEMURON(r), the median onset time is 60 seconds (30 - 200 sec.) and the clinical duration is 26 min. (17 - 39 min. ). Maintenance doses of 0.1 or 0.125 mg/kg (100 or 125 mcg/kg) ZEMURON(r) in children under halothane anesthesia provided a median clinical duration of 7 and 10 minutes, respectively. The median rate of spontaneous recovery of T1 from 25 - 75% was 9.5 minutes (4 - 29 minutes). The clinical durations of action of 0.6 and 0.8 mg/kg doses of ZEMURON(r) are approximately 30-60% longer in infants aged 3 months to 1 year than in children aged 1-13 yrs (see Table 1). Geriatrics: Geriatric patients (> 65 yrs) under opioid/N2O/O2 anesthesia show a longer onset time and duration of block than adults (18-65 yrs) at equivalent doses. At doses of 0.6, 0.9 and 1.2 mg/kg (600, 900 and 1200 mcg/kg) of ZEMURON(r), median onset times of 3.7 (1.3-11.3), 2.5 (1.2-5.0), and 1.3 (1.2-4.7) minutes, respectively, have been reported for geriatric patients compared with 1.8 (0.6-13.0), 1.4 (0.8-6.2), and 1.0 (0.6-4.7) minutes, respectively for adults. Thus, ZEMURON(r) is not recommended for rapid sequence tracheal intubation in geriatric patients. Median clinical duration times at these doses were 46 (22-73), 62 (49-75), and 94 (64-138) minutes, respectively for geriatric patients versus 31 (15-85), 58 (27-111), and 67 (38-160) minutes, respectively for adults. The median rate of spontaneous recovery of T1 from 25-75% after a dose of 0.6 mg/kg (600 mcg/kg) was 21 (11- 56) minutes in geriatric patients (70-90 yrs) compared with 12 (5-36) minutes in young adults (18-60 yrs). Hepatic Impairment: The influence of hepatic impairment on the pharmacodynamics of a 0.60 mg/kg dose of ZEMURON(r) was investigated in a study in which 9 patients with alcoholic cirrhosis were compared to 10 patients with normal hepatic function. Relative to the normal group, the patients with hepatic impairment exhibited an increased clinical duration of action (60 versus 42 min). The recovery index (time for recovery from 25-75% T1 suppression) was also prolonged in the cirrhotic patients (53 versus 20 min). Renal Failure: Three single centre clinical trials have been performed to compare the pharmacodynamic characteristics of a 0.6 mg/kg dose of ZEMURON(r) in patients having normal renal function (n=31) to those for patients (n=30) having renal impairment undergoing kidney transplantation or AV shunt/peritoneal catheter implantation surgery for haemodialysis while receiving steady-state isoflurane anesthesia. The pharmacodynamic characteristics of ZEMURON(r) were not altered in a consistent manner in the patients with renal impairment although clinical duration and recovery times were more variable than in patients with normal renal function. Dosage adjustments are not recommended for patients with renal impairment receiving ZEMURON(r). Hemodynamics: In most clinical trials, the monitoring of haemodynamic parameters during the period immediately following the administration of ZEMURON(r) was confounded by laryngoscopy and intubation, events in themselves associated with elevations of heart rate and mean arterial blood pressure. In one study in which a six minute period was permitted to elapse between the administration of ZEMURON(r) at 0.6, 0.9, and 1.2 mg/kg doses and subsequent intubation, no dose-dependent changes in heart rate or mean arterial pressure were observed. Histamine Release: In studies of histamine release, a clinically significant elevation of plasma histamine concentration occurred in 1 of 88 patients. Clinical signs of histamine release (flushing, rash, or bronchospasm) associated with the administration of ZEMURON(r) (rocuronium bromide) Injection were assessed in clinical trials and reported in 9 of 1137 (0.8%) patients. Pharmacokinetics: The pharmacokinetic characteristics of intravenously administered ZEMURON(r) are best described by a three compartment open model. The comparative population estimates for geriatrics and other adult surgical patients receiving a single 0.6 mg/kg dose of ZEMURON(r) during opioid/N2O/O2 anesthesia are presented in Table 3. Table 3. Pharmacokinetic Parameters * in Adults (n=22; ages 27-58 yr) and Geriatrics (n=20; 65-78 yrs) during Opioid/N2O/O2 Anesthesia Mean + SD

• Data from the in vivo pharmacokinetics studies were used to generate population estimates for the parameters and a measure of the estimate variability.

The comparative population estimates for normal adults, patients with renal impairment undergoing cadaver renal transplantation, and patients with hepatic cirrhosis receiving a single 0.6 mg/kg dose of ZEMURON(r) during isoflurane anesthesia are presented in Table 4. Table 4. Pharmacokinetic Parameters * in Adults with Normal Renal and Hepatic Function (n=10, ages 23-65), Renal Transplant Patients (n=10, ages 21-45) and Hepatic Dysfunction Patients (n=9, ages 31-67) During Isoflurane Anesthesia Mean + SD 2.4 + 0.8

Data from the in vivo pharmacokinetics studies were used to generate population estimates for the parameters and a measure of the estimate variability.

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Differences in the calculated T

b and Cl between this study and the study in young adults vs. geriatrics (> 65 years) are

related to the different sample populations and anesthetic techniques.

Elderly: In a study of the comparative pharmacokinetics of a 0.60 mg/kg dose of ZEMURON(r) in 22 adult (27-58 yrs) and 20 geriatric (70-78 yrs) patients, advanced age was associated with a significant decrease in clearance and steady-state volume of distribution, although the elimination half-life remained unaltered.

Pediatric:

* only estimates from three compartment model included (n=18)

In pediatric patients receiving a single 0.8 mg/kg bolus dose of ZEMURON(r), the observed half-life values were in the same order of magnitude as those reported for adult patients. The half-life values for rocuronium decreased with advancing pediatric age. Clearance tended to be somewhat higher in the 3-8 year olds than in the younger patients. The steady-state volume of distribution was significantly higher in the 3-12 month age group than in the 3-8 year age group. No statistically significant differences were observed between the three age groups in terms of the plasma levels of rocuronium at 25%, 75%, and 90% recovery.

Hepatic and Renal Impairment:

The steady-state volume of distribution was increased by about 30% in patients undergoing cadaver renal transplantation (n=10) and 100% in patients with hepatic dysfunction associated with alcoholic cirrhosis (n=9) relative to patients with normal renal and hepatic function (n=10). The beta elimination half-life was increased by approximately 80% in

patients with hepatic impairment, but was unaffected in the renally impaired patient group. Inhalational Anesthesia: Plasma levels of ZEMURON(r) during continuous infusion were determined in patients receiving steady-state opioid/N2O/O2 (n=10), enflurane (n=9), or isoflurane (n=9) anesthesia. At the end of the second hour of continuous infusion, lower mean plasma concentrations were required to maintain 90-95% neuromuscular blockade during steady-state isoflurane (1223 ng/mL) and enflurane (1117 ng/mL) anesthesia than during opioid/N2O/O2 (1358 ng/mL) anesthesia.

Metabolism:

Following administration of a single 1.0 mg/kg bolus dose to 10 adult patients, metabolites in the plasma or urine were either absent or below the limit of detection (5 ng/mL).

Excretion:

Following administration of a single 1.0 mg/kg bolus dose to 10 adult patients, total urinary excretion was 33% over a 24 hr period. Of this, 65% was recovered during the first 2 hrs and 94% over the first 6 hrs.

Placental Transfer: The placental transfer of ZEMURON(r) was investigated in two studies involving a total of 17 neonates born to women receiving 0.6 mg/kg ZEMURON(r) during Cesarean section. The mean umbilical venous to maternal venous plasma ratio ranged from 16-22% in these studies.

