Cisatracurium Besylate

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 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 ( 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.

Cisatracurium Besylate Injection, USP is available as a clear solution in the following strength: 200 mg of cisatracurium per 20 mL (10 mg per mL) in single-dose vials (equivalent to 13.38 mg per mL cisatracurium besylate) Injection: 200 mg per 20 mL (10 mg per mL) in single-dose vials ( 3 )

Cisatracurium Besylate Injection is contraindicated in patients with known hypersensitivity to cisatracurium. Severe anaphylactic reactions to Cisatracurium Besylate Injection have been reported [see Warnings and Precautions ( 5.4 )] . Known hypersensitivity to cisatracurium ( 4 )

Residual Paralysis : Patients with neuromuscular diseases are at higher risk. Use a lower initial bolus dose and consider using a reversal agent in these patients. ( 2.2 , 5.1 ) Risk of Seizure : Monitor level of neuromuscular blockade during long-term administration to limit exposure to toxic metabolites ( 5.3 ) Hypersensitivity Reactions and Anaphylaxis : Severe hypersensitivity reactions including anaphylactic reactions have been reported. Consider cross-reactivity among neuromuscular blocking agents, both depolarizing and non-depolarizing. ( 4 , 5.4 ) Risk of Death due to Medication Errors : Accidental administration can cause death. ( 5.5 ) Inadequate Anesthesia : Use Cisatracurium Besylate Injection in the presence of appropriate sedation or general anesthesia and monitor patients to ensure level of anesthesia is adequate ( 5.6 )

5.1 Residual Paralysis Cisatracurium Besylate Injection has been associated with residual paralysis. Patients with neuromuscular diseases (e.g., myasthenia gravis and myasthenic syndrome) and carcinomatosis may be at higher risk of residual paralysis; thus, a lower maximum initial bolus is recommended in these patients [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.10 )] . To prevent complications resulting from Cisatracurium Besylate Injection-associated residual paralysis, extubation is recommended only after the patient has recovered sufficiently from neuromuscular blockade. Consider use of a reversal agent especially in cases where residual paralysis is more likely to occur [see Overdosage ( 10 )] .

5.3 Risk of Seizure Laudanosine, an active metabolite of Cisatracurium Besylate Injection, has been shown to cause seizures in animals. Cisatracurium Besylate Injection-treated patients with renal or hepatic impairment may have higher metabolite concentrations (including laudanosine) than patients with normal renal and hepatic function [see Clinical Pharmacology ( 12.3 )] . Therefore, patients with renal or hepatic impairment receiving extended administration of Cisatracurium Besylate Injection may be at higher risk of seizures. The level of neuromuscular blockade during long-term Cisatracurium Besylate Injection administration should be monitored with a nerve stimulator to titrate Cisatracurium Besylate Injection administration to the patients' needs and limit exposure to toxic metabolites.

5.4 Hypersensitivity Reactions Including Anaphylaxis Severe hypersensitivity reactions, including fatal and life-threatening anaphylactic reactions, have been reported [see Contraindications ( 4 )] . There have been reports of wheezing, laryngospasm, bronchospasm, rash and itching following Cisatracurium Besylate Injection administration in pediatric patients. Due to the potential severity of these reactions, appropriate precautions such as the immediate availability of appropriate emergency treatment should be taken. Precautions should also be taken in those patients who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported.

5.5 Risk of Death Due to Medication Errors Administration of Cisatracurium Besylate Injection results in paralysis, which may lead to respiratory arrest and death, a progression that may be more likely to occur in a patient for whom it is not intended. Confirm proper selection of intended product and avoid confusion with other injectable solutions that are present in critical care and other clinical settings. If another healthcare provider is administering the product, ensure that the intended dose is clearly labeled and communicated.

5.6 Risks Due to Inadequate Anesthesia Neuromuscular blockade in the conscious patient can lead to distress. Use Cisatracurium Besylate Injection in the presence of appropriate sedation or general anesthesia. Monitor patients to ensure that the level of anesthesia is adequate.

5.7 Risk for Infection The 20 mL vial of Cisatracurium Besylate Injection is intended only for administration as an infusion for use in a single patient in the ICU. The 20 mL vial should not be used multiple times because there is a higher risk of infection (the 20 mL vial does not contain a preservative).

5.8 Potentiation of Neuromuscular Blockade Certain drugs may enhance the neuromuscular blocking action of Cisatracurium Besylate Injection including inhalational anesthetics, antibiotics, magnesium salts, lithium, local anesthetics, procainamide and quinidine [see Drug Interactions ( 7.1 )] . Additionally, acid-base and/or serum electrolyte abnormalities may potentiate the action of neuromuscular blocking agents. Use peripheral nerve stimulation and monitor the clinical signs of neuromuscular blockade to determine the adequacy of the level of neuromuscular blockage and the need to adjust the Cisatracurium Besylate Injection dosage.

