Cisatracurium Besylate (Page 5 of 9)

8.5 Geriatric Use

Of the total number of subjects (135) in clinical studies of cisatracurium besylate, 57, 63, and 15 subjects were 65 to 70 years old, 70 to 80 years old, and greater than 80 years old, respectively. The geriatric population included a subset of patients with significant cardiovascular disease [see Clinical Pharmacology (12.3)].

Because the time to maximum neuromuscular blockade is approximately 1 minute slower in geriatric patients compared to younger patients, consider extending the interval between administering cisatracurium besylate and attempting intubation by at least 1 minute to achieve adequate intubation conditions [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)].

The time to maximum neuromuscular blockade is approximately 1 minute slower in geriatric patients, a difference that should be taken into account when selecting a neuromuscular blocking agent (e.g., the need to rapidly secure the airway) and when initiating laryngoscopy [see Clinical Pharmacology (12.3)]. Minor differences in the pharmacokinetics of cisatracurium between elderly and young adult patients were not associated with clinically significant differences in the recovery profile of cisatracurium besylate following a single 0.1 mg/kg dose.

Besides the differences noted above, no overall differences in safety or effectiveness were observed between geriatric and younger subjects, and other reported clinical experience has not identified differences in responses between geriatric and younger subjects, but greater sensitivity of some older individuals to cisatracurium besylate cannot be ruled out.

8.6 Patients with Renal Impairment

The time to 90% neuromuscular blockade was 1 minute slower in patients with end-stage renal disease than in patients with normal renal function. Therefore, consider extending the interval between administering cisatracurium besylate and attempting intubation by at least 1 minute to achieve adequate intubation conditions [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)].

There was no clinically significant alteration in the recovery profile of cisatracurium besylate in patients with end-stage renal disease following a 0.1 mg/kg dose of cisatracurium besylate. The recovery profile of cisatracurium besylate is unchanged in patients with renal impairment, which is consistent with predominantly organ-independent elimination [see Clinical Pharmacology (12.3)].

8.7 Patients with Hepatic Impairment

The pharmacokinetic study analysis in patients with end-stage liver disease undergoing liver transplantation and healthy subjects undergoing elective surgery indicated slightly larger volumes of distribution in liver transplant patients with slightly higher plasma clearances of cisatracurium. The times to maximum neuromuscular blockade were approximately one minute faster in liver transplant patients than in healthy adult patients receiving 0.1 mg/kg cisatracurium besylate. These minor differences in pharmacokinetics were not associated with clinically significant differences in the recovery profile of cisatracurium besylate [see Clinical Pharmacology (12.3)].

8.8 Burn Patients

Patients with burns have been shown to develop resistance to nondepolarizing neuromuscular blocking agents. The extent of altered response depends upon the size of the burn and the time elapsed since the burn injury. Cisatracurium besylate has not been studied in patients with burns. However, based on its structural similarity to another neuromuscular blocking agent, consider the possibility of increased dosage requirements and shortened duration of action if cisatracurium besylate is administered to burn patients.

8.9 Patients with Hemiparesis or Paraparesis

Patients with hemiparesis or paraparesis may demonstrate resistance to nondepolarizing muscle relaxants in the affected limbs. To avoid inaccurate dosing, perform neuromuscular monitoring on a non-paretic limb.

8.10 Patients with Neuromuscular Disease

Profound and prolonged neuromuscular blockade may occur in patients with neuromuscular diseases (e.g., myasthenia gravis and myasthenic syndrome) and carcinomatosis. Therefore, a lower maximum initial bolus is recommended in these patients [see Dosage and Administration (2.2)].

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 T4 :T1 ratio ≥ 70% in an average of 9 to 10 minutes. The times from 25% recovery of the muscle twitch response to a T4 :T1 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 T4 :T1 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.

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 is one of 10 isomers of atracurium besylate and constitutes approximately 15% of that mixture. Cisatracurium besylate is [1R — [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 C53 H72 N2 O12 and the molecular weight is 929.2. The molecular formula of cisatracurium as the besylate salt is C65 H82 N2 O18 S2 and the molecular weight is 1243.50. The structural formula of cisatracurium besylate is:

Structural Formula of Cisatracurium Besylate
(click image for full-size original)

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 aqueous solution provided in 5 mL, 10 mL, and 20 mL vials. The pH is adjusted to 3.25 to 3.65 with benzenesulfonic acid.

  • The 5 mL single-dose vials contain 2 mg per mL cisatracurium, equivalent to 2.68 mg per mL cisatracurium besylate.
  • The 10 mL multiple-dose vials contain 2 mg per mL cisatracurium, equivalent to 2.68 mg per mL cisatracurium besylate, and 0.9% benzyl alcohol as a preservative.
  • The 20 mL single-dose vials contain 10 mg per mL cisatracurium, equivalent to 13.38 mg per mL cisatracurium besylate.
Structural Formula of Cisatracurium Besylate

12 CLINICAL PHARMACOLOGY

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