Reduced Plasma Cholinesterase Activity:

No differences from patients with normal plasma cholinesterase activity are expected since rocuronium metabolism does not depend on plasma cholinesterase.

CONTRAINDICATIONS

ZEMURON(r) (rocuronium bromide) Injection is contraindicated in patients known to have an allergic hypersensitivity to the drug or any component of its formulation.

WARNINGS

General: ZEMURON(r) (ROCURONIUM BROMIDE) INJECTION SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED DOSAGES BY OR UNDER THE SUPERVISION OF EXPERIENCED CLINICIANS WHO ARE FAMILIAR WITH ITS 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 NEUROMUSCULAR BLOCKING AGENTS SUCH AS ZEMURON(r) EMPLOY A PERIPHERAL NERVE STIMULATOR TO MONITOR DRUG RESPONSE, NEED FOR ADDITIONAL RELAXANT, AND ADEQUACY OF SPONTANEOUS RECOVERY OR ANTAGONISM.

Intensive Care Unit: To reduce the possibility of prolonged neuromuscular blockade and other complications that might occur following long-term use in the ICU, ZEMURON(r) or any other neuromuscular relaxant should be administered in carefully adjusted doses by or under the supervision of experienced clinicians who are familiar with its actions and with appropriate peripheral nerve stimulator muscle monitoring techniques.

Neuromuscular Disease:

In patients with myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, small doses of non-depolarizing neuromuscular blocking agents may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants. For patients having conditions in which prolonged neuromuscular blockade is a possibility (e.g., neuromuscular disease, carcinomatosis, severe cachexia, or debilitation), a peripheral nerve stimulator and use of a small test dose may be of particular value in assessing and monitoring dosage requirements.

Compatibility: ZEMURON(r) (rocuronium bromide) Injection, which has an acid pH, should not be mixed with alkaline solutions (e.g. barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle. Anaphylaxis: Although very rare, severe anaphylactic reactions to neuromuscular blocking agents, including ZEMURON(r), have been reported. These reactions have, in some cases, been life threatening. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Special precautions should be taken in patients who have had previous anaphylactic reactions to other neuromuscular blocking agents, since allergic cross-reactivity has been reported in this class of drugs.

PRECAUTIONS

Rapid Sequence Tracheal Intubation: Rapid sequence tracheal intubation has not been adequately studied at time points of less than 60 seconds post-administration of ZEMURON(r). As the onset of action of ZEMURON(r) is delayed in geriatric patients relative to other adults, the use of ZEMURON(r) for rapid sequence intubation is not recommended in patients over 65 years of age. Cardiovascular Effects: ZEMURON(r) was associated with a slight elevation of heart rate and blood pressure in some studies (mean increase < 10% over baseline) in which haemodynamic measurements were performed prior to intubation and initiation of surgery. The increase in heart rate and mean arterial pressure which occurs during endotracheal intubation may be accentuated in the presence of ZEMURON(r). In the North American studies, laryngoscopy and tracheal intubation following ZEMURON(r) administration were accompanied by transient tachycardia (> 30% increases) in about one-third of adult patients under opioid/N2O/O2 anesthesia. Experience with ZEMURON(r) in patients undergoing cardiovascular surgery is limited to two small clinical trials. In one of these, seventeen patients scheduled for aortic surgery were anaesthetized with fentanyl and flunitrazepam then intubated prior to receiving single bolus doses of 0.6 or 0.9 mg/kg ZEMURON(r). Mean arterial pressure was significantly increased over baseline levels at 2, 5, and 10 minute time points in the 0.6 mg/kg (15-24% increases over baseline) but not the 0.9 mg/kg (3-7% increases over baseline) group. In another study, the hemodynamic effects of single bolus doses of 0.9 mg/kg ZEMURON(r) and 0.15 mg/kg vecuronium were studied in ASA 3 and 4 patients scheduled for coronary artery bypass grafting in whom anesthesia had been induced with midazolam and sufentanil. ZEMURON(r) (n=11) was associated with statistically significant increases in mean arterial blood pressure at 5 minutes post-administration (13% increase over baseline) and 10 minutes post-intubation (9% increase over baseline) which were not seen in the vecuronium group (n=10). These increases did not, however, represent an elevation over mean arterial blood pressure values prior to the induction of anesthesia. In both of these studies, mean increases in heart rate of 6-8% over post-induction baseline values were observed. Tachycardia (> 30%) occurred in 12 of 127 children. Most of the children developing tachycardia were from a single study in which the patients were anesthetized with halothane and did not receive atropine for induction. Pulmonary Vascular Resistance: Caution is appropriate in patients with pulmonary hypertension or valvular heart disease. In one clinical trial, 10 patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft surgery received an initial dose of 0.6 mg/kg ZEMURON(r) (rocuronium bromide) Injection. Neuromuscular block was maintained during surgery with bolus maintenance doses of 0.3 mg/kg. Following induction, continuous 0.008 mg/kg/min infusion of ZEMURON(r) produced relaxation sufficient to support mechanical ventilation for 6 to 12 hours in the surgical intensive care unit (SICU) while the patients were recovering from surgery. Hypertension and tachycardia were reported in some patients but these occurrences were less frequent in patients receiving beta or calcium channel blocking drugs. In 7 of these 10 patients ZEMURON(r) was associated with transient increases (> 30%) in pulmonary vascular resistance. In another clinical trial of 17 patients undergoing abdominal aortic surgery, transient increases (> 30%) in pulmonary vascular resistance were observed in 4 of 17 patients receiving ZEMURON(r) 0.6 or 0.9 mg/kg. Anaphylaxis: There have been rare reports of severe anaphylactic reactions to ZEMURON(r), including some that have been life threatening. Clinicians should be prepared for the possibility of these reactions and take the necessary precautions, including the immediate availability of emergency treatment (see WARNINGS). Long-term Use in I.C.U. : No information is available concerning the efficacy and safety of long- term (days to weeks) intravenous ZEMURON(r) infusion to facilitate mechanical ventilation in the intensive care unit. In rare cases, long-term use of neuromuscular blocking drugs to facilitate mechanical ventilation in I.C.U. settings has been associated with prolonged paralysis and/or skeletal muscle weakness that is first noted during attempts to wean patients from the ventilator. In these patients, the actions of the neuromuscular blocking agent may be enhanced by other drugs (e.g., broad spectrum antibiotics, narcotics and/or steroids) or by conditions such as acid-base or electrolyte imbalance, hypoxic episodes of varying duration, or extreme debilitation. Additionally, patients immobilized for extended periods frequently develop symptoms consistent with disuse muscle atrophy. The recovery picture may vary from regaining movement and strength in all muscles to initial recovery of movement of the facial muscles and small muscles of the extremities then to the remaining muscles. In rare cases, recovery may involve an extended period of time or even require rehabilitation. Therefore, when there is a need for long-term mechanical ventilation, the benefits-to-risk ratio of neuromuscular blockade must be considered. The syndrome of critical illness polyneuropathy associated with sepsis and multiorgan failure may be associated with prolonged skeletal muscle paralysis, but can also occur without the use of muscle relaxants. Thus, the role of muscle relaxants in the etiology of prolonged paralysis in the I.C.U. is not known with certainty. Continuous infusion or intermittent bolus dosing to support long term mechanical ventilation has not been studied sufficiently to support dosage recommendations. WHENEVER THE USE OF ZEMURON(r) OR ANY NEUROMUSCULAR BLOCKING AGENT IS CONTEMPLATED IN THE ICU, IT IS RECOMMENDED THAT NEUROMUSCULAR TRANSMISSION BE MONITORED CONTINUOUSLY DURING ADMINISTRATION AND RECOVERY WITH THE HELP OF A NERVE STIMULATOR. ADDITIONAL DOSES OF ZEMURON(r) OR ANY OTHER NEUROMUSCULAR BLOCKING AGENT SHOULD NOT BE GIVEN BEFORE THERE IS A DEFINITE RESPONSE TO T1 OR TO THE FIRST TWITCH. IF NO RESPONSE IS ELICITED, INFUSION ADMINISTRATION SHOULD BE DISCONTINUED UNTIL A RESPONSE RETURNS. Pregnancy: A teratogenicity study has been conducted in rats using intravenously administered doses of ZEMURON(r) up to 0.3 mg/kg. No teratogenic effects were observed at the sub-paralyzing doses used in this study. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies have not been performed under conditions that would approximate those of clinical use, ZEMURON(r) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Use in Obstetrics (Cesarean section): ZEMURON(r)(rocuronium bromide) Injection 0.6 mg/kg (600 mcg/kg) was administered with thiopental, 3-4 mg/kg (n=13) or 4-6 mg/kg (n=42), for rapid sequence induction of anesthesia for cesarean section. The umbilical venous plasma concentrations were 18% of maternal concentrations at delivery. No neonate had APGAR scores of <7 at 5 minutes post-delivery. Intubating conditions were poor or inadequate in 5 of 13 women receiving 3-4 mg/kg thiopental when intubation was attempted 60 seconds after drug injection. Therefore, ZEMURON(r) is not recommended for rapid sequence induction in cesarean section patients. The possibility of respiratory depression in the neonate should always be considered following a cesarean section during which a neuromuscular blocking agent has been administered. Nursing Mothers: It is not known whether ZEMURON(r) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZEMURON(r) is administered to a nursing woman. Pediatric Use: The use of ZEMURON(r) in children less than 3 months of age has not been investigated. (See ACTIONS AND CLINICAL PHARMACOLOGY and the "Use in Pediatrics" subsection of DOSAGE AND ADMINISTRATION for clinical experience and recommendations for use in infants and children 3 months to 14 years of age.) Although the potency of ZEMURON(r) is similar in infants and older children (estimated ED95 values of 0.39 mg/kg for infants 1-12 months, 0.35 mg/kg for children 1-4 yrs, 0.40 mg/kg for children 4-13 yrs under halothane anesthesia), the duration of clinically effective blockade tends to be longer in infants less than 12 months in age. Of the children anesthetized with halothane who did not receive atropine with induction, about 80% experienced a transient increase (> 30%) in heart rate after intubation. Geriatric Use: ZEMURON(r) has been administered to 43 elderly patients (65-78 yrs) in clinical trials. The duration of neuromuscular blockade tends to be slightly longer in elderly patients (see ACTIONS AND CLINICAL PHARMACOLOGY). As the onset of action of ZEMURON(r) is delayed in geriatric patients relative to other adults, the use of ZEMURON(r) for rapid sequence intubation is not recommended in patients over 65 years of age. Hepatic Disease: ZEMURON(r) has been studied in a limited number of patients (n=38) with clinically significant hepatic disease. In 9 patients with alcoholic cirrhosis receiving stable isoflurane anesthesia, the median clinical duration of a 0.6 mg/kg (600 mcg/kg) dose was moderately prolonged (60 min) compared to that observed in 10 patients with normal hepatic function (42 min). The median recovery rate (25-75% recovery of twitch suppression) was also prolonged in patients with cirrhosis (53 min) compared to patients with normal hepatic function (20 min). Because ZEMURON(r) is primarily excreted by the liver, it should be used with caution in patients having clinically significant hepatic disease. Four of eight patients with cirrhosis, who received ZEMURON(r) 0.6 mg/kg under opioid/N O/O anesthesia, did not achieve complete block. These