5.9 Resistance to Neuromuscular Blockade with Certain Drugs Shorter durations of neuromuscular block may occur and Cisatracurium Besylate Injection infusion rate requirements may be higher in patients chronically administered phenytoin or carbamazepine [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . Use peripheral nerve stimulation and monitor the clinical signs of neuromuscular blockade to determine the adequacy of neuromuscular blockage and the need to adjust the Cisatracurium Besylate Injection dosage.

5.10 Malignant Hyperthermia (MH) Cisatracurium Besylate Injection has not been studied in MH-susceptible patients. Because MH can develop in the absence of established triggering agents, the clinician should be prepared to recognize and treat MH in any patient undergoing general anesthesia.

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 Avenacy at 1-855-283-6229 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.

Succinylcholine : May decrease time to onset of maximum neuromuscular blockade ( 7.1 ) Inhalational anesthetics, antibiotics, local anesthetics, magnesium salts, procainamide, lithium, quinidine : May potentiate or prolong neuromuscular blockade action of Cisatracurium Besylate Injection. Use peripheral nerve stimulator and monitor clinical signs of neuromuscular blockade. ( 5.8 , 7.1 ) Phenytoin and Carbamazepine : May shorten duration of neuromuscular blockade. Use peripheral nerve stimulator and monitor clinical signs of neuromuscular blockade. ( 5.9 , 7.1 )

7.1 Clinically Significant Drug Interactions Table 4 displays clinically significant drug interactions with Cisatracurium Besylate Injection. Table 4: Clinically Significant Drug Interactions with Cisatracurium Besylate Injection * The use of peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of Cisatracurium Besylate Injection, and to determine whether adjustments need to be made to the dose with subsequent administration. † Examples: aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, sodium colistimethate Drug or Drug Class Clinical Implications * Succinylcholine The use of succinylcholine prior to Cisatracurium Besylate Injection administration may decrease the time to onset of maximum neuromuscular blockade but has no effect on the duration of neuromuscular blockade. Inhalational Anesthetics Administration of inhalational anesthetics with nitrous oxide/oxygen for greater than 30 minutes to achieve

1.25 Minimum Alveolar Concentration (MAC) may prolong the duration of action of initial and maintenance doses of Cisatracurium Besylate Injection. This may potentiate the neuromuscular blockade. Antibiotics † Local anesthetics Magnesium salts Procainamide Lithium Quinidine May prolong the neuromuscular blockade action of Cisatracurium Besylate Injection Phenytoin, Carbamazepine May increase resistance to the neuromuscular blockade action of Cisatracurium Besylate Injection resulting in shorter durations of neuromuscular blockade and infusion rate requirements may be higher.

7.2 Drugs Without Clinically Significant Drug Interactions With Cisatracurium Besylate Injection In clinical studies, propofol had no effect on the duration of action or dosing requirements for Cisatracurium Besylate Injection. Cisatracurium Besylate Injection is not compatible with propofol for Y-site administration.

Patients with Hemiparesis or Paraparesis : Perform neuromuscular monitoring on non-paretic limb ( 8.9 )

8.1 Pregnancy Risk Summary The 10 mL Cisatracurium Besylate Injection multiple-dose vials contain the preservative benzyl alcohol. Therefore, if Cisatracurium Besylate Injection is needed during pregnancy, consider using a benzyl alcohol-free formulation (i.e., 5 mL and 20 mL Cisatracurium Besylate Injection single-dose vials). Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Contraindications ( 4 ) and Use in Specific Populations ( 8.4 )] . There are no available clinical trial data on cisatracurium use in pregnancy to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal studies conducted in rats administered cisatracurium besylate during organogenesis (Gestational Day 6 to 15) found no evidence of fetal harm at 0.8 times (ventilated rats) the exposure from a human starting IV bolus dose of 0.2 mg/kg (see Data ). The estimated background risk for major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Labor or Delivery The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of preeclampsia or eclampsia of pregnancy. Data Animal Data Two embryofetal developmental reproductive toxicity studies were conducted in rats. In a non-ventilated rat study, pregnant animals were treated with cisatracurium besylate subcutaneously twice per day from Gestational Day 6 to 15 using subparalyzing doses (2 and 4 mg/kg daily; equivalent to 6- and 12-times, respectively, the AUC exposure in humans following a bolus dose of 0.2 mg/kg IV). In the ventilated rat study, pregnant animals were treated with cisatracurium besylate intravenously once a day between Gestational Day 6 to 15 using paralyzing doses (0.5 and 1 mg/kg; equivalent to 0.4- and 0.8-times, respectively, the exposure in humans following a bolus dose of 0.2 mg/kg IV based on mg/m 2 comparison). Neither of these studies revealed maternal or fetal toxicity or malformations.

