CISATRACURIUM Drug Interactions: What You Need to Know

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 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.

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 )
• 10 mL multiple-dose vials contain benzyl alcohol and are contraindicated in pediatric patients less than 1 month of age and low birth-weight infants. ( 4 )

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 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.10 )]</span> . 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 <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span> . 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 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.

5.8 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )]</span> . 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.

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.10 )]</span> . 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 <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span> .

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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 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.

5.8 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )]</span> . 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.