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findings are consistent with the increase in volume of distribution at steady state observed in patients with significant hepatic disease. If used for rapid sequence induction in patients with ascites, an increased initial dosage may be necessary to assure complete block. Duration will be prolonged in these cases. The use of single bolus doses higher than 0.6 mg/kg has not been studied in patients with hepatic impairment. Renal Failure: ZEMURON(r) has been studied at the dose of 0.6 mg/kg (600 mcg/kg) in a limited number of patients (n=10) undergoing renal transplant surgery, recently dialyzed in preparation for cadaver renal transplant. The median clinical duration was not considered to be prolonged relative to patients with normal renal function (53 min versus 42 min), however there was substantial variation within the renal transplant group (range: 22 - 90 minutes). The median spontaneous recovery rate from 25 to 75% of control in renal transplant patients was similar to that in normal patients (30 [7-35] min vs. 20 [12 - 67]min). Two additional studies have been performed in which ZEMURON(r) was administered to a total of 20 patients undergoing nephrectomy, AV shunt surgery, or implantation of peritoneal catheters. These studies did not demonstrate a consistent trend for prolongation of recovery time. Due to the limited role of the kidney in the excretion of ZEMURON(r), usual dosing guidelines should generally be suitable for patients with renal failure. Concomitant Disease States: As with other neuromuscular blocking agents, ZEMURON(r) may have profound neuromuscular blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with carcinomatosis. In these or other patients in whom potentiation of neuromuscular block or difficulty with reversal may be anticipated, a decrease from the recommended initial dose should be considered. Resistance to non-depolarizing neuromuscular blocking agents may be associated with burns, disuse atrophy, denervation, cerebral palsy, and direct muscle trauma. Obesity: ZEMURON(r) (rocuronium bromide) Injection 0.6 mg/kg has been administered according to actual body weight (ABW) (n=12) or ideal body weight (IBW) (n=11) in a clinical trial in obese patients. Obese patients dosed according to IBW had a longer time to maximum block (median 135 sec. [73-203] vs. 83 sec. [57-102]) and a shorter clinical duration (median 25 min. [14-29] vs. 34 min. [24-52]) than obese patients dosed according to ABW. Patients dosed according to IBW did not achieve intubating conditions comparable to those dosed based on ABW. A third group consisting of non-obese patients receiving 0.6 mg/kg ZEMURON(r), exhibited a time to maximum block of 116 (61-165) seconds and a clinical duration of 28 (19-38) minutes. These results support the recommendation that obese patients be dosed based on actual body weight. Hypothermia: Hypothermia (25o-28oC) has been associated with a decreased requirement for nondepolarizing neuromuscular blocking agents. Malignant Hyperthermia (MH): Malignant hyperthermia has not been reported in association with the administration of ZEMURON(r). Because ZEMURON(r) is always used with other agents, and because the occurrence of malignant hyperthermia during anesthesia is possible even in the absence of known triggering agents, clinicians should be familiar with early signs, confirmatory diagnosis and treatment of malignant hyperthermia prior to the start of any anesthetic. In an animal study in MH-susceptible swine, the administration of ZEMURON(r) was not associated with the development of malignant hyperthermia.

Burns:

Resistance to nondepolarizing neuromuscular blocking agents may develop in patients with burns, depending upon the time elapsed since the injury and the size of the burn.

Delayed Onset of Action: The onset of action of nondepolarizing neuromuscular blockers may be delayed in patients having conditions associated with slower circulation time (e.g., cardiovascular disease or advanced age) or an increased volume of distribution (e.g., edematous states). Because higher doses of ZEMURON(r) produce a longer duration of action, the initial dosage should not usually be increased in these patients to enhance onset time; instead, more time should be allowed for the drug to achieve its maximum effect. Central Nervous System: ZEMURON(r) has no known effect on consciousness, pain threshold or cerebration. Therefore, administration must be accompanied by adequate anesthesia or sedation.

