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 ( 1 )

2 DOSAGE & 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, USP 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-induced paralysis ( 2.1 ) See the Full Prescribing Information for: 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 ) Continuous infusion rates ( 2.6 ) Preparation instructions ( 2.7 ) 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 include: 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: ◦ Determine the adequacy of neuromuscular blockade (e.g., need for additional Cisatracurium besylate injection doses, reduction of the infusion rate). ◦ Minimize risk of overdosage or underdosage. ◦ Assess the extent of recovery from neuromuscular blockade (e.g., spontaneous recovery or recovery after administration of a reversal agent, e.g., neostigmine). ◦ Appropriately titrate doses to potentially limit exposure to toxic metabolites. ◦ Facilitate more rapid reversal of the Cisatracurium besylate -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 )] . Pat…

5 WARNINGS AND PRECAUTIONS 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 ) Benzyl Alcohol: Consider combined daily load of benzyl alcohol from all sources when the 10 mL multiple dose vials are used in infants ( 4 , 5.2 ) 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 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 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-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 )] . 5.2 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative in 10 mL Multiple-Dose Vials Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Cisatracurium besylate injection (10 mL multiple-dose vials). This warning is not applicable to the 5 mL and 20 mL Cisatracurium besylate injection single-dose vials because these vials do not contain benzyl alcohol. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing the 10 mL multiple-dose Cisatracurium besylate injection vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including Cisatracurium besylate injection (multiple-dose vials contain 9 mg of benzyl alcohol per ml) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations ( 8.4 )]. The use of 10 mL Cisatracurium besylate injection multiple-dose vials is contraindicated in pediatric patients less than 1 month of age and low birth-weight infants because these patients are more likely to develop benzyl alcohol toxicity [see Contraindications ( 4 )] . 5.3 Risk of Seizure Laudanosine, an active metabolite of Cisatracurium besylate has been shown to cause seizures in animals. Cisatracurium besylate -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 may be at higher risk of seizures. The level of neuromuscular blockade during long-term Cisatracurium besylate administration should be monitored with a nerve stimulator to titrate Cisatracurium besylate 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 Contraind…

4 CONTRAINDICATIONS 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 )] . The use of 10 mL Cisatracurium besylate Injection multiple-dose vials is contraindicated for use in pediatric patients less than 1 month of age and low birth-weight infants because the formulation contains benzyl alcohol [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.4 )] Known hypersensitivity to cisatracurium ( 4 )

7 DRUG INTERACTIONS 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. 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. Table 4. Clinically Significant Drug Interactions with Cisatracurium besylate Drug or Drug Class Clinical Implications * Succinylcholine The use of succinylcholine prior to Cisatracurium besylate 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. This may potentiate the neuromuscular blockade. Antibiotics † Local anesthetics Magnesium salts Procainamide Lithium Quinidine May prolong the neuromuscular blockade action of Cisatracurium besylate Phenytoin, Carbamazepine May increase resistance to the neuromuscular blockade action of Cisatracurium besylate resulting in shorter durations of neuromuscular blockade and infusion rate requirements may be higher. * 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, 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 7.2 Drugs Without Clinically Significant Drug Interactions With Cisatracurium besylate In clinical studies, propofol had no effect on the duration of action or dosing requirements for Cisatracurium besylate. Cisatracurium besylate is not compatible with propofol for Y-site administration.

8.1 Pregnancy Risk Summary The 10 mL Cisatracurium besylate injection multiple-dose vials contain the preservative benzyl alcohol. Therefore, if Cistracurium 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 ), Warnings and Precautions ( 5.2 ), 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 2-4% and 15-20%, 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.

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 Piramal Pharma Solutions Inc. at 1-626-206-0832 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 in Surgical Patients The data presented below are based on studies involving 945 surgical patients who received Cisatracurium besylate in conjunction with other drugs in US and European clinical studies in a variety of procedures [see Clinical Studies ( 14.1 )] . Table 3 displaysadverse reactions that occurred at a rate of less than 1%. Table 3. Adverse Reactions in Clinical Trials of Cisatracurium besylate 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 in Intensive Care Unit Patients The adverse reactions presented below were from studies involving 68 adult ICU patients who received Cisatracurium besylate 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 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 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: anaphylaxis, histamine release, prolonged neuromuscular block, muscle weakness, myopathy.