CISATRACURIUM BESYLATE- cisatracurium besylate injection

United States - English - NLM (National Library of Medicine)

Buy It Now

Active ingredient:
CISATRACURIUM BESYLATE (UNII: 80YS8O1MBS) (CISATRACURIUM - UNII:QX62KLI41N)
Available from:
Jiangsu Hengrui Medicine Co., Ltd.
INN (International Name):
CISATRACURIUM BESYLATE
Composition:
CISATRACURIUM 2 mg in 1 mL
Administration route:
INTRAVENOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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 contraindicated in patients with known hypersensitivity to cisatracurium. Severe anaphylactic reactions to cisatracurium have been reported [see Warnings and Precautions ( 5.4)] . The use of 10 mL cisatracurium 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
Product summary:
Cisatracurium Besylate Injection, USP is a clear solution supplied as follows: 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 from refrigeration to room temperature storage conditions (25°C/77°F), use Cisatracurium Besylate Injection, USP within 21 days, even if re-refrigerated.
Authorization status:
Abbreviated New Drug Application
Authorization number:
57884-3061-1, 57884-3063-1

CISATRACURIUM BESYLATE- cisatracurium besylate injection

Jiangsu Hengrui Medicine Co., Ltd.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use CISATRACURIUM BESYLATE INJECTION

safely and effectively. See full prescribing information for CISATRACURIUM BESYLATE INJECTION.

CISATRACURIUM BESYLATE injection, for intravenous use

Initial U.S. Approval: 1995

RECENT MAJOR CHANGES

Dosage and Administration ( 2.1)

7/2018

Warnings and Precautions, Residual Paralysis ( 5.1)

7/2018

Warnings and Precautions, Risk of Death Due to Medication Errors ( 5.5)

7/2018

INDICATIONS AND USAGE

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)

DOSAGE AND ADMINISTRATION

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 injection 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 injection-induced paralysis ( 2.1)

See the Full Prescribing Information for:

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)

Continuous infusion rates ( 2.6)

Preparation instructions ( 2.7)

Drug compatibility ( 2.8)

DOSAGE FORMS AND STRENGTHS

Inje ction:

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 ( 3)

CONTRAINDICATIONS

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)

WARNINGS 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 in the presence of appropriate sedation or general anesthesia and monitor

patients to ensure level of anesthesia is adequate ( 5.6)

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 eVenus Pharmaceutical Laboratories, Inc at 1-609-

395-8625 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. 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)

USE IN SPECIFIC POPULATIONS

Patients with Hemiparesis or Paraparesis: Perform neuromuscular monitoring on non-paretic limb ( 8.9)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 10/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

2.2 Recommended Cisatracurium Besylate Injection Dose for Performing Tracheal Intubation

2.3 Recommended Maintenance Bolus Cisatracurium Besylate Injection Doses in Adult Surgical

Procedures

2.4 Dosage in Burn Patients

2.5 Dosage for Continuous Infusion

2.6 Rate Tables for Continuous Infusion

2.7 Preparation of Cisatracurium Besylate Injection

2.8 Drug Compatibility

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Residual Paralysis

5.2 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative in 10 mL

Multiple-Dose Vials

5.3 Risk of Seizure

5.4 Hypersensitivity Reactions Including Anaphylaxis

5.5 Risk of Death Due to Medication Errors

5.6 Risks Due to Inadequate Anesthesia

5.7 Risk for Infection

5.8 Potentiation of Neuromuscular Blockade

5.9 Resistance to Neuromuscular Blockade with Certain Drugs

5.10 Malignant Hyperthermia (MH)

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Clinically Significant Drug Interactions

7.2 Drugs Without Clinically Significant Drug Interactions With Cisatracurium

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Renal Impairment

8.7 Patients with Hepatic Impairment

8.8 Burn Patients

8.9 Patients with Hemiparesis or Paraparesis

8.10 Patients with Neuromuscular Disease

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Skeletal Muscle Relaxation for Intubation of Adult Patients

14.2 Skeletal Muscle Relaxation for Intubation of Pediatric Patients

14.3 Skeletal Muscle Relaxation in ICU Patients

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

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

Sections or subsections omitted from the full prescribing information are not listed.