Acid-Base or Electrolyte Abnormalities:

Electrolyte and/or acid-base imbalances may enhance or inhibit neuromuscular blockade. For example, hyperkalemia has been reported to antagonize nondepolarizing agents while hypokalemia has been associated with an enhancement of their activity.

Intramuscular Use: No data are available to support the use of ZEMURON(r) by intramuscular injection. Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies in animals have not been performed to evaluate carcinogenic potential or impairment of fertility. Mutagenicity studies (Ames test, mammalian cell, and micronucleus test) conducted with ZEMURON(r) revealed no mutagenic potential.

DRUG INTERACTIONS

Succinylcholine: The use of ZEMURON(r) before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been sufficiently studied. If ZEMURON(r) is administered following succinylcholine, it should not be given until recovery from succinylcholine has been observed. When a 0.6 mg/kg (600 mcg/kg) dose of ZEMURON(r) was administered after a 1 mg/kg dose of succinylcholine following recovery of T1 to 75% of control, the mean clinical duration of action was slightly prolonged relative to that observed without succinylcholine (mean 36 vs. 30 minutes). Other Nondepolarizing Muscle Relaxants: There are no controlled studies documenting the use of ZEMURON(r) before or after other non-depolarizing muscle relaxants. Interactions have been observed when other non-depolarizing muscle relaxants have been administered in succession.

(r)

Inhalation Anesthetics: The ED50 of ZEMURON in adult patients determined under stable end- tidal concentrations of isoflurane, halothane, and enflurane was reduced by 20%, 41%, and 46% respectively, as compared with that determined under opioid/N2O/O2 anesthesia. ED95 doses were, however, similar for patients receiving opioid/N2O/O2, halothane, and isoflurane anesthesia. The ED95 under conditions of enflurane anesthesia was approximately 40% lower than that determined for other types of anesthesia. Since the neuromuscular blocking agents are routinely administered before, or shortly after, the administration of inhalation anesthetics, minimal effects on onset time and peak effect are generally observed. In routine use of neuromuscular blocking agents, only spontaneous recovery is generally affected (prolonged). No definite interaction between ZEMURON(r) and halothane, as used clinically, has been demonstrated. In one study use of enflurane in 10 patients, resulted in a 20% increase in the mean clinical duration of the initial intubating dose, and a 37% increase in the duration of subsequent maintenance doses, when compared in the same study to 10 patients under opioid/N2O/O2 anesthesia. Potentiation by these agents is also observed with respect to the infusion rates of ZEMURON(r) required to maintain approximately 95% neuromuscular block. Under isoflurane and enflurane anesthesia, the infusion rates are approximately 30-40% lower than under conditions of opioid/N2O/O2 anesthesia. The median spontaneous recovery time from 25 to 75% of control T1 is prolonged by enflurane and isoflurane by 15% and 62% respectively. Halothane did not prolong the spontaneous recovery rate. Reversal-induced recovery of ZEMURON(r) neuromuscular block is similar regardless of anesthetic technique. Intravenous Anesthetics: The use of propofol for induction and maintenance of anesthesia does not alter the clinical duration or recovery characteristics following recommended doses of ZEMURON(r). Anticonvulsants: There are limited data (4 patients in 4 trials) from clinical trials in which patients received ZEMURON(r) during chronic anticonvulsant therapy with phenytoin. In two of these patients, apparent resistance to the effects of ZEMURON(r) was observed in the form of diminished magnitude of neuromuscular block or shortened clinical duration. In patients receiving chronic treatment with anticonvulsants such as phenytoin and carbamazepine, the possibility of diminished effect or shortened duration should be considered when ZEMURON(r) is administered. Infusion rates may need to be increased.

Antibiotics:

Parenteral/intraperitoneal administration of high doses of certain antibiotics may produce neuromuscular block or intensify the blockade induced by non-depolarizing neuromuscular relaxants. The following antibiotics have been associated with various degrees of paralysis: aminoglycosides (such as neomycin, streptomycin, kanamycin, gentamicin, and dihydrostreptomycin), vancomycin, tetracyclines, bacitracin, polymyxin B, colistin, and sodium colistimethate.

If these or other newly introduced antibiotics are used in conjunction with ZEMURON(r) during surgery, prolongation of neuromuscular block should be considered a possibility. Three antibiotics, cefuroxime (20 mg/kg i.v. ), netilmicin (2 mg/kg i.v. ), and metronidazole (7.5 mg/kg i.v. ), were studied for their interactive effects with ZEMURON(r). Administration of these antibiotics 5 minutes prior to a 0.60 mg/kg dose of ZEMURON(r) has no effect on the onset time to maximum blockade. The mean clinical duration of action tended to be longer in the patients receiving concomitant antibiotic treatment (38 min with saline, 43 min with metronidazole, 44-49 min with cefuroxime, and 50 min with netilmicin), although the observed differences were not statistically significant. The duration of maintenance doses of ZEMURON(r) was not increased in the presence of the antibiotics. Other: Experience concerning injection of quinidine during recovery from use of other muscle relaxants suggests that recurrent paralysis may occur. This possibility must also be considered for ZEMURON(r). Magnesium salts, administered for the management of toxemia of pregnancy, may enhance neuromuscular blockade. Lithium, local anesthetics, and procainamide have been reported to increase the duration of neuromuscular block with non-depolarizing neuromuscular blocking agents. Infusion requirements may be lower in the presence of these drugs.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No cases of significant accidental or intentional overdose have been reported. The possibility of iatrogenic overdosage can be minimized by carefully monitoring the muscle twitch response to peripheral nerve stimulation. Overdosage with neuromuscular 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 until recovery of normal respiration is assured. Upon evidence of spontaneous recovery from neuromuscular blockade, further recovery may be facilitated by administration of an anticholinesterase agent (e.g., neostigmine or edrophonium) in conjunction with an appropriate anticholinergic agent. A peripheral nerve stimulator should be used to monitor recovery. As overdosage may increase the risk of hemodynamic side effects, intensified monitoring of vital organ function is required for the period of paralysis and during an extended period post recovery.

Antagonism of Neuromuscular Blockade: ANTAGONISTS (SUCH AS NEOSTIGMINE) SHOULD NOT BE ADMINISTERED PRIOR TO THE DEMONSTRATION OF SOME SPONTANEOUS RECOVERY FROM NEUROMUSCULAR BLOCKADE. THE USE OF A NERVE STIMULATOR TO DOCUMENT RECOVERY AND ANTAGONISM OF NEUROMUSCULAR BLOCKADE IS RECOMMENDED. THE TIME REQUIRED FOR ANTICHOLINESTERASE-MEDIATED RECOVERY IS LONGER FOR REVERSALS ATTEMPTED AT DEEPER LEVELS OF BLOCKADE.

Patients should be evaluated for adequate clinical evidence of antagonism, e.g., 5 second head lift, adequate phonation, ventilation and upper airway maintenance. Ventilation must be supported until no longer required. Antagonism may be delayed in the presence of debilitation, carcinomatosis, and concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular blockade or depress respiratory function. Under such circumstances the management is the same as that of prolonged neuromuscular blockade.

