Cisatracurium Besylate

1 INDICATIONS AND USAGE Cisatracurium besylate injection is indicated: • as an adjunct to general anesthesia to facilitate tracheal intubation in adults and in pediatric patients 1 month to 12 years of age • to provide skeletal muscle relaxation in adults during surgical procedures or during mechanical ventilation in the ICU • to provide skeletal muscle relaxation during surgical procedures via infusion in pediatric patients 2 years and older Limitations of Use Cisatracurium besylate injection is not recommended for rapid sequence endotracheal intubation due to the time required for its onset of action. Cisatracurium besylate injection is a nondepolarizing neuromuscular blocker indicated: as an adjunct to general anesthesia to facilitate tracheal intubation in adults and in pediatric patients 1 month to 12 years of age (1) to provide skeletal muscle relaxation during surgery in adults and in pediatric patients 2 to 12 years of age as a bolus or infusion maintenance (1) for mechanical ventilation in the ICU in adults (1) Limitations of Use: Cisatracurium besylate injection is not recommended for rapid sequence endotracheal intubation due to the time required for its onset of action.

2 DOSAGE AND ADMINISTRATION Store cisatracurium besylate injection with the cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product (2.1) Administer intravenously only by or under the supervision of experienced clinicians familiar with drug’s actions and possible complications (2.1) Use only if personnel and facilities for resuscitation and life support, and a cisatracurium besylate injection antagonist are immediately available (2.1) Use a peripheral nerve stimulator to determine adequacy of blockade (e.g., need for additional doses), minimize risk of overdosage or underdosage, assess extent of recovery from blockade, potentially limit exposure to toxic metabolites through dose titration, and facilitate more rapid reversal of cisatracurium besylate injection-induced paralysis (2.1) See the Full Prescribing Information for: o Dosage and administration instructions in adults, pediatric patients, geriatric patients, patients with neuromuscular disease, burns, end-stage renal disease, and patients undergoing coronary artery bypass graft surgery with induced hypothermia (2.2, 2.3, 2.4, 2.5) o Continuous infusion rates (2.6) o Preparation instructions (2.7) o Drug compatibility (2.8) 2.1 Important Dosage and Administration Instructions Risk of Medication Errors Accidental administration of neuromuscular blocking agents may be fatal. Store cisatracurium besylate injection with the cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product [see Warnings and Precautions (5.5)] . Important Administration Instructions : Cisatracurium besylate injection is for intravenous use only. Administer cisatracurium besylate injection in carefully adjusted dosage by or under the supervision of experienced clinicians who are familiar with the drug’s actions and the possible complications. Use cisatracurium besylate injection only if the following are immediately available: personnel and facilities for resuscitation and life support (tracheal intubation, artificial ventilation, oxygen therapy); and an antagonist of cisatracurium besylate injection [see Overdosage (10)] . The dosage information which follows is intended to serve as an initial guide for individual patients; base subsequent cisatracurium besylate injection dosage on the patients’ responses to the initial doses. Use a peripheral nerve stimulator to: o Determine the adequacy of neuromuscular blockade (e.g., need for additional cisatracurium besylate injection doses, reduction of the infusion rate). o Minimize risk of overdosage or underdosage. o Assess the extent of recovery from neuromuscular blockade (e.g., spontaneous recovery or recovery after administration of a reversal agent e.g., neostigmine). o Appropriately titrate doses to potentially limit exposure to toxic metabolites. o Facilitate more rapid reversal of the cisatracurium besylate injection-induced paralysis. 