Cisatracurium Besylate Injection is not recommended for rapid sequence endotracheal intubation due to

the time required for its onset of action.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

Important administration instructions include:Important administration instructions include:

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 injection dosage on the patients’ responses to the initial

doses.

Use a peripheral nerve stimulator to:

Determine the adequacy of neuromuscular blockade (e.g., need for additional cisatracurium

besylate injection doses, reduction of the infusion rate).

Minimize risk of overdosage or underdosage.

Assess the extent of recovery from neuromuscular blockade (e.g., spontaneous recovery or

recovery after administration of a reversal agent, e.g., neostigmine).

Appropriately titrate doses to potentially limit exposure to toxic metabolites.

Facilitate more rapid reversal of the cisatracurium besylate injection-induced paralysis.

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)] .

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)] .

Patients with Neuromuscular Disease

The maximum recommended initial bolus dose of cisatracurium besylate injection is 0.02 mg/kg in

patients with neuromuscular diseases (e.g., myasthenia gravis and myasthenic syndrome and

carcinomatosis) [see Warnings and Precautions ( 5.1)] .

Geriatric Patients and Patients with End-Stage Renal Disease

Because the time to maximum neuromuscular blockade is approximately 1 minute slower in geriatric

patients compared to younger patients (and in patients with end-stage renal disease than in patients with

normal renal function), consider extending the interval between administering cisatracurium besylate

injection and attempting intubation by at least 1 minute to achieve adequate intubation conditions in

geriatric patients and patients with end-stage renal disease. A peripheral nerve stimulator should be

used to determine the adequacy of muscle relaxation for the purposes of intubation and the timing and

amounts of subsequent doses [see Use in Specific Populations ( 8.5, 8.6) and Clinical Pharmacology (

12.3)] .

Tracheal Intubation in Pediatric Patients

Infants 1 to 23 Months of Age

The recommended dose of cisatracurium besylate injection for intubation of pediatric patients ages 1

month to 23 months is 0.15 mg/kg administered over 5 to 10 seconds. When administered during stable

opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg of cisatracurium besylate injection produced

maximum neuromuscular blockade in about 2 minutes (range: 1.3 to 4.3 minutes) with a clinically

effective block (time to 25% recovery) for about 43 minutes (range: 34 to 58 minutes) [see Clinical

Studies ( 14.2)] .

Pediatric Patients 2 to 12 Years of Age

The recommended weight-based bolus dose of cisatracurium besylate injection for pediatric patients 2

to 12 years of age is 0.1 mg/kg to 0.15 mg/kg administered over 5 to 10 seconds. When administered

during stable opioid/nitrous oxide/oxygen anesthesia, 0.1 mg/kg cisatracurium besylate injection

produced maximum neuromuscular blockade in an average of 2.8 minutes (range: 1.8 to 6.7 minutes)

with a clinically effective block (time to 25% recovery) for 28 minutes (range: 21 to 38 minutes). When

administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg cisatracurium besylate

injection produced maximum neuromuscular blockade 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) [see Clinical Studies (

14.2)] .

2.3 Recommended Maintenance Bolus Cisatracurium Besylate Injection Doses in Adult Surgical

Procedures

Determine if maintenance bolus doses are needed based on clinical criteria including the response to

peripheral nerve stimulation. The recommended maintenance bolus dose of cisatracurium besylate

injection is 0.03 mg/kg; however, smaller or larger maintenance doses may be administered based on the

required duration of action. Administer the first maintenance bolus dose starting:

40 to 50 minutes after an initial dose of cisatracurium besylate injection 0.15 mg/kg;

50 to 60 minutes after an initial dose of cisatracurium besylate injection 0.2 mg/kg.

For long surgical procedures using inhalational anesthetics administered with nitrous oxide/oxygen at

the 1.25 MAC level for at least 30 minutes, consider administering less frequent maintenance bolus

doses or lower maintenance bolus doses of cisatracurium besylate injection [see Clinical Pharmacology

( 12.2)] . No adjustment to the initial cisatracurium besylate injection maintenance bolus dose should be

necessary when cisatracurium besylate injection is administered shortly after initiation of volatile agents

or when used in patients receiving propofol anesthesia.

