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 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 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: 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 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 )] . Patien …

3 DOSAGE FORMS AND STRENGTHS Cisatracurium besylate injection, USP is available as a clear colorless to slightly yellow or greenish-yellow color solution in the following strengths: • 10 mg of cisatracurium per 5 mL (2 mg/mL) in single-dose vials (equivalent to 2.68 mg/mL cisatracurium besylate). • 20 mg of cisatracurium per 10 mL (2 mg/mL) in multiple-dose vials (equivalent to 2.68 mg/mL cisatracurium besylate) with benzyl alcohol as a preservative. • 200 mg of cisatracurium per 20 mL (10 mg/mL) in single-dose vials. Injection: • 10 mg/5 mL (2 mg/mL) in single-dose vials (3) • 20 mg/10 mL (2 mg/mL) and benzyl alcohol as a preservative in multiple-dose vials (3) • 200 mg/20 mL (10 mg/mL) in single-dose vials

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)

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 Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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.

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 o …

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 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 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. * 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 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.

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 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. * 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 …

8 USE IN SPECIFIC POPULATIONS 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), 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/m2 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 contains 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), Warnings and Precautions (5.2) 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 …

12.1 Mechanism of Action 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 .

11 DESCRIPTION Cisatracurium besylate injection, USP is a nondepolarizing skeletal neuromuscular blocker for intravenous administration. Compared to other neuromuscular blockers, it is intermediate in its onset and duration of action. Cisatracurium besylate injection, USP contains cisatracurium besylate as the active pharmaceutical ingredient. Cisatracurium besylate is one of 10 isomers of atracurium besylate and constitutes approximately 15% of that mixture. Cisatracurium besylate is [1 R -[1α,2α(1' R *,2' R *)]]-2,2'-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium] dibenzenesulfonate. The molecular formula of the cisatracurium parent bis-cation is C 53 H 72 N 2 O 12 and the molecular weight is 929.2. The molecular formula of cisatracurium as the besylate salt is C 65 H 82 N 2 O 18 S 2 and the molecular weight is 1243.49. The structural formula of cisatracurium besylate is: The log of the partition coefficient of cisatracurium besylate is -2.12 in a 1-octanol/distilled water system at 25°C. Cisatracurium besylate injection, USP is a sterile, non-pyrogenic, clear colorless to slightly yellow or greenish-yellow solution. Each mL in the single-dose vials contains 2 mg of cisatracurium (equivalent to 2.68 mg of cisatracurium besylate, USP), and benzenesulfonic acid as pH adjuster in water for injection. Each mL in the multiple-dose vials contains 2 mg of cisatracurium (equivalent to 2.68 mg of cisatracurium besylate, USP), benzenesulfonic acid as pH adjuster, and also contains 9 mg of benzyl alcohol as preservative, in water for injection. The pH of cisatracurium besylate injection, USP is between 3.0 and 3.8. Chemical Structure

10 OVERDOSAGE Overdosage with neuromuscular blocking agents may result in neuromuscular blockade beyond the time needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway and controlled ventilation until recovery of normal neuromuscular function is assured. Once recovery from neuromuscular block begins, further recovery may be facilitated by administration of a cholinesterase inhibitor (e.g., neostigmine, edrophonium) in conjunction with an appropriate cholinergic inhibitor. Cholinesterase inhibitors should not be administered when complete neuromuscular blockade is evident or suspected because the reversal of paralysis may not be sufficient to maintain a patent airway and support an appropriate level of spontaneous ventilation. • Neostigmine : Administration of 0.04 to 0.07 mg/kg of neostigmine at approximately 10% recovery from neuromuscular blockade (range: 0 to 15%) produced 95% recovery of the muscle twitch response and a T 4 :T 1 ratio ≥ 70% in an average of 9 to 10 minutes. The times from 25% recovery of the muscle twitch response to a T 4 :T 1 ratio ≥ 70% following these doses of neostigmine averaged 7 minutes. The mean 25% to 75% recovery index following reversal was 3 to 4 minutes. • Edrophonium : Administration of 1 mg/kg of edrophonium at approximately 25% recovery from neuromuscular blockade (range: 16% to 30%) produced 95% recovery and a T 4 :T 1 ratio ≥ 70% in an average of 3 to 5 minutes. For providers treating patients treated with cholinesterase inhibitors: • Use a peripheral nerve stimulator to evaluate recovery and antagonism of neuromuscular blockade • Evaluate for evidence of adequate clinical recovery (e.g., 5-second head lift and grip strength). • Support ventilation until adequate spontaneous ventilation has resumed. The onset of antagonism may be delayed in the presence of debilitation, cachexia, carcinomatosis, and the concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular block or separately cause respiratory depression [see Drug Interactions ( 7.1 )] . Under such circumstances the management is the same as that of prolonged neuromuscular block.

16 HOW SUPPLIED/STORAGE AND HANDLING Cisatracurium besylate injection, USP is a clear solution supplied as follows: Strength (mg of cisatracurium) Containers NDC# Preservative 10 mg/5 mL (2 mg/mL) 5 mL Single dose vial in a carton 31722-313-01 Does not contain benzyl alcohol 5 mL Single dose vial 31722-313-02 5 mL Single dose vials in a Carton of 10 31722-313-10 20 mg/10 mL (2 mg/mL) 10 mL Multiple-dose vial in a carton 31722-314-01 Contains 0.9% w/v benzyl alcohol [see Warnings and Precautions ( 5.2 )] 10 mL Multiple-dose vial 31722-314-02 10 mL Multiple-dose vials in a Carton of 10 31722-314-10 200 mg/20 mL (10 mg/mL) 5 mL Single dose vial in a carton 31722-312-01 Does not contain benzyl alcohol 5 mL Single dose vial 31722-312-02 5 mL Single dose vials in a Carton of 10 31722-312-10 Discard unused portion of the 5 mL and 20 mL single-dose vials. Storage Refrigerate Cisatracurium besylate injection, USP at 2° to 8°C (36° to 46°F) in the carton to preserve potency. Protect from light. DO NOT FREEZE. Upon removal of unused vials from refrigeration to room temperature storage conditions (25°C/77°F), use Cisatracurium besylate injection, USP within 21 days, even if re-refrigerated.