Cisatracurium Besylate (Page 8 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of cisatracurium besylate have not been performed.

Mutagenesis

Cisatracurium besylate was evaluated in a battery of four genotoxicity assays. Evaluation of cisatracurium besylate in the in vitro mouse lymphoma forward gene mutation assay resulted in mutations in the presence and absence of exogenous metabolic activation. The in vitro bacterial reverse gene mutation (Ames) assay, in vitro human lymphocyte chromosomal aberration assay, and an in vivo rat bone marrow cytogenetic assay did not demonstrate evidence of mutagenicity or clastogenicity.

Impairment of Fertility

Studies to determine if cisatracurium besylate impacts fertility have not been completed.

14 CLINICAL STUDIES

14.1 Skeletal Muscle Relaxation for Intubation of Adult Patients

The efficacy of cisatracurium besylate to provide skeletal muscle relaxation to facilitate tracheal intubation during surgery was established in six studies in adult patients. In all these studies patients had general anesthesia and mechanical ventilation.

  • Cisatracurium besylate doses between 0.15 and 0.2 mg/kg were evaluated in 240 adults. Maximum neuromuscular blockade generally occurred in within 4 minutes for this dose range.
  • When administered during induction using thiopental or propofol and co-induction agents (i.e., fentanyl and midazolam), excellent to good intubating conditions were generally achieved within 2 minutes (excellent intubation conditions most frequently achieved with the 0.2 mg/kg dose of cisatracurium besylate).
  • Following the induction of general anesthesia with propofol, nitrous oxide/oxygen, and co-induction agents (e.g., fentanyl and midazolam), good or excellent conditions for tracheal intubation occurred in 96/102 (94%) patients in 1.5 to 2 minutes following cisatracurium besylate doses of 0.15 mg/kg and in 97/110 (88%) patients in 1.5 minutes following cisatracurium besylate doses of 0.2 mg/kg.

In Study 1, the clinically effective duration of action for 0.15 and 0.2 mg/kg cisatracurium besylate using propofol anesthesia was 55 minutes (range: 44 to 74 minutes) and 61 minutes (range: 41 to 81 minutes), respectively.

In Studies 2 and 3, cisatracurium besylate doses of 0.25 and 0.4 mg/kg were evaluated in 30 patients under opioid/nitrous oxide/oxygen anesthesia and provided 78 (66 to 86) and 91 (59 to 107) minutes of clinical relaxation, respectively.

In Study 4, two minutes after fentanyl and midazolam were administered, patients received thiopental anesthesia. Intubating conditions were assessed at 120 seconds following administration of 0.15 mg/kg or 0.2 mg/kg of cisatracurium besylate in 51 patients (see Table 11).

Table 11. Intubating Conditions at 120 Seconds after Cisatracurium Besylate Administration with Thiopental Anesthesia in Adult Surgery Patients in Study 4

* Excellent: Easy passage of tube without coughing. Vocal cords relaxed and abducted.

Good: Passage of tube with slight coughing and/or bucking. Vocal cords relaxed and abducted.

Cisatracurium Besylate 0.15 mg/kg (n = 26) Cisatracurium Besylate 0.20 mg/kg (n = 25)
Excellent and Good 88% 96%
95% CI 76, 100 88, 100
Excellent 31% 60%
Good 58% 36%

Excellent intubating conditions were more frequently achieved with the 0.2 mg/kg dose (60%) than the 0.15 mg/kg dose (31%) when intubation was attempted 120 seconds following cisatracurium besylate.

Study 5 evaluated intubating conditions after 3 and 4 × ED95 (0.15 mg/kg and 0.20 mg/kg) following induction with fentanyl and midazolam and either thiopental or propofol anesthesia. This study compared intubation conditions produced by these doses of cisatracurium besylate after 90 seconds. Table 12 displays these results.

Table 12. Intubating Conditions at 90 Seconds after Cisatracurium Besylate Administration with Thiopental or Propofol Anesthesia in Study 5

* Excellent: Easy passage of tube without coughing. Vocal cords relaxed and abducted.