2.4 Dosage in Burn Patients

Burn patients have been shown to develop resistance to nondepolarizing neuromuscular blocking agents;

therefore, consider increasing the cisatracurium besylate injection dosages for intubation and

maintenance [see Use in Specific Populations ( 8.8)] .

2.5 Dosage for Continuous Infusion

Continuous Infusion for Surgical Procedures in Adults and Pediatric Patients

During extended surgical procedures, cisatracurium besylate injection may be administered by

continuous infusion to adults and pediatric patients aged 2 or more years if patients have spontaneous

recovery after the initial cisatracurium besylate injection bolus dose. Following recovery from

neuromuscular blockade, it may be necessary to re-administer a bolus dose to quickly re-establish

neuromuscular blockade prior to starting the continuous infusion.

If patients have had recovery of neuromuscular function, the recommended initial cisatracurium besylate

injection infusion rate is 3 mcg/kg/minute [see Dosage and Administration ( 2.6)] . Subsequently reduce

the rate to 1 mcg/kg/minute to 2 mcg/kg/minute to maintain continuous neuromuscular blockade. Use

peripheral nerve stimulation to assess the level of neuromuscular blockade and to appropriately titrate

the cisatracurium besylate injection infusion rate. If no response is elicited to peripheral nerve

stimulation, discontinue the infusion until a response returns.

Consider reducing the infusion rate by up to 30% to 40% when cisatracurium besylate injection is

administered during stable isoflurane anesthesia for at least 30 minutes (administered with nitrous

oxide/oxygen at the 1.25 MAC level) [see Clinical Pharmacology ( 12.2)] . Greater reductions in the

cisatracurium besylate injectioninfusion rate may be required with longer durations of administration of

isoflurane or with the administration of other inhalational anesthetics.

Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery

Consider reducing the infusion rate in patients undergoing CABG with induced hypothermia to half the

rate required during normothermia [see Clinical Pharmacology ( 12.2)] . Spontaneous recovery from

neuromuscular block following discontinuation of cisatracurium besylate injection infusion is expected

to proceed at a rate comparable to that following administration of a single bolus dose.

Continuous Infusion for Mechanical Ventilation in the Intensive Care Unit in Adults

During extended need for mechanical ventilation and skeletal muscle relaxation in the intensive care unit

(ICU), cisatracurium besylate injection may be administered by continuous infusion to adults if a patient

has spontaneous recovery of neuromuscular function after the initial cisatracurium besylate injection

bolus dose. Following recovery from neuromuscular blockade, it may be necessary to re-administer a

bolus dose to quickly re-establish neuromuscular blockade prior to starting the continuous infusion.

The recommended cisatracurium besylate injection infusion rate in adult patients in the ICU is 3

mcg/kg/minute (range: 0.5 mcg/kg/minute to 10.2 mcg/kg/minute) [see Dosage and Administration ( 2.6)] .

Use peripheral nerve stimulation to assess the level of neuromuscular blockade and to appropriately

titrate the cisatracurium besylate injection infusion rate.

2.6 Rate Tables for Continuous Infusion

The intravenous infusion rate depends upon the cisatracurium besylate injection concentration, the

desired dose, the patient's weight, and the contribution of the infusion solution to the fluid requirements

of the patient. Tables 1 and Table 2 provide guidelines for the cisatracurium besylate injection infusion

rate, in mL/hour (equivalent to microdrops/minute when 60 microdrops = 1 mL), in concentrations of 0.1

mg/mL or 0.4 mg/mL, respectively.