2.2 Recommended Cisatracurium Besylate Injection Dose for Performing Tracheal Intubation Tracheal Intubation in Adults Prior to selecting the initial cisatracurium besylate injection bolus dose, consider the desired time to tracheal intubation and the anticipated length of surgery, factors affecting time to onset of complete neuromuscular block such as age and renal function, and factors that may influence intubation conditions such as the presence of co-induction agents (e.g., fentanyl and midazolam) and the depth of anesthesia. In conjunction with a propofol/nitrous oxide/oxygen induction-intubation technique or a thiopental/nitrous oxide/oxygen induction-intubation technique, the recommended starting weight-based dose of cisatracurium besylate injection is between 0.15 mg/kg and 0.2 mg/kg administered by bolus intravenous injection. Doses up to 0.4 mg/kg have been safely administered by bolus intravenous injection to healthy patients and patients with serious cardiovascular disease [ see Clinical Pharmacology (12.2) ]. Patients with Neuromuscular Disease The maximum recommended initial bolus dose of cisatracurium besylate injection is 0.02 mg/kg in patients with neuromuscular diseases (e.g., myasthenia gravis and myasthenic syndrome and carcinomatosis) [ see Warnings and Precautions (5.1) ]. Geriatric Patients and Patients with End-Stage Renal Disease Because the time to maximum neuromuscular blockade is approximately 1 minute slower in geriatric patients compared to younger patients (and in patients with end-stage renal disease than in patients with normal renal function), consider extending the interval between administering cisatracurium besylate injection and attempting intubation by at least 1 minute to achieve adequate intubation conditions in geriatric patients and patients with end-stage renal disease. A peripheral nerve stimulator should be used to determine the adequacy of muscle relaxation for the purposes of intubation and the timing and amounts of subsequent doses [ see Use in Specific Populations (8.5, 8.6) and Clinical Pharmacology (12.3) ]. Tracheal Intubation in Pediatric Patients Infants 1 to 23 Months of Age The recommended dose of cisatracurium besylate injection for intubation of pediatric patients ages 1 month to 23 months is 0.15 mg/kg administered over 5 to 10 seconds. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg of cisatracurium besylate injection produced maximum neuromuscular blockade in about 2 minutes (range: 1.3 to 4.3 minutes) with a clinically effective block (time to 25% recovery) for about 43 minutes (range: 34 to 58 minutes) [ see Clinical Studies (14.2) ]. Pediatric Patients 2 to 12 Years of Age The recommended weight-based bolus dose of cisatracurium besylate injection for pediatric patients 2 to 12 years of age is 0.1 to 0.15 mg/kg administered over 5 to 10 seconds. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.1 mg/kg cisatracurium besylate injection produced maximum neuromuscular blockade in an average of 2.8 minutes (range: 1.8 to 6.7 minutes) with a clinically effective block (time to 25% recovery) for 28 minutes (range: 21 to 38 minutes). When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg cisatracurium besylate injection produced maximum neuromuscular blockade in an average of about 3 minutes (range: 1.5 to 8 minutes) with a clinically effective block for 36 minutes (range: 29 to 46 minutes) [ see Clinical Studies (14.2) ]. 2.3 Recommended Maintenance Bolus Cisatracurium Besylate Injection Doses in Adult Surgical Procedures Determine if maintenance bolus doses are needed based on clinical criteria including the response to peripheral nerve stimulation. The recommended maintenance bolus dose of cisatracurium besylate injection is 0.03 mg/kg; however, smaller or larger maintenance doses may be administered based on the required duration of action. Administer the first maintenance bolus dose starting: • 40 to 50 minutes after an initial dose of cisatracurium besylate injection 0.15 mg/kg; • 50 to 60 minutes after an initial dose of cisatracurium besylate injection 0.2 mg/kg. For long surgical procedures using inhalational anesthetics administered with nitrous oxide/oxygen at the 1.25 MAC level for at least 30 minutes, consider administering less frequent maintenance bolus doses or lower maintenance bolus doses of cisatracurium besylate injection [see Clinical Pharmacology (12.2)]. No adjustment to the initial cisatracurium besylate injection maintenance bolus dose should be necessary when cisatracurium besylate injection is administered shortly after initiation of volatile agents or when used in patients receiving propofol anesthesia. 