8.2 Lactation Risk Summary The 10 mL Cisatracurium Besylate Injection multiple-dose vials contain the preservative benzyl alcohol. Therefore, if Cisatracurium Besylate Injection is needed during lactation, consider using a benzyl alcohol-free formulation (i.e., 5 mL and 20 mL Cisatracurium Besylate Injection single-dose vials). Because benzyl alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Contraindications ( 4 ) and Use in Specific Populations ( 8.4 )] . There are no data on the presence of cisatracurium besylate in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Cisatracurium Besylate Injection and any potential adverse effects on the breastfed child from Cisatracurium Besylate Injection or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of Cisatracurium Besylate Injection as an adjunct to general anesthesia to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery in pediatric patients 1 month through 12 years of age were established from three studies in pediatric patients [see Dosing and Administration ( 2.2 , 2.5 ) and Clinical Studies ( 14.2 )] . The three open-label studies are summarized below. The safety and effectiveness of Cisatracurium Besylate Injection have not been established in pediatric patients less than 1 month of age. Tracheal Intubation A study of 0.15 mg/kg Cisatracurium Besylate Injection evaluated 230 pediatric patients (ages 1 month to 12 years). Excellent or good intubating conditions were produced 120 seconds following 0.15 mg/kg of Cisatracurium Besylate Injection in 88 of 90 of patients induced with halothane and in 85 of 90 of patients induced with thiopentone and fentanyl. The study also evaluated 50 pediatric patients during opioid anesthesia, with maximum neuromuscular blockade achieved in an average of about 3 minutes and a clinically effective block for 36 minutes in patients ages 2 to 12 years, and maximum neuromuscular block in about 2 minutes and a clinically effective block for about 43 minutes in infants 1 to 23 months [see Clinical Studies ( 14.2 )] . In a study of 0.1 mg/kg Cisatracurium Besylate Injection administered in 16 pediatric patients (ages 2 to 12 years) during opioid/nitrous oxide/oxygen anesthesia, maximum neuromuscular blockade was achieved in an average of 2.8 minutes with a clinically effective block for 28 minutes [see Clinical Studies ( 14.2 )] . Skeletal Muscle Relaxation During Surgery In a study of Cisatracurium Besylate Injection administered during halothane/nitrous oxide/oxygen anesthesia, 18 pediatric patients (ages 2 to 12 years) were scheduled for surgical procedures that required neuromuscular block for 60 minutes or longer. The average duration of continuous infusion was 62.8 minutes (range: 17 to 145 minutes). The overall mean infusion rate for 9 patients whose infusion was 45 minutes or longer was 1.7 mcg/kg/minute (range: 1.19 to 2.14 mcg/kg/minute).

8.5 Geriatric Use Of the total number of subjects (135) in clinical studies of Cisatracurium Besylate Injection, 57, 63, and 15 subjects were 65 to 70 years old, 70 to 80 years old, and greater than 80 years old, respectively. The geriatric population included a subset of patients with significant cardiovascular disease [see Clinical Pharmacology ( 12.3 )] . Because the time to maximum neuromuscular blockade is approximately 1 minute slower in geriatric patients compared to younger patients, consider extending the interval between administering Cisatracurium Besylate Injection and attempting intubation by at least 1 minute to achieve adequate intubation conditions [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.2 )] . The time to maximum neuromuscular blockade is approximately 1 minute slower in geriatric patients, a difference that should be taken into account when selecting a neuromuscular blocking agent (e.g., the need to rapidly secure the airway) and when initiating laryngoscopy [see Clinical Pharmacology ( 12.3 )] . Minor differences in the pharmacokinetics of cisatracurium between elderly and young adult patients were not associated with clinically significant differences in the recovery profile of Cisatracurium Besylate Injection following a single 0.1 mg/kg dose. Besides the differences noted above, no overall differences in safety or effectiveness were observed between geriatric and younger subjects, and other reported clinical experience has not identified differences in responses between geriatric and younger subjects, but greater sensitivity of some older individuals to Cisatracurium Besylate Injection cannot be ruled out.

8.6 Patients with Renal Impairment The time to 90% neuromuscular blockade was 1 minute slower in patients with end-stage renal disease than in patients with normal renal function. […]

Cisatracurium Besylate Injection binds competitively to cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in blockade of neuromuscular transmission. This action is antagonized by acetylcholinesterase inhibitors such as neostigmine.