Table 1. Cisatracurium Besylate Injection Infusion Rates for Maintenance of Neuromuscular

Blockade During Opioid/Nitrous Oxide/Oxygen Anesthesia with a Concentration of 0.1 mg/mL

Drug Delivery Rate (mcg/kg/minute)

1

1.5

2

3

5

Patient Weight

Infusion Delivery Rate (mL/hour)

10 kg

45 kg

70 kg

100 kg

Table 2. Cisatracurium Besylate Injection Infusion Rates for Maintenance of Neuromuscular

Blockade During Opioid/Nitrous Oxide/Oxygen Anesthesia with a Concentration of 0.4 mg/mL

Drug Delivery Rate (mcg/kg/minute)

1

1.5

2

3

5

Patient Weight

Infusion Delivery Rate (mL/hour)

10 kg

45 kg

10.1

13.5

20.3

33.8

70 kg

10.5

15.8

31.5

52.5

100 kg

22.5

2.7 Preparation of Cisatracurium Besylate Injection

Visually inspect cisatracurium besylate injection for particulate matter and discoloration prior to

administration. If a cisatracurium besylate injection solution is cloudy or contains visible particulates,

do not use cisatracurium besylate injection. Cisatracurium besylate injection is a colorless to slightly

yellow or greenish-yellow solution.

Cisatracurium besylate injection may be diluted to 0.1 mg/mL in the following solutions:

5% Dextrose Injection, USP

0.9% Sodium Chloride Injection, USP, or

5% Dextrose and 0.9% Sodium Chloride Injection, USP

Store these diluted cisatracurium besylate injection solutions either in a refrigerator or at room

temperature for 24 hours without significant loss of potency.

Cisatracurium besylate injection also may be diluted to 0.1 mg/mL or 0.2 mg/mL in the following

solution:

Lactated Ringer’s and 5% Dextrose Injection

Store this diluted cisatracurium besylate injection solution under refrigeration for no more than 24

hours.

Do not dilute cisatracurium besylate injectionin Lactated Ringer’s Injection, USP due to chemical

instability.

2.8 Drug Compatibility

Cisatracurium besylate injection is compatible and may be administered with the following solutions

through Y-site administration:

5% Dextrose Injection, USP

0.9% Sodium Chloride Injection, USP

5% Dextrose and 0.9% Sodium Chloride Injection, USP

Sufentanil Citrate Injection, diluted as directed

Alfentanil Hydrochloride Injection, diluted as directed

Fentanyl Citrate Injection, diluted as directed

Midazolam Hydrochloride Injection, diluted as directed

Droperidol Injection, diluted as directed

Cisatracurium besylate injection is acidic (pH 3.25 to 3.65 for 10 mL vials and pH 3.0 to 3.7 for 5 mL

and 20 mL vials) and may not be compatible with alkaline solution having a pH greater than 8.5 (e.g.,

barbiturate solutions). Therefore, do not administer cisatracurium besylate injection and alkaline

solutions simultaneously in the same intravenous line.

Cisatracurium besylate injection is not compatible with propofol injection or ketorolac injection for Y-

site administration. Compatibility studies with other parenteral products have not been conducted.

3 DOSAGE FORMS AND STRENGTHS

Cisatracurium Besylate Injection, USP is available as a clear 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) and benzyl alcohol as a preservative in multiple-dose

vials (equivalent to 2.68 mg/mL cisatracurium besylate).

200 mg of cisatracurium per 20 mL (10 mg/mL) in single-dose vials (equivalent to 13.38 mg/mL

cisatracurium besylate); intended only for administration as an infusion in a single patient in the ICU.

4 CONTRAINDICATIONS

Cisatracurium besylate injection is contraindicated in patients with known hypersensitivity to

cisatracurium. Severe anaphylactic reactions to cisatracurium have been reported [see Warnings and

Precautions ( 5.4)] .

The use of 10 mL cisatracurium 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)] .

5 WARNINGS AND PRECAUTIONS

5.1 Residual Paralysis

Cisatracurium 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-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 (10 mL multiple-dose vials). This

warning is not applicable to the 5 mL and 20 mL cisatracurium 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 vials in infants consider the combined daily

metabolic load of benzyl alcohol from all sources including cisatracurium (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 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, has been shown to cause seizures in animals.

Cisatracurium-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 may be at higher risk of seizures.

The level of neuromuscular blockade during long-term cisatracurium administration should be

monitored with a nerve stimulator to titrate cisatracurium 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 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 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 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 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 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 dosage.