DOSAGE AND ADMINISTRATION

ZEMURON(r) (ROCURONIUM BROMIDE) INJECTION IS FOR INTRAVENOUS USE ONLY. THIS DRUG SHOULD BE ADMINISTERED BY OR UNDER THE SUPERVISION OF EXPERIENCED CLINICIANS FAMILIAR WITH THE USE OF NEUROMUSCULAR BLOCKING AGENTS. DOSAGE MUST BE INDIVIDUALIZED IN EACH CASE. To avoid distress to the patient, ZEMURON(r) should not be administered before unconsciousness has been induced. It should not be mixed in the same syringe or administered simultaneously through the same needle with alkaline solutions (e.g., barbiturate solutions). The dosage information which follows is derived from studies in which the administration of ZEMURON(r) was based upon units of drug per unit of body weight. It is expressed in this section in terms of units of mg/kg (instead of mcg/kg) to assist the clinician in calculating individual patient dosage requirements relative to the product as supplied for clinical use. It is intended to serve as an initial guide to the use of ZEMURON(r) by clinicians familiar with other neuromuscular blocking agents (see ACTIONS AND CLINICAL PHARMACOLOGY, and the "Maintenance Dosing" subsection of DOSAGE AND ADMINISTRATION). It is recommended that clinicians administering neuromuscular blocking agents such as ZEMURON(r) employ a peripheral nerve stimulator to monitor drug response, determine the need for additional relaxant and adequacy of spontaneous recovery or antagonism.

Use in Adults:

For intubating times, onset times, and clinical duration for various doses, (see ACTIONS AND CLINICAL PHARMACOLOGY).

Rapid Intubation:

In appropriately pre-medicated and adequately anesthetized patients, doses of

0.60 - 1.2 mg/kg (600 - 1200 mcg/kg) ZEMURON(r) will provide good or excellent intubating conditions in most patients in 60-90 seconds. At initial doses of 0.6 mg/kg, neuromuscular block sufficient for intubation (> 80% block) is attained in a median (range) time of 1 (0.4-6) minute(s). Maximum blockade is achieved in most patients in a median (range) of 1.8 (0.6-13.0) minutes. This dose may be expected to provide 31 (15-85) minutes of clinical relaxation under opioid/N2O/O2 anesthesia. Under halothane, isoflurane, and enflurane anesthesia, some extension of the period of clinical relaxation should be expected (see the "Inhalation Anesthetics" subsection of, PRECAUTIONS). Should there be reason for the selection of a larger bolus dose in individual patients, initial doses of 0.9 or 1.2 mg/kg can be administered during surgery under opioid/N2O/O2 anesthesia. These doses will provide > 80% block in most patients in 1.1 and 0.7 minutes, respectively, with maximum blockade occurring in most patients in 1.4 and 1.0 minute, respectively. Doses of 0.9 and 1.2 mg/kg may be expected to provide 58 (27-111) and 67 (38-160) minutes, respectively, of clinical relaxation under opioid/N2O/O2 anesthesia. Doses for Routine Endotracheal Intubation: The recommended initial dose regardless of anesthetic regimen is 0.6 mg/kg (see Rapid Intubation). A lower dose of ZEMURON(r) (rocuronium bromide) Injection (0.45 mg/kg) may be used. Neuromuscular block sufficient for intubation (> 80%) is attained in a median (range) time of 1.3 (0.8-6.2) minute(s) and most patients have intubation completed within 1.6 (1.0 - 7.0) minutes. Maximum blockade is achieved in most patients in 3.0 (1.3-8.2) minutes. This dose may be expected to provide 22 (12-31) minutes of clinical relaxation under opioid/N2O/O2 anesthesia. Patients receiving this low dose of 0.45 mg/kg who achieve less than 90% block (about 16% of these patients) may have a more rapid time to 25% recovery, 12-15 minutes.

Inhalation Anesthetics:

Maximum blockade, onset times, intubation times, and intubation scores

are similar whether ZEMURON(r) is administered during opioid/N O/O anesthesia or during anesthesia with enflurane, isoflurane, or halothane. The choice of an intubating dose of ZEMURON(r) should not, therefore, be reduced below 0.60 mg/kg if rapid intubation is to be performed or below 0.45 mg/kg if routine tracheal intubation is to be performed. Increases in the clinical duration (25-35%) and recovery time (20-70%) may be apparent, however, in the presence of halogenated inhalation agents. Maintenance Dosing: Maintenance doses of 0.1, 0.15, and 0.2 mg/kg (100, 150, and 200 mcg/kg) ZEMURON(r), administered at 25% recovery of control T1, provide a median 12, 17, and 24 minutes of clinically effective neuromuscular blockade during opioid/N2O/O2 anesthesia (see ACTIONS AND CLINICAL PHARMACOLOGY). Smaller or less frequent bolus maintenance doses should be considered during anesthesia with halogenated inhalation agents. In all cases, dosing should be guided based on the clinical duration following initial dose or prior maintenance dose and not administered until signs of neuromuscular function are evident. Cumulation of effect with repetitive maintenance dosing has been observed (see ACTIONS AND CLINICAL PHARMACOLOGY), but it is not of clinical significance. Use by Continuous Infusion: After evidence of early spontaneous recovery (<10% of control T1) from initial doses of 0.45 - 0.60 mg/kg (450 - 600 mcg/kg), a continuous infusion of 0.01-0.012 mg/kg/min (10-12 mcg/kg/min) can be initiated with the rate of infusion being adjusted thereafter to maintain a 90% suppression of twitch response. The infusion of ZEMURON(r) should be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as determined by peripheral nerve stimulation. Infusion rates may range from 0.004 to 0.016 mg/kg/min (4 to 16 mcg/kg/min). Initiation of the infusion after substantial return of neuromuscular function (more than 10% of control T1), may necessitate additional bolus doses to maintain adequate block for surgery. Halogenated inhalation anesthetics, particularly enflurane and isoflurane may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants. In the presence of steady-state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion by 30% - 50%. Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of ZEMURON(r) infusion may be expected to proceed at rates similar to those following comparable total doses administered by repetitive bolus injections (see ACTIONS AND CLINICAL PHARMACOLOGY). Infusion solutions of ZEMURON(r) can be prepared by mixing ZEMURON(r) with an appropriate infusion solution such as 5% Dextrose Injection, USP. Unused portions of infusion solutions should be discarded.

Use in Pediatrics:

Initial Doses:

Initial doses of 0.6 mg/kg (600 mcg/kg) in children (3 mon-12 yrs) under halothane anesthesia produce 100% neuromuscular blockade and excellent to good intubating conditions within approximately 60 to 90 seconds. This dose will provide approximately 25-30 minutes of clinical relaxation in children aged 1 to 12 years receiving halothane anesthesia. For infants aged 3-12 months, the duration of action of a 0.6 mg/kg dose is longer than in older pediatric patients, averaging 42 minutes under conditions of halothane anesthesia.

Maintenance Doses:

In children aged 4-13 yrs maintenance doses of 0.075 - 0.125 mg/kg (75 - 125 mcg/kg), administered upon return of T1 to 25% of control, provide clinical relaxation for a median of 7 - 10 minute (see ACTIONS AND CLINICAL PHARMACOLOGY).

Use by Continuous Infusion: A continuous infusion of ZEMURON(r) initiated at a rate of 0.012 mg/kg/min (12 mcg/kg/min) upon return of T1 to 10% of control has been demonstrated to maintain neuromuscular blockade at 89-99% in children receiving halothane anesthesia. The infusion of ZEMURON(r) must be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as determined by peripheral nerve stimulation. Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of ZEMURON(r) infusion may be expected to proceed at rates comparable to that following similar total exposure to single bolus doses (see ACTIONS AND CLINICAL PHARMACOLOGY). Use in Geriatrics: Although the potency of rocuronium is similar in geriatric patients and adults, the onset of action is delayed in patients > 65 years. The choice of an intubating dose of ZEMURON(r) should not be reduced below 0.60 mg/kg if routine tracheal intubation is to be performed. Rapid sequence tracheal intubation is not recommended in the elderly. Geriatric patients (> 65 yrs) exhibit a slightly prolonged median (range) clinical duration of 46 (22 - 73) minutes, 62 (49 - 75) minutes and 94 (64 - 138) minutes under opioid/N2O/O2 anesthesia following doses of 0.6, 0.9, and 1.2 mg/kg, respectively. The median (range) rate of spontaneous recovery of T1 from 25 to 75% in geriatric patients is 16.5 (7 - 56) minutes which is not different from that in adults (see ACTIONS AND CLINICAL PHARMACOLOGY). Maintenance doses of 0.1 and 0.15 mg/kg (100 - 150 mcg/kg) ZEMURON(r), administered at 25% recovery of T1, provide approximately 13 and 33 minutes of clinical duration under opioid/N2O/O2 anesthesia.

