Cisatracurium Besylate (Page 3 of 9)

5 WARNINGS AND PRECAUTIONS

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 (10 mL multiple-dose vials). This warning is not applicable to the 5 mL and 20 mL cisatracurium besylate 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 vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including cisatracurium besylate (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 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 Contraindications (4)]. There have been reports of wheezing, laryngospasm, bronchospasm, rash and itching following cisatracurium besylate 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 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 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 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 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 dosage.

5.9 Resistance to Neuromuscular Blockade with Certain Drugs

Shorter durations of neuromuscular block may occur and cisatracurium besylate 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 dosage.

5.10 Malignant Hyperthermia (MH)

Cisatracurium besylate 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.

6 ADVERSE REACTIONS

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 displays adverse 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.

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