5.9 Resistance to Neuromuscular Blockade with Certain Drugs

Shorter durations of neuromuscular block may occur and cisatracurium 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 dosage.

5.10 Malignant Hyperthermia (MH)

Cisatracurium 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 in Surgical Patients

The data presented below are based on studies involving 945 surgical patients who received

cisatracurium 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 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 in Intensive Care Unit Patients

The adverse reactions presented below were from studies involving 68 adult ICU patients who

received cisatracurium 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 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 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: anaphylaxis, histamine release, prolonged neuromuscular block, muscle

weakness, myopathy.

7 DRUG INTERACTIONS

7.1 Clinically Significant Drug Interactions

Table 4 displays clinically significant drug interactions with cisatracurium.

Table 4. Clinically Significant Drug Interactions with Cisatracurium

Drug or Drug

Clas s

Clinical Implications*

Succinylcholine

The use of succinylcholine prior to cisatracurium 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. This may

potentiate the neuromuscular blockade.

Antibiotics†

Local

anesthetics

Magnesium

salts

Procainamide

Lithium

Quinidine

May prolong the neuromuscular blockade action of cisatracurium

Phenytoin,

Carbamazepine

May increase resistance to the neuromuscular blockade action of cisatracurium

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, 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

In clinical studies, propofol had no effect on the duration of action or dosing requirements for

cisatracurium. Cisatracurium is not compatible with propofol for Y-site administration.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies of cisatracurium in pregnant women. Animal studies

conducted in rats administered cisatracurium besylate during organogenesis 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. The

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% to 4% and 15% to 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 mg/kg 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 mg/kg 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/m

comparison). Neither of these studies revealed maternal or fetal toxicity or teratogenic effects.

8.2 Lactation

It is not known whether cisatracurium besylate is present in human milk. The developmental and health

benefits of breastfeeding should be considered along with the mother's clinical need for cisatracurium

and any potential adverse effects on the breastfed child from cisatracurium or from the underlying

maternal condition.

8.4 Pediatric Use

The safety and effectiveness of cisatracurium as an adjunct to general anesthesia to facilitate tracheal

intubation, and to provide skeletal muscle relaxation during surgery in pediatric patients 1 month through

12 years of age were established from three studies in pediatric patients [see Dosing and Administration

( 2.2, 2.5) and Clinical Studies ( 14.2)] . The three open-label studies are summarized below.

The safety and effectiveness of cisatracurium have not been established in pediatric patients less than 1

month of age.

Tracheal Intubation

A study of 0.15 mg/kg cisatracurium evaluated 230 pediatric patients (ages 1 month to 12 years).

Excellent or good intubating conditions were produced 120 seconds following 0.15 mg/kg of

cisatracurium in 88 of 90 of patients induced with halothane and in 85 of 90 of patients induced with

thiopentone and fentanyl. The study also evaluated 50 pediatric patients during opioid anesthesia, with

maximum neuromuscular blockade achieved in an average of about 3 minutes and a clinically effective

block for 36 minutes in patients ages 2 to 12 years, and maximum neuromuscular block in about 2 minutes

and a clinically effective block for about 43 minutes in infants 1 to 23 months [see Clinical Studies (

14.2)] .

In a study of 0.1 mg/kg cisatracurium administered in 16 pediatric patients (ages 2 to 12 years) during

opioid/nitrous oxide/oxygen anesthesia, maximum neuromuscular blockade was achieved in an average

of 2.8 minutes with a clinically effective block for 28 minutes [see Clinical Studies ( 14.2)] .

Skeletal Muscle Relaxation During Surgery

In a study of cisatracurium administered during halothane/nitrous oxide/oxygen anesthesia, 18 pediatric

patients (ages 2 to 12 years) were scheduled for surgical procedures that required neuromuscular block

for 60 minutes or longer. The average duration of continuous infusion was 62.8 minutes (range: 17 to

145 minutes). The overall mean infusion rate for 9 patients whose infusion was 45 minutes or longer

was 1.7 mcg/kg/minute (range: 1.19 mcg/kg/minute to 2.14 mcg/kg/minute).

Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative in 10 mL Multiple-Dose

Vials

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature

neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as

a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of

benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to

1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures,

intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure,

hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more

likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

When prescribing the 10 mL multiple-dose cisatracurium vials in infants consider the combined daily

metabolic load of benzyl alcohol from all sources including cisatracurium (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 Warnings and

Precautions ( 5.2)] . This warning is not applicable to the 5 mL and 20 mL cisatracurium single-dose

vials because these vials do not contain benzyl alcohol.

The use of 10 mL cisatracurium 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.

8.5 Geriatric Use

Of the total number of subjects (135) in clinical studies of cisatracurium, 57, 63, and 15 subjects were

65-70 years old, 70-80 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 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

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 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 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 in patients with

end-stage renal disease following a 0.1 mg/kg dose of cisatracurium. The recovery profile of

cisatracurium 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. These minor differences in

pharmacokinetics were not associated with clinically significant differences in the recovery profile of

cisatracurium [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 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 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 mg/kg 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

ratio ≥ 70% in an average of 9 to 10 minutes. The times from 25%

recovery of the muscle twitch response to a T

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

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 [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

and the molecular weight is 929.2. The molecular

formula of cisatracurium as the besylate salt is C

and the molecular weight is

1243.50. 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 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 for 10 mL vials.

The pH is adjusted to 3.0 to 3.7 with benzenesulfonic acid for 5 mL and 20 mL vials.

The 5 mL single-dose vials contain 2 mg/mL cisatracurium, equivalent to 2.68 mg/mL cisatracurium

besylate.

The 10 mL multiple-dose vials contain 2 mg/mL cisatracurium, equivalent to 2.68 mg/mL

cisatracurium besylate, and 0.9% benzyl alcohol as a preservative.

The 20 mL single-dose vials contain 10 mg/mL cisatracurium, equivalent to 13.38 mg/mL

cisatracurium besylate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cisatracurium 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.

12.2 Pharmacodynamics

The average ED

(dose required to produce 95% suppression of the adductor pollicis muscle twitch

response to ulnar nerve stimulation) of cisatracurium is 0.05 mg/kg (range: 0.048 to 0.053) in adults

receiving opioid/nitrous oxide/oxygen anesthesia.

The pharmacodynamics of various cisatracurium doses administered over 5 to 10 seconds during

opioid/nitrous oxide/oxygen anesthesia are summarized in Table 5. When the cisatracurium dose is

doubled, the clinically effective duration of blockade increases by approximately 25 minutes. Once

recovery begins, the rate of recovery is independent of dose.

Isoflurane or enflurane administered with nitrous oxide/oxygen to achieve 1.25 MAC (Minimum

Alveolar Concentration) prolonged the clinically effective duration of action of initial and maintenance

cisatracurium doses, and decreased the average infusion rate requirement of cisatracurium. The

magnitude of these effects depended on the duration of administration of the volatile agents:

Fifteen to 30 minutes of exposure to 1.25 MAC isoflurane or enflurane had minimal effects on the

duration of action of initial doses of cisatracurium.

In surgical procedures during enflurane or isoflurane anesthesia greater than 30 minutes, less

frequent maintenance dosing, lower maintenance doses, or reduced infusion rates of cisatracurium

were required. The average infusion rate requirement was decreased by as much as 30% to 40%

[see Drug Interactions ( 7.1)] .

The onset, duration of action, and recovery profiles of cisatracurium during propofol/oxygen or

propofol/nitrous oxide/oxygen anesthesia were similar to those during opioid/nitrous oxide/oxygen

anesthesia (see Table 5).

Repeated administration of maintenance cisatracurium doses or a continuous cisatracurium infusion for

up to 3 hours was not associated with development of tachyphylaxis or cumulative neuromuscular

blocking effects. The time needed to recover from successive maintenance doses did not change with

the number of doses administered when partial recovery occurred between doses. The rate of

spontaneous recovery of neuromuscular function after cisatracurium infusion was independent of the

duration of infusion and comparable to the rate of recovery following initial doses (see Table 5).