PHARMACEUTICAL INFORMATION

Drug Substance

Common Name: rocuronium bromide Chemical Name: 1-[17b-(acetyloxy)-3a-hydroxy-2b-(4-morpholinyl)-5a-androstan-16b-yl]-1- (2-propenyl) pyrrolidinium bromide Molecular Formula: C32H53BrN2O4 Molecular Weight: 609.70 Structural Formula: Physical Form: rocuronium bromide is an off-white to pale yellow, or slightly pink amorphous powder. Solubility: soluble in 15 parts of ethanol, in 20 parts of water, acetone and chloroform. Practically insoluble in ethyl acetate and n-hexane. pKa: 7.11 determined in a 1% m/v solution in water

Composition:

ZEMURON(r) is a sterile non-pyrogenic solution. ZEMURON(r) without preservative Each ml contains: rocuronium bromide 10.00 mg sodium acetate, trihydrate 2.00 mg sodium chloride approx. 3.3 mg water for injection q.s to 1 ml nitrogen present ZEMURON(r) may contain: sodium hydroxide and/or glacial acetic acid to adjust the pH to approximately 4.0.

Stability and Storage Recommendations:

ZEMURON(r) should be stored under refrigeration (2-8o C) until ready to use. To facilitate use in the operating room, the unopened vials may be stored up to 60 days at room temperature (15-30o C). Use punctured vials of ZEMURON(r) within 30 days.

Compatibility:

ZEMURON(r) is compatible in solution with: 0.9% Sodium Chloride Injection, USP 5% Dextrose Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP Sterile Water for Injection, USP Lactated Ringer's Solution Use within 24 hours of mixing with the above solutions. ZEMURON(r) Injection 10 mg/mL may be added to an appropriate amount of product in i.v. infusion bottles, bags and PCA syringe pumps to yield a final concentration of 0.5 mg/mL and 2 mg/mL. The following tables show the volume ratios of i.v. fluid/ZEMURON(r) in each of the i.v. fluids to an approximate yield of 0.5 mg/mL (Table A) and 2.0 mg/mL (Table B). The bottles and bags should be thoroughly mixed.

TABLE A

Quantity of i.v. fluid in mL and quantity of ZEMURON(r) in mL replacement.

TABLE B

Quantity of i.v. fluid in mL and quantity of ZEMURON(r) in mL replacement. Parenteral drug products should be inspected visually for particulate matter and clarity prior to administration whenever solution and container permit.

Route of Administration:

For intravenous injection only.

AVAILABILITY OF DOSAGE FORMS

ZEMURON(r) (rocuronium bromide) Injection is available in the following forms in boxes of 10:

WITHOUT PRESERVATIVE:

VIALS

5 mL multiple dose vials containing 50 mg ZEMURON(r) (10 mg/mL) 10 mL multiple dose vials containing 100 mg ZEMURON(r) (10 mg/mL)

PHARMACOLOGY

Pharmacodynamics: The neuromuscular blocking activity of rocuronium, determined in vitro in mouse, rat and guinea pig phrenic nerve-hemidiaphragm preparations demonstrated a wide variation in potency, with IC50 values of 1.6mcM in the guinea pig, 2.3 mcM in the mouse, and 12.4 mcM in the rat. Recovery rates (spontaneous recovery of force of contraction from 25 to 75% of control) also varied among species, with a recovery rate of 0.8 minutes in the mouse, 3.3 minutes in the rat, and 14.5 minutes in the guinea pig. The percentage maximal recovery was similar for all species. Addition of neostigmine completely antagonized the rocuronium induced neuromuscular block in mice and guinea pigs, but returned it to only 91% of control in rats. Rocuronium was also administered intravenously to rats and guinea pigs to determine

in vivo

was found to be lower than that of pancuronium or vecuronium in all species investigated.

The potency of rocuronium ranged from one-fifth to one-tenth that of vecuronium in Beagle dogs, Rhesus monkeys, cats, and Landrace-Welsh pigs. However, the onset of action in dogs, monkeys, and cats was significantly faster than that of vecuronium. In cats and monkeys, the recovery times for rocuronium were shorter than for vecuronium, whereas, in dogs and pigs, similar recovery times were reported for the two neuromuscular blockers. Cumulative effects of rocuronium were observed only between administration of the first and second doses in the cats. In anaesthetized cats, an ED90 dose of rocuronium was associated with a transient increase in mean arterial blood pressure over the first minute post-injection. In anaesthetized dogs, mean arterial pressure was not affected at doses up to five times the ED90. Heart rates were slightly increased in dogs receiving the 5 X ED90 dose. Rocuronium only slightly inhibited bradycardia produced by vagal nerve stimulation, had negligible ganglion blocking effects, and showed no direct effect on muscle. Respiratory acidosis and alkalosis did not significantly modify the neuromuscular blocking potency of rocuronium or vecuronium in Landrace-Welsh pigs. Metabolic acidosis and alkalosis were associated with an increase in potency for both of these neuromuscular relaxants. The durations of action of rocuronium and vecuronium were significantly prolonged during respiratory and metabolic acidosis. Like other steroid-based muscle relaxants, rocuronium inhibited neuromuscular transmission both presynaptically, by inhibiting mobilization of acetylcholine to release sites, and postsynaptically, by inhibiting the interaction of acetylcholine with the cholinergic receptors of the post-junctional membrane. The contribution of the pre- and post-synaptic components to the effects of rocuronium varied with the species studied. Rocuronium has only weak anti-muscarinic activity and does not appear to exert any local anesthetic effects at clinically effective doses. Hormonal activity studies were not supportive of estrogenic, androgenic, anabolic, gonad-inhibiting, glucocorticoid-like, or other hormonal activity. Rocuronium did not produce hemolysis, increased red cell fragility, or plasma protein precipitation when administered intravenously to rats or when studied in vitro in human blood samples. The drug interactions observed with rocuronium in cats resembled those found with other non-depolarizing muscle relaxants. Halothane, enflurane, thiopental, and ketamine significantly potentiated the neuromuscular blocking activity of rocuronium, while N2O, alfentanil, and propofol had no effect. All three inhalation anesthetics and ketamine lengthened the recovery time after rocuronium administration, but this was significant only for ketamine. Pretreatment with morphine and chlorpromazine potentiated the effects of rocuronium, while diazepam, streptomycin, and succinylcholine had no effect. Fentanyl, etomidate, midazolam, and droperidol had no effect on the potency or time course of action of rocuronium. Pharmacokinetics: Studies of distribution, metabolism, and excretion in cats and dogs indicate that rocuronium is eliminated primarily by the liver. In cats cumulative excretion 6 hours after a 6 x ED90 dose was 9% in the urine and 54% in the bile. Consistent with the limited role of the kidney in the elimination of rocuronium, renal pedicle ligation did not substantially alter its time course in cats although clearance was significantly reduced. In contrast, hepatic exclusion in the cat significantly increased the duration of action of rocuronium, suggestive of a substantial role for the liver in the elimination of this compound. The rocuronium analog, 17-desacetyl-rocuronium (ORG 9943), has been rarely observed in the plasma, urine or bile of cats, or in the plasma or urine of humans administered single doses of 0.5-1 mg/kg (500-1000 mcg/kg) rocuronium with or without a subsequent infusion of rocuronium. ORG 9943 has approximately one-twentieth the potency of rocuronium as a neuromuscular blocker in the cat. Following administration of rocuronium in dogs, small amounts of ORG 9943 (< 1.5% of the administered dose) have been observed in plasma and urine.