2.4 Dosage in Burn Patients Burn patients have been shown to develop resistance to nondepolarizing neuromuscular blocking agents; therefore, consider increasing the cisatracurium besylate injection dosages for intubation and maintenance [ see Use in Specific Populations (8.8) ]. 2.5 Dosage for Continuous Infusion Continuous Infusion for Surgical Procedures in Adults and Pediatric Patients During extended surgical procedures, cisatracurium besylate injection may be administered by continuous infusion to adults and pediatric patients aged 2 or more years if patients have spontaneous recovery after the initial cisatracurium besylate injection bolus dose. Following recovery from neuromuscular blockade, it may be necessary to re-administer a bolus dose to quickly re-establish neuromuscular blockade prior to starting the continuous infusion. If patients have had recovery of neuromuscular function, the recommended initial cisatracurium besylate injection infusion rate is 3 mcg/kg/minute [see Dosage and Administration (2.6)]. Subsequently reduce the rate to 1 to 2 mcg/kg/minute to maintain continuous neuromuscular blockade. Use peripheral nerve stimulation to assess the level of neuromuscular blockade and to appropriately titrate the cisatracurium besylate injection infusion rate. If no response is elicited to peripheral nerve stimulation, discontinue the infusion until a response returns. Consider reducing the infusion rate by up to 30% to 40% when cisatracurium besylate injection is administered during stable isoflurane anesthesia for at least 30 minutes (administered with nitrous oxide/oxygen at the 1.25 MAC level) [ see Clinical Pharmacology (12.2) ]. Greater reductions in the cisatracurium besylate injection infusion rate may be required with longer durations of administration of isoflurane or with the administration of other inhalational anesthetics. Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery Consider reducing the infusion rate in patients undergoing CABG with induced hypothermia to half the rate required during normothermia [ see Clinical Pharmacology (12.2) ]. Spontaneous recovery from neuromuscular block following discontinuation of cisatracurium besylate injection infusion is expected to proceed at a rate comparable to that following administration of a single bolus dose. Continuous Infusion for Mechanical Ventilation in the Intensive Care Unit in Adults During extended need for mechanical ventilation and skeletal muscle relaxation in the intensive care unit (ICU), cisatracurium besylate injection may be administered by continuous infusion to adults if a patient has spontaneous recovery of neuromuscular function after the initial cisatracurium besylate injection bolus dose. Following recovery from neuromuscular blockade, it may be necessary to re-administer a bolus dose to quickly re-establish neuromuscular blockade prior to starting the continuous infusion. The recommended cisatracurium besylate injection infusion rate in adult patients in the ICU is 3 mcg/kg/minute (range: 0.5 to 10.2 mcg/kg/minute) [see Dosage and Administration (2.6) ]. Use peripheral nerve stimulation to assess the level of neuromuscular blockade and to appropriately titrate the cisatracurium besylate injection infusion rate. 2.6 Rate Tables for Continuous Infusion The intravenous infusion rate depends upon the cisatracurium besylate injection concentration, the desired dose, the patient's weight, and the contribution of the infusion solution to the fluid requirements of the patient. Tables 1 and 2 provide guidelines for the cisatracurium besylate injection infusion rate, in mL/hour (equivalent to microdrops/minute when 60 microdrops = 1 mL), in concentrations of 0.1 mg/mL or 0.4 mg/mL, respectively. Table 1. Cisatracurium Besylate Injection Infusion Rates for Maintenance of Neuromuscular Blockade During Opioid/Nitrous Oxide/Oxygen Anesthesia with a Concentration of 0.1 mg/mL Drug Delivery Rate (mcg/kg/minute) 1 1.5 2 3 5 Patient Weight Infusion Delivery Rate (mL/hour) 10 kg 6 9 12 18 30 45 kg 27 41 54 81 135 70 kg 42 63 84 126 210 100 kg 60 90 120 180 300 Table 2. Cisatracurium Besylate Injection Infusion Rates for Maintenance of Neuromuscular Blockade During Opioid/Nitrous Oxide/Oxygen Anesthesia with a Concentration of 0.4 mg/mL Drug Delivery Rate (mcg/kg/minute) 1 1.5 2 3 5 Patient Weight Infusion Delivery Rate (mL/hour) 10 kg 1.5 2.3 3 4.5 7.5 45 kg 6.8 10.1 13.5 20.3 33.8 70 kg 10.5 15.8 21 31.5 52.5 100 kg 15 22.5 30 45 75 2.7 Preparation of Cisatracurium Besylate Injection Visually inspect cisatracurium besylate injection for particulate matter and discoloration prior to administration. If a cisatracurium besylate injection solution is cloudy or contains visible particulates, do not use cisatracurium besylate injection. Cisatracurium besylate injection is a colorless to slightly yellow or greenish-yellow solution. Discard unused portion of the 5 mL and 20 mL single-dose vials. Cisatracurium besylate injection may be diluted to 0.1 mg/mL in the following solutions: • 5% Dextrose Injection, USP • 0.9% Sodium Chloride Injection, USP, or • 5% Dextrose and 0.9% Sodium Chloride Injection, USP Store these diluted cisatracurium besylate injection solutions either in a refrigerator or at room temperature for 24 hours without significant loss of potency. Cisatracurium besylate injection also may be diluted to 0.1 mg/mL or 0.2 mg/mL in the following solution: • Lactated Ringer’s and 5% Dextrose Injection Store this diluted cisatracurium besylate injection solution under refrigeration for no more than 24 hours. Do not dilute cisatracurium besylate injection in Lactated Ringer’s Injection, USP due to chemical instability 2.8 Drug Compatibility Cisatracurium besylate injection is compatible and may be administered with the following solutions through Y-site administration: • 5% Dextrose Injection, USP • 0.9% Sodium Chloride Injection, USP • 5% Dextrose and 0.9% Sodium Chloride Injection, USP • Sufentanil Citrate Injection, diluted as directed • Alfentanil Hydrochloride Injection, diluted as directed • Fentanyl Citrate Injection, diluted as directed • Midazolam Hydrochloride Injection, diluted as directed • Droperidol Injection, diluted as directed Cisatracurium besylate injection is acidic (pH = 3.25 to 3.65) and may not be compatible with alkaline solution having a pH greater than 8.5 (e.g., barbiturate solutions). Therefore, do not administer cisatracurium besylate injection and alkaline solutions simultaneously in the same intravenous line. Cisatracurium besylate injection is not compatible with propofol injection or ketorolac injection for Y-site administration. Compatibility studies with other parenteral products have not been conducted.

6 ADVERSE REACTIONS The most common adverse reactions (0.1% to 0.4%) were bradycardia, hypotension, flushing, bronchospasm, and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 866-770-7144 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials of Cisatracurium Besylate Injection in Surgical Patients The data presented below are based on studies involving 945 surgical patients who received cisatracurium besylate injection in conjunction with other drugs in US and European clinical studies in a variety of procedures [see Clinical Studies (14.1)]. Table 3 displays adverse reactions that occurred at a rate of less than 1%. Table 3. Adverse Reactions in Clinical Trials of Cisatracurium Besylate Injection in Surgical Patients Adverse Reaction Incidence Bradycardia 0.4% Hypotension 0.2% Flushing 0.2% Bronchospasm 0.2% Rash 0.1% Adverse Reactions in Clinical Trials of Cisatracurium Besylate Injection in Intensive Care Unit Patients The adverse reactions presented below were from studies involving 68 adult ICU patients who received cisatracurium besylate injection in conjunction with other drugs in US and European clinical studies [see Clinical Studies (14.3)]. One patient experienced bronchospasm. In one of the two ICU studies, a randomized and double-blind study of ICU patients using TOF neuromuscular monitoring, there were two reports of prolonged recovery (range: 167 and 270 minutes) among 28 patients administered cisatracurium besylate injection and 13 reports of prolonged recovery (range: 90 minutes to 33 hours) among 30 patients administered vecuronium. 6.2 Postmarketing Experience The following events have been identified during post-approval use of cisatracurium besylate injection in conjunction with one or more anesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to cisatracurium besylate injection: anaphylaxis, histamine release, prolonged neuromuscular block, muscle weakness, myopathy.