Good: Passage of tube with slight coughing and/or bucking. Vocal cords relaxed and abducted.

Intubating Condition Cisatracurium Besylate 0.15 mg/kg with Propofol (n = 31) Cisatracurium Besylate 0.15 mg/kg with Thiopental (n = 31) Cisatracurium Besylate 0.20 mg/kg with Propofol (n = 30) Cisatracurium Besylate 0.20 mg/kg with Thiopental (n = 28)
Excellent and Good 94% 90% 93% 96%
95% CI 85, 100 80, 100 84, 100 90, 100
Excellent 58% 55% 70% 57%
Good 35% 35% 20% 39%

Excellent intubating conditions were more frequently observed with the 0.2 mg/kg dose when intubation was attempted 90 seconds following cisatracurium besylate.

14.2 Skeletal Muscle Relaxation for Intubation of Pediatric Patients

The efficacy of cisatracurium besylate to provide skeletal muscle relaxation to facilitate tracheal intubation was established in studies in pediatric patients aged 1 month to 12 years old. In these studies, patients had general anesthesia and mechanical ventilation.

In Study 6, a cisatracurium besylate dose of 0.1 mg/kg was evaluated in 16 pediatric patients (ages 2 years to 12 years) during opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, maximum neuromuscular blockade was achieved in an average of 2.8 minutes (range: 1.8 to 6.7 minutes) with a clinically effective block for 28 minutes (range: 21 to 38 minutes).

In Study 7, a cisatracurium besylate dose of 0.15 mg/kg was evaluated in 50 pediatric patients (ages 1 month to 12 years) during opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, maximum neuromuscular blockade was achieved in an average of about 3 minutes (range: 1.5 to 8 minutes) with a clinically effective block for 36 minutes (range: 29 to 46 minutes) in 24 patients ages 2 to 12 years. In 27 infants (1 to 23 months), maximum neuromuscular block was achieved in about 2 minutes (range: 1.3 to 4.3 minutes) with a clinically effective block for about 43 minutes (range: 34 to 58 minutes) with this dose.

Study 7 also evaluated intubating conditions in 180 pediatric patients (ages 1 month to 12 years) after administration of cisatracurium besylate doses of 0.15 mg/kg following induction with either halothane (with halothane/nitrous oxide/oxygen maintenance) or thiopentone and fentanyl (with thiopentone/fentanyl nitrous oxide/oxygen maintenance). Table 13 displays the intubating conditions by type of anesthesia, and pediatric age group. Excellent or good intubating conditions were produced 120 seconds following 0.15 mg/kg of cisatracurium besylate in 88/90 (98%) of patients induced with halothane and in 85/90 (94%) of patients induced with thiopentone and fentanyl. There were no patients for whom intubation was not possible, but there were 7/120 patients aged 1 year to 12 years old for whom intubating conditions were described as poor.

Table 13. Intubating Conditions at 120 Seconds* in Pediatric Patients Ages 1 Month to 12 Years Old in Study 7

* Excellent: Easy passage of the tube without coughing. Vocal cords relaxed and abducted.

Good: Passage of tube with slight coughing and/or bucking. Vocal cords relaxed and abducted.

Poor: Passage of tube with moderate coughing and/or bucking. Vocal cords moderately adducted. Response of patient requires adjustment of ventilation pressure and/or rate.

Cisatracurium Besylate 0.15 mg/kg 1 to 11 mo. Cisatracurium Besylate 0.15 mg/kg 1 to 4 years Cisatracurium Besylate 0.15 mg/kg 5 to 12 years
Halothane Anesthesia (n = 30) Thiopentone/ Fentanyl Anesthesia (n = 30) Halothane Anesthesia (n = 30) Thiopentone/ Fentanyl Anesthesia (n = 30) Halothane Anesthesia (n = 30) Thiopentone/ Fentanyl Anesthesia (n = 30)
Excellent and Good 100% 100% 97% 87% 97% 97%
Excellent 100% 83% 90% 63% 73% 70%
Good 0% 17% 7% 23% 23% 27%
Poor 0% 0% 3% 13% 3% 3%

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