Pediatric patients including infants generally had a shorter time to maximum neuromuscular blockade and

a faster recovery from neuromuscular blockade compared to adults treated with the same weight-based

doses (see Table 5).

Table 5. Pharmacodynamic Dose Response* of Cisatracurium During Opioid/Nitrous

Oxide/Oxygen Anesthesia

Cisatracurium

Dos e

Time to

90%

Block in

minutes

Time to

Maximum

Block in

minutes

5%

Recovery

in minutes

25%

Recovery

in minutes

95%

Recovery

in minutes

T

:T

Ratio

≥ 70%

in minutes

25%-

75%

Recovery

Index

in minutes

Adults

0.1 mg/kg

(2 × ED

= 98)

(1.0-8.7)

(1.2-17.2)

(15-51)

(22-63)

(25-93)

(32-91)

(5-30)

0.15

mg/kg

(3 × ED

(1.0-4.4)

(1.6-6.8)

(28-65)

(44-74)

(60-103)

(63-98)

(11-16)

4

1

(n = 39)

0.2 mg/kg

(4 × ED

(n = 30)

(1.5-4.5)

(1.9-5.2)

(31-103)

(43-103)

(53-114)

(55-114)

(2-30)

0.25 mg/kg

(5 × ED

(n = 15)

(0.8-3.3)

(1.2-3.7)

(58-85)

(66-86)

(76-109)

(82-113)

(5-12)

0.4 mg/kg

(8 × ED

(n = 15)

(1.3-1.8)

(1.4-2.3)

(37-103)

(59-107)

(110-134)

(115-137)

(10-18)

Infants (1-23 months of age)

0.15 mg/kg**

(n = 18-26)

(0.7-3.2)

(1.3-4.3)

(28-50)

(34-58)

(54-84)

(49-76)

11.3

(7.3-18.3)

Pediatric Patients 2-12 years

0.08 mg/kg

(2 × ED

(n = 60)

(1.2-6.8)

(1.7-9.7)

(11-38)

(20-46)

(37-64)

(37-62)

(7-15)

0.1 mg/kg

(n = 16)

(1.3-2.7)

(1.8-6.7)

(13-31)

(21-38)

(37-58)

(36-58)

(7-12)

0.15 mg/kg **

(n = 23-24)

(1.3-2.8)

(1.5-8.0)

(19-38)

(29-46)

(45-72)

(44-66)

10.6

(8.5-17.7)

* Values shown are the median values from the means from individual studies. Values in parentheses

are ranges of individual patient values.

† Clinically effective duration of block

‡ Train-of-four ratio

§ n=the number of patients with Time to Maximum Block data

|| Propofol anesthesia

¶ Halothane anesthesia

** Thiopentone, alfentanil, N

anesthesia

Hemodynamics Profile

Cisatracurium had no dose-related effects on mean arterial blood pressure (MAP) or heart rate (HR)

following doses ranging from 0.1 mg/kg to 0.4 mg/kg, administered over 5 to 10 seconds, in healthy

adult patients (see Figure 1) or in patients with serious cardiovascular disease (see Figure 2).

A total of 141 patients undergoing coronary artery bypass graft (CABG) surgery were administered

cisatracurium in three active-controlled clinical trials and received doses ranging from 0.1 mg/kg to 0.4

mg/kg. While the hemodynamic profile was comparable in both the cisatracurium and active control

groups, data for doses above 0.3 mg/kg in this population are limited.