12.3 Pharmacokinetics The neuromuscular blocking activity of cisatracurium besylate injection is due to parent drug. Cisatracurium plasma concentration-time data following IV bolus administration are best described by a two-compartment open model (with elimination from both compartments) with an elimination half-life (t ½ β) of 22 minutes, a plasma clearance (CL) of 4.57 mL/min/kg, and a volume of distribution at steady state (Vss) of 145 mL/kg. Results from population pharmacokinetic/pharmacodynamic (PK/PD) analyses from 241 healthy surgical patients are summarized in Table 6. Table 6. Key Population PK/PD Parameter Estimates for Cisatracurium in Healthy Surgical Patients* Following 0.1 (2 × ED 95 ) to 0.4 mg/kg (8 × ED 95 ) of Cisatracurium Besylate Injection Parameter Estimate † Magnitude of Interpatient Variability (CV) ‡ CL (mL/min/kg) 4.57 16% Vss (mL/kg) § 145 27% keo (min-1) ll 0.0575 61% EC 50 (ng/mL) ¶ 141 52% * Healthy male non-obese patients 19-64 years of age with creatinine clearance values greater than 70 mL/minute who received cisatracurium besylate injection during opioid anesthesia and had venous samples collected † The percent standard error of the mean (%SEM) ranged from 3% to 12% indicating good precision for the PK/PD estimates. ‡ Expressed as a coefficient of variation; the %SEM ranged from 20% to 35% indicating adequate precision for the estimates of interpatient variability. § Vss is the volume of distribution at steady state estimated using a two-compartment model with elimination from both compartments. Vss is equal to the sum of the volume in the central compartment (Vc) and the volume in the peripheral compartment (Vp); interpatient variability could only be estimated for Vc. ll Rate constant describing the equilibration between plasma concentrations and neuromuscular block ¶ Concentration required to produce 50% T 1 suppression; an index of patient sensitivity. The magnitude of interpatient variability in CL was low (16%), as expected based on the importance of Hofmann elimination. The magnitudes of interpatient variability in CL and volume of distribution were low in comparison to those for keo and EC 50 . This suggests that any alterations in the time course of cisatracurium besylate injection-induced neuromuscular blockade were more likely to be due to variability in the PD parameters than in the PK parameters. Parameter estimates from the population PK analyses were supported by noncompartmental PK analyses on data from healthy patients and from specific populations. Conventional PK analyses have shown that the PK of cisatracurium are proportional to dose between 0.1 (2 × ED 95 ) and 0.2 (4 × ED 95 ) mg/kg cisatracurium. In addition, population PK analyses revealed no statistically significant effect of initial dose on CL for doses between 0.1 (2 × ED 95 ) and 0.4 (8 × ED 95 ) mg/kg cisatracurium. Distribution The volume of distribution of cisatracurium is limited by its large molecular weight and high polarity. The Vss was equal to 145 mL/kg (Table 6) in healthy 19- to 64-year-old surgical patients receiving opioid anesthesia. The Vss was 21% larger in similar patients receiving inhalation anesthesia. The binding of cisatracurium to plasma proteins has not been successfully studied due to its rapid degradation at physiologic pH. Inhibition of degradation requires nonphysiological conditions of temperature and pH which are associated with changes in protein binding. Elimination Organ-independent Hofmann elimination (a chemical process dependent on pH and temperature) is the predominant pathway for the elimination of cisatracurium. The liver and kidney play a minor role in the elimination of cisatracurium but are primary pathways for the elimination of metabolites. Therefore, the t½β values of metabolites (including laudanosine) are longer in patients with renal or hepatic impairment and metabolite concentrations may be higher after long-term administration [ see Warnings and Precautions (5.3) ]. The