TOXICOLOGY

Acute Toxicity: Rocuronium was administered at doses up to 135 mg/kg (750 times the ED90) i.v. bolus in dogs and 87.5 mg/kg (350 times the ED90) i.v. bolus or i.v. infusion in cats. The administration of rocuronium to cats resulted in transient, but severe, decreases in blood pressure and minor decreases in heart rate. Possible drug-related increases in SGOT and blood glucose, and decreases in cholesterol were reported in cats receiving the highest dose. In dogs, a transient, slight increase in blood pressure and heart rate was observed at all dose levels. The 135 mg/kg dose was associated with severe depression of cardiovascular function, arrhythmia, and death. Minor centrilobular vacuolization of the liver was evident. Two deaths were reported in the dogs. One male died at a total dose of 150 times the ED90 (27 mg/kg), but this was not drug-related. One female died at a total dose of 750 times the ED90 (135 mg/kg) due to profound hypotension and cardiac collapse. Two deaths were also reported in the cats, one in a control animal and one in the low dose (2.5 mg/kg) group. Both deaths were not drug-related.

Subacute Toxicity:

The effects of repeated administration of rocuronium were studied in two four-week studies, one in beagle dogs at dosage levels of 1.2, 3.6, and 10.8

mg/kg/day and one in cats at dosage levels of 1, 3, and 9.3 mg/kg/day. The highest doses represent 60 and 36 times the ED90 for each species, respectively.

Dogs:

Anesthetized Beagle dogs were treated with i.v. doses of 0, 1.2, 3.6, or 10.8 mg/kg/day (3 animals/sex/dose) of rocuronium in three equally divided portions administered at 30 minute intervals. Doses were administered once a day, twice weekly, with an interval of two to four days between dosing. Dogs were anesthetized and ventilated during administration. Rocuronium was generally well-tolerated with few clinical signs other than those due to its pharmacologic action, although there was a minimal increase in heart rate lasting less than one minute after the administration of each treatment. No significant effects on hematology or urinalysis parameters were observed, although erratic changes in clinical chemistry parameters were noted in the form of increases of SGOT, SGPT, alkaline phosphatase, glucose, blood urea nitrogen, cholesterol, and creatine phosphokinase. No treatment-related effects were seen on gross or histopathological examination. Ophthalmoscopic examination at the end of the study revealed pulsation in the vessels of the fundus in two dogs which received the high dose treatment.

Three of the six dogs treated with 10.8 mg/kg/day died during the study. The deaths were considered to be due to experimental procedures in combination with the high dose of rocuronium administered. No remarkable clinical signs were observed in these animals. The mortalities were most likely due to disconnecting the animals from the respirator or extubation before recovery of neuromuscular function was adequate to maintain normal sustained ventilation. There was no indication that plasma concentrations of rocuronium increased due to redistribution of the drug.

Cats:

Cats were treated with 0, 1, 3 or 9.3 mg/kg/day of rocuronium (3 animals/sex/dose) as an i.v. bolus dose in three divided doses administered at 30 minute intervals. These animals, when treated under halothane anesthesia two days a week for

four weeks, showed no untoward or unexpected treatment related pharmacological or toxicological signs or symptoms throughout the study. There was no evidence of toxicity on gross or histopathologic examination. In the 9.3 mg/kg treatment group, elevations of SGOT, SGPT, and lactic dehydrogenase were observed. Special Studies: Rocuronium did not induce malignant hyperthermia in susceptible swine when administered for 2 hrs at an infusion rate adjusted to maintain 90-95% neuromuscular blockade (72 :g/kg/min). Following the cessation of rocuronium infusion, the animals were allowed to undergo 100% recovery from neuromuscular blockade before being challenged with halothane and succinylcholine as triggering agents for malignant hyperthermia. Only one of the ten animals treated with rocuronium developed malignant hyperthermia when challenged with halothane and succinylcholine following 100% recovery from neuromuscular blockade. After a period of one week, seven of the eight pigs from the initial phase developed some signs of malignant hyperthermia (i.e., hypotension, acidosis, tachycardia, decreased respiratory rate) in the absence of increased rectal temperature or muscle rigidity during the rechallenge phase with halothane and succinylcholine. Rocuronium was well-tolerated after intravenous, intra-arterial and perivenous administration in New Zealand White rabbits. The only finding was a slight irritation of surrounding tissues after perivenous administration. A decomposition product of rocuronium, 17-desacetyl-rocuronium (Org 9943), did not produce neuromuscular blockade or significant clinical findings in cats after administration of five 0.72 mg/kg sub-doses at 30 minute intervals. In a study of anesthetized cats administered heat sterilized rocuronium at dosage levels of 2.5, 5 or 12.5 mg/kg, neuromuscular blockade was produced without signs of toxicity.

Reproductive Studies:

In a segment II reproductive study, Sprague-Dawley rats treated intravenously with 0.05, 0.1, or 0.3 mg/kg/day of rocuronium on days 6-17 of gestation, demonstrated no maternotoxicity at any dosage level. No significant differences were observed between the rocuronium treated and control groups with respect to abnormal litter rate or malformation rate. Ossification variance and the number and type of minor defects in the treated groups were comparable to the control. However, as this study was performed at sub-paralyzing doses in non-ventilated animals, the relevance of these studies to the clinical use of the drug cannot be assessed.

Mutagenicity: Three Ames tests were conducted with rocuronium in three separate laboratories. The first Ames test demonstrated a dose-related (1000-5000 mcg/plate), but weak (2 to 3 fold increase), mutagenic response in one S. typhimurium tester strain (TA 98). Four other strains showed no increase in the number of revertants, either with or without metabolic activation. Two additional tests were conducted employing the same S. typhimurium strains, at concentrations of rocuronium up to 5000 mcg/plate. One study showed an increase in the frequency of mutation in tester strain TA 98, however, the increase (less than 2-fold) was below the criteria established for a positive effect. The result of the other test was negative. Rocuronium was negative in a reverse mutation assay in E. coli (at concentrations up to 5000 mcg/plate), an in vitro mammalian cell gene mutation assay in Chinese hamster V79 cells (up to 5000 mcg/ml), an in vitro chromosomal aberrations test in human lymphocytes (up to 5000 mcg/ml), and an in vivo micronucleus test in rat bone marrow (up to 900 mcg/kg/day). The results of these in vitro and in vivo studies demonstrated that rocuronium is not a mutagenic compound.

REFERENCES

1. Foldes, FF. Determination of the single dose response, safety, and pharmacodynamics of ORG 9426 under balanced anesthesia. Clinical Study - 021-001. Data on file with Organon Canada.

2. Quill TJ, Glass PA, Gorback M. Determination of the single dose response, safety and pharmacodynamics of ORG 9426 under isoflurane anesthesia. Clinical Study - 021-002. Data on file with Organon Canada.

3. Bartkowski RR, Witkowski T, Azad SS. Determination of the single dose response, safety, and pharmacodynamics of ORG 9426 under enflurane anesthesia. Clinical Study - 021-003. Data on file with Organon Canada.

4. Tullock WC. Determination of the single dose response safety and pharmacodynamics of ORG 9426 under halothane anesthesia. Clinical Study - 021-004. Data on file with Organon Canada.