mean CL values for cisatracurium ranged from 4.5 to 5.7 mL/min/kg in studies of healthy surgical patients. The compartmental PK modeling suggests that approximately 80% of the cisatracurium CL is accounted for by Hofmann elimination and the remaining 20% by renal and hepatic elimination. These findings are consistent with the low magnitude of interpatient variability in CL (16%) estimated as part of the population PK/PD analyses and with the recovery of parent and metabolites in urine. In studies of healthy surgical patients, mean t ½ β values of cisatracurium ranged from 22 to 29 minutes and were consistent with the t ½ β of cisatracurium in vitro (29 minutes). The mean ± SD t ½ β values of laudanosine were 3.1 ± 0.4 hours in healthy surgical patients receiving cisatracurium besylate injection (n = 10). Metabolism The degradation of cisatracurium was largely independent of liver metabolism. Results from in vitro experiments suggest that cisatracurium undergoes Hofmann elimination (a pH and temperature-dependent chemical process) to form laudanosine [see Warnings and Precautions (5.3)] and the monoquaternary acrylate metabolite, neither of which has any neuromuscular blocking activity. The monoquaternary acrylate undergoes hydrolysis by non-specific plasma esterases to form the monoquaternary alcohol (MQA) metabolite. The MQA metabolite can also undergo Hofmann elimination but at a much slower rate than cisatracurium. Laudanosine is further metabolized to desmethyl metabolites which are conjugated with glucuronic acid and excreted in the urine. The laudanosine metabolite of cisatracurium has been noted to cause transient hypotension and, in higher doses, cerebral excitatory effects when administered to several animal species. The relationship between CNS excitation and laudanosine concentrations in humans has not been established [ see Warnings and Precautions (5.3) ]. During IV infusions of cisatracurium besylate injection, peak plasma concentrations (Cmax) of laudanosine and the MQA metabolite were approximately 6% and 11% of the parent compound, respectively. The Cmax values of laudanosine in healthy surgical patients receiving infusions of cisatracurium besylate injection were mean ± SD Cmax: 60 ± 52 ng/mL. Excretion: Following 14C-cisatracurium administration to 6 healthy male patients, 95% of the dose was recovered in the urine (mostly as conjugated metabolites) and 4% in the feces; less than 10% of the dose was excreted as unchanged parent drug in the urine. In 12 healthy surgical patients receiving non-radiolabeled cisatracurium who had Foley catheters placed for surgical management, approximately 15% of the dose was excreted unchanged in the urine. Special Populations Geriatric Patients The results of conventional PK analysis from a study of 12 healthy elderly patients and 12 healthy young adult patients who received a single IV cisatracurium besylate injection dose of 0.1 mg/kg are summarized in Table 7. Plasma clearances of cisatracurium were not affected by age; however, the volumes of distribution were slightly larger in elderly patients than in young patients resulting in slightly longer t½ β values for cisatracurium. The rate of equilibration between plasma cisatracurium concentrations and neuromuscular blockade was slower in elderly patients than in young patients (mean ± SD keo: 0.071 ± 0.036 and 0.105 ± 0.021 minutes-1, respectively); there was no difference in the patient sensitivity to cisatracurium-induced block, as indicated by EC 50 values (mean ± SD EC 50 : 91 ± 22 and 89 ± 23 ng/mL, respectively). These changes were consistent with the 1-minute slower times to maximum block in elderly patients receiving 0.1 mg/kg cisatracurium besylate injection, when compared to young patients receiving the same dose. The minor differences in PK/PD parameters of cisatracurium between elderly patients and young patients were not associated with clinically significant differences in the recovery profile of cisatracurium besylate injection. Table 7. Pharmacokinetic Parameters* of Cisatracurium in Healthy Elderly and Young Adult Patients Following 0.1 mg/kg (2 × ED 95 ) of Cisatracurium Besylate Injection (Isoflurane/Nitrous Oxide/Oxygen Anesthesia) Parameter Healthy Elderly Patients Healthy Young Adult Patients Elimination Half-Life (t ½ β, min) 25.8 ± 3.6 † 22.1 ± 2.5 Volume of Distribution at Steady State ‡ (mL/kg) 156 ± 17 † 133 ± 15 Plasma Clearance (mL/min/kg) 5.7 ± 1.0 5.3 ± 0.9 * Values presented are mean ± SD. † P < 0.05 for comparisons between healthy elderly and healthy young adult patients ‡ Volume of distribution is underestimated because elimination from the peripheral compartment is ignored. Patients with Hepatic Impairment: Table 8 summarizes the conventional PK analysis from a study of cisatracurium besylate injection in 13 patients with end-stage liver disease undergoing liver transplantation and 11 healthy adult patients undergoing elective surgery. The slightly larger volumes of distribution in liver transplant patients were associated with slightly higher plasma clearances of cisatracurium. The parallel changes in these parameters resulted in no difference in t ½ β values. There were no differences in k eo or EC 50 between patient groups. The times to maximum neuromuscular blockade were approximately one minute faster in liver transplant patients than in healthy adult patients receiving 0.1 mg/kg cisatracurium besylate injection. These minor PK differences were not associated with clinically significant differences in the recovery profile of cisatracurium besylate injection. The t ½ β values of metabolites are longer in patients with hepatic disease and concentrations may be higher after long-term administration. Table 8. Pharmacokinetic Parameters* of Cisatracurium in Healthy Adult Patients and inPatients Undergoing Liver Transplantation Following 0.1 mg/kg (2 × ED 95 ) of Cisatracurium Besylate Injection (Isoflurane/Nitrous Oxide/Oxygen Anesthesia) Parameter Liver Transplant Patients Healthy Adult Patients Elimination Half-Life (t ½ β, min) 24.4 ± 2.9 23.5 ± 3.5 Volume of Distribution at Steady State ‡ (mL/kg) 195 ± 38 † 161 ± 23 Plasma Clearance (mL/min/kg) 6.6 ± 1.1 † 5.7 ± 0.8 * Values presented are mean ± SD. † P < 0.05 for comparisons between liver transplant patients and healthy adult patients ‡ Volume of distribution is underestimated because elimination from the peripheral compartment is ignored. Patients with Renal Impairment: Results from a conventional PK study of cisatracurium besylate injection in 13 healthy adult patients and 15 patients with end-stage renal disease (ESRD) who had elective surgery are summarized in Table 9. The PK/PD parameters of cisatracurium were similar in healthy adult patients and ESRD patients. The times to 90% neuromuscular blockade were approximately one minute slower in ESRD patients following 0.1 mg/kg cisatracurium besylate injection. There were no differences in the durations or rates of recovery of cisatracurium besylate injection between ESRD and healthy adult patients. The t ½ β values of metabolites are longer in patients with ESRD and concentrations may be higher after long-term administration. Population PK analyses showed that patients with creatinine clearances ≤ 70 mL/min had a slower rate of equilibration between plasma concentrations and neuromuscular block than patients with normal renal function; this change was associated with a slightly slower (~ 40 seconds) predicted time to 90% T 1 suppression in patients with renal impairment following 0.1 mg/kg cisatracurium besylate injection. There was no clinically significant alteration in the recovery profile of cisatracurium besylate injection in patients with renal impairment. The recovery profile of cisatracurium besylate injection is unchanged in the presence of renal or hepatic failure, which is consistent with predominantly organ-independent elimination. Table 9. Pharmacokinetic Parameters* for Cisatracurium in Healthy Adult Patients