5. Bihkazi GB, Marin F. Determination of the single dose response, safety, and pharmacodynamics of ORG 9426 in pediatric patients under halothane anesthesia. Clinical Study - 021-005. Data on file with Organon Canada.

6. Brandom BW, Woelfel SK, Wilks. Determination of the pharmacodynamics and safety of the single dose response and continuous infusion requirements of ORG 9426 in pediatric patients under halothane anesthesia. Clinical Study - 021-006. Data on file with Organon Canada.

7. Bevan DR, Fiset P. Determination of the single dose response, safety and pharmacodynamics ORG 9426 in geriatric patients under balanced anesthesia. Clinical Study - 021-007. Data on file with Organon Canada.

8. Larijani G, Gratz I, and Silverberg M. Determination of the pharmacokinetics and pharmacodynamics of ORG 9426 administered by a combined bolus and infusion regimen in patients receiving balanced or isoflurane anesthesia. Clinical Study - 021-008. Data on file with Organon Canada.

9. Miller, RD, Caldwell JE, Majorian T. Determination of the pharmacokinetics, pharmacodynamics and safety of ORG 9426 in patients with renal failure and in patients with hepatic dysfunction under isoflurane anesthesia. Clinical Study - 021-009. Data on file with Organon Canada.

10. Hawkins JL, Joyce TH III, Rivers JM. Evaluation of the Neuromuscular blocking effects and safety of ORG 9426 in patients undergoing surgery for cesarean section and postpartum bilateral tubal ligation. Clinical Study - 021-010. Data on file with Organon Canada.

11. Powers DM. Determination of the intubating dose of ORG 9426 under balanced anesthesia. Clinical Study - 021-011. Data on file with Organon Canada.

12. Dubois, M. Determination of the optimal intubating dose and pharmacodynamics of maintenance doses of ORG 9426 in patients receiving balanced or enflurane anesthesia. Clinical Study - 021-012. Data on file with Organon Canada.

13. Dunbar BS, Vuksanaj D. Determination of the pharmacodynamics and safety of intubating and maintenance doses of ORG 9426 in pediatric patients receiving halothane anesthesia. Clinical Study - 021-013. Data on file with Organon Canada.

14. Matteo RS, Ornstein E. Determination of the pharmacokinetics, pharmacodynamics and safety of ORG 9426 in young adults and geriatric patients under balanced anesthesia. Clinical Study - 021-014. Data on file with Organon Canada.

15. Dubois, MY. Comparison of the pharmacodynamics and safety of ORG 9426 with and without prior administration of succinylcholine in patients under balanced anesthesia. Clinical Study - 021-015. Data on file with Organon Canada.

16. Weber, S. A study of the pharmacodynamics and safety of pipecuronium bromide with and without prior administration of either succinylcholine or ORG 9426 in patients receiving balanced anesthesia. Clinical Study - 021-016. Data on file with Organon Canada.

17. Bromley H, Bailey M. Determination of the hemodynamic effects of ORG 9426 during sufentanil anesthesia in patients undergoing surgery for myocardial revascularization or valvular disease and during short term (8-12 HR) mechanical ventilation in the immediate postoperative period. Clinical Study - 021-017. Data on file with Organon Canada.

18. Lowdon JD, Isaacson I, Levy J. Determination of the pharmacodynamics, safety and histamine releasing potential of ORG 9426 when administered in increased doses under balanced anesthesia. Clinical Study - 021-018. Data on file with Organon Canada.

19. Shanks CA, Fragen, R. Evaluation of the continuous intravenous infusion of ORG 9426 following a single bolus intubating dose in patients receiving balanced, enflurane or isoflurane anesthesia. Clinical Study - 021-020. Data on file with Organon Canada.

20. Pearson K, Sokoll M. Determination of the pharmacodynamics and safety of intubating and maintenance doses of ORG 9426 in obese patients under balanced anesthesia. Clinical Study 021- 021. Data on file with Organon Canada.

21. Foldes FF, Nigashima H. Determination of the pharmacodynamics and safety of different intubating regimens and maintenance doses of ORG 9426 under balanced anesthesia. Clinical Study - 021-022. Data on file with Organon Canada.

22. Miller R, Magorian T. Determination of the pharmacodynamics and safety of ORG 9426, vecuronium and succinylcholine for rapid sequence induction and intubation in patients under balanced anesthesia. Clinical Study - 021-023. Data on file with Organon Canada.

23. Katz R. A study of the pharmacodynamics and safety of ORG 9426 in patients with pre-end stage renal dysfunction and patients with normal renal function. Clinical Study - 021-024. Data on file with Organon Canada.

24. Miller R, Meistelman C. Determination and comparison of the pharmacodynamic parameters of ORG 9426 and succinylcholine as measured at the adductor pollicis and vocal cords. Clinical Study - 021-025. Data on file with Organon Canada.

25. Multicenter. Evaluation of the neuromuscular blocking effects and safety of ORG 9426 in patients undergoing surgery for cesarean section. Clinical Study - 021-026. Data on file with Organon Canada.

26. Khuenl-Brady K, et al. The neuromuscular blocking effects and pharmacokinetics of ORG 9426 and ORG 9616 in the cat. 021-1043D. Data on file with Organon Canada.

27. Meistelman C, Miller R. Determination and comparison of the pharmacokinetics and pharmacodynamics of ORG 9426 and vecuronium induced neuromuscular blockade at the laryngeal and adductor pollicis muscles. Clinical Study - 021-028. Data on file with Organon Canada.

28. Drummond L, et al. Comparison of the neuromuscular, autonomic and cardiovascular effects of vecuronium, ORG 9426 and its potential 17-hydroxy metabolite (ORG 9943) in the anaesthetized cat. 021-1048A. Data on file with Organon Canada.

29. Malignant hyperthermia study in swine. 021-1069. Data on file with Organon Canada.

30. Muir AW, et al. Effects of acute changes in pH and acid-base balance on neuromuscular blockade produced by ORG 9426 and vecuronium in the anaesthetized pig and in the isolated guinea-pig diaphragm. 021-1008. Data on file with Organon Canada.

31. Joosten HFP, et al. A Salmonella Microsome Mutagenicity Test (Ames Test) with ORG 9426. 021-1006A. Data on file with Organon Canada.

32. Enninga IC, et al. Mutagenic activity of ORG 9426 in the Ames Salmonella/Microsome Test, 021-1028. Data on file with Organon Canada.

33. Jagannath DR, et al. Mutagenicity Test on ORG 9426 in the Ames Salmonella/ Microsomes Reverse Mutation Assay. 021-1030. Data on file with Organon Canada.

34. Enninga IC, et al. Evaluation of the mutagenic activity of ORG 9426 in an in vitro Mammalian Cell Gene Mutation Test with V79 Chinese Hamster Cells. 021-1029. Data on file with Organon Canada.

35. Joosten HFP, et al. A Micronucleus Test in rats with ORG 9426. 021-1007. Data on file with Organon Canada.

36. Yih TD, et al. Report on an embryotoxicity study with ORG 9426 in Rats. 021-1049B. Data on file with Organon Canada.

37. Agoston S, et al. The influence of the hepatic uptake on the neuromuscular block induced by ORG 7617, ORG 9616, ORG 9273 and ORG 9426 in the Cat. 021-1017. Data on file with Organon Canada.

38. Booij LHDJ, Knape HTA. The neuromuscular blocking effect of ORG 9426. Anaesthesia, 1991, 46:341-343.

39. Brandom B, et al. Determination of the Pharmacodynamics and Safety of the Single Dose Response and Continuous Infusion Requirements of ORG 9426 in Pediatric Patients under Halothane Anesthesia, Clinical Study 021-019. Data on file with Organon Canada.