and in Patients With End-Stage Renal Disease (ESRD) Who Received 0.1 mg/kg (2 × ED 95 ) of Cisatracurium Besylate Injection (Opioid/Nitrous Oxide/Oxygen Anesthesia) Parameter Healthy Adult Patients ESRD Patients Elimination Half-Life (t ½ β, min) 29.4 ± 4.1 32.3 ± 6.3 Volume of Distribution at Steady State † (mL/kg) 149 ± 35 160 ± 32 Plasma Clearance (mL/min/kg) 4.66 ± 0.86 4.26 ± 0.62 * Values presented are mean ± SD. † Volume of distribution is underestimated because elimination from the peripheral compartment is ignored. Intensive Care Unit (ICU) Patients: The PK of cisatracurium and its metabolites were determined in six ICU patients who received cisatracurium besylate injection and are presented in Table 10. The relationships between plasma cisatracurium concentrations and neuromuscular blockade have not been evaluated in ICU patients. Limited PK data are available for ICU patients with hepatic or renal impairment who received cisatracurium besylate injection. Relative to cisatracurium besylate injection-treated ICU patients with normal renal and hepatic function, metabolite concentrations (plasma and tissues) may be higher in cisatracurium besylate injection-treated ICU patients with renal or hepatic impairment [ see Warnings and Precautions (5.3) ]. Table 10. Parameter Estimates* for Cisatracurium and Metabolites in ICU Patients After Long-Term (24 to 48 Hour) Administration of Cisatracurium Besylate Injection Parameter Cisatracurium (n = 6) Parent Compound CL (mL/min/kg) 7.45 ± 1.02 t ½ β (min) 26.8 ± 11.1 Vβ (mL/kg) † 280 ± 103 Laudanosine Cmax (ng/mL) 707 ± 360 t ½ β (hrs) 6.6 ± 4.1 MQA metabolite Cmax (ng/mL) 152 to 181 ‡ t ½ β (min) 26 to 31 ‡ * Presented as mean ± standard deviation † Volume of distribution during the terminal elimination phase, an underestimate because elimination from the peripheral compartment is ignored. ‡ n = 2, range presented Pediatric Population: The population PK/PD of cisatracurium were described in 20 healthy pediatric patients ages 2 to 12 years during halothane anesthesia, using the same model developed for healthy adult patients. The CL was higher in healthy pediatric patients (5.89 mL/min/kg) than in healthy adult patients (4.57 mL/min/kg) during opioid anesthesia. The rate of equilibration between plasma concentrations and neuromuscular blockade, as indicated by k eo , was faster in healthy pediatric patients receiving halothane anesthesia (0.1330 minutes -1 ) than in healthy adult patients receiving opioid anesthesia (0.0575 minutes -1 ). The EC 50 in healthy pediatric patients (125 ng/mL) was similar to the value in healthy adult patients (141 ng/mL) during opioid anesthesia. The minor differences in the PK/PD parameters of cisatracurium were associated with a faster time to onset and a shorter duration of cisatracurium-induced neuromuscular blockade in pediatric patients. Sex and Obesity: Although population PK/PD analyses revealed that sex and obesity were associated with effects on the PK and/or PD of cisatracurium; these PK/PD changes were not associated with clinically significant alterations in the predicted onset or recovery profile of cisatracurium besylate injection. Use of Inhalation Agents: The use of inhalation agents was associated with a 21% larger Vss, a 78% larger keo, and a 15% lower EC50 for cisatracurium. These changes resulted in a slightly faster (~ 45 seconds) predicted time to 90% T 1 suppression in patients who received 0.1 mg/kg cisatracurium during inhalation anesthesia than in patients who received the same dose of cisatracurium during opioid anesthesia; however, there were no clinically significant differences in the predicted recovery profile of cisatracurium besylate injection between patient groups. Drug Interaction Studies Carbamazepine and phenytoin: The systemic clearance of cisatracurium was higher in patients who were on prior chronic anticonvulsant therapy of carbamazepine or phenytoin [ see Warning and Precautions (5.9) and Drug Interactions (7.1) ].