Figure 1. Maximum Percent Change from Preinjection in HR and MAP During First 5 Minutes

after Initial 4 × ED

to 8 × ED

Cisatracurium Doses in Healthy Adults Who Received

Opioid/Nitrous Oxide/Oxygen Anesthesia (n = 44)

Figure 2. Percent Change from Preinjection in HR and MAP 10 Minutes After an Initial 4 × ED

to 8 × ED

Cisatracurium Dose in Patients Undergoing CABG Surgery Receiving

Oxygen/Fentanyl/Midazolam/Anesthesia (n = 54)

9 5

9 5

9 5

9 5

No clinically significant changes in MAP or HR were observed following administration of doses up to

0.1 mg/kg cisatracurium over 5 to 10 seconds in 2- to 12-year-old pediatric patients who received

either halothane/nitrous oxide/oxygen or opioid/nitrous oxide/oxygen anesthesia. Doses of 0.15 mg/kg

cisatracurium administered over 5 seconds were not consistently associated with changes in HR and

MAP in pediatric patients aged 1 month to 12 years who received opioid/nitrous oxide/oxygen or

halothane/nitrous oxide/oxygen anesthesia.

12.3 Pharmacokinetics

The neuromuscular blocking activity of cisatracurium is due to parent drug. Cisatracurium plasma

concentration-time data following IV bolus administration are best described by a two-compartment

open model (with elimination from both compartments) with an elimination half-life (t

β) of 22 minutes,

a plasma clearance (CL) of 4.57 mL/min/kg, and a volume of distribution at steady state (V

) of 145

mL/kg.

Results from population pharmacokinetic/pharmacodynamic (PK/PD) analyses from 241 healthy surgical

patients are summarized in Table 6.

Table 6. Key Population PK/PD Parameter Estimates for Cisatracurium in Healthy Surgical

Patients* Following 0.1 (2 × ED

) to 0.4 mg/kg (8 × ED

) of Cisatracurium

Parameter

Estimate

Magnitude of Interpatient

Variability (CV)

CL (mL/min/kg)

4.57

(mL/kg)

(min-1)

0.0575

(ng/mL)

* Healthy male non-obese patients 19-64 years of age with creatinine clearance values greater than 70

mL/minute who received cisatracurium during opioid anesthesia and had venous samples collected

† The percent standard error of the mean (%SEM) ranged from 3% to 12% indicating good precision

9 5

9 5

for the PK/PD estimates.

‡ Expressed as a coefficient of variation; the %SEM ranged from 20% to 35% indicating adequate

precision for the estimates of interpatient variability.

§ V

is the volume of distribution at steady state estimated using a two-compartment model with

elimination from both compartments. V

is equal to the sum of the volume in the central compartment

) and the volume in the peripheral compartment (V

); interpatient variability could only be estimated

for V

ll Rate constant describing the equilibration between plasma concentrations and neuromuscular block

¶ Concentration required to produce 50% T

suppression; an index of patient sensitivity.

The magnitude of interpatient variability in CL was low (16%), as expected based on the importance of

Hofmann elimination . The magnitudes of interpatient variability in CL and volume of distribution were

low in comparison to those for k

and EC

. This suggests that any alterations in the time course of

cisatracurium-induced neuromuscular blockade were more likely to be due to variability in the PD

parameters than in the PK parameters. Parameter estimates from the population PK analyses were

supported by noncompartmental PK analyses on data from healthy patients and from specific populations.

Conventional PK analyses have shown that the PK of cisatracurium are proportional to dose between 0.1

(2 × ED

) and 0.2 (4 × ED

) mg/kg cisatracurium. In addition, population PK analyses revealed no

statistically significant effect of initial dose on CL for doses between 0.1 (2 × ED

) and 0.4 (8 × ED

) mg/kg cisatracurium.

Distribution

The volume of distribution of cisatracurium is limited by its large molecular weight and high polarity.

The V

was equal to 145 mL/kg ( Table 6) in healthy 19- to 64-year-old surgical patients receiving

opioid anesthesia. The V

was 21% larger in similar patients receiving inhalation anesthesia.

The binding of cisatracurium to plasma proteins has not been successfully studied due to its rapid

degradation at physiologic pH. Inhibition of degradation requires nonphysiological conditions of

temperature and pH which are associated with changes in protein binding.

Elimination

Organ-independent Hofmann elimination (a chemical process dependent on pH and temperature) is the

predominant pathway for the elimination of cisatracurium. The liver and kidney play a minor role in the

elimination of cisatracurium but are primary pathways for the elimination of metabolites. Therefore, the

β values of metabolites (including laudanosine) are longer in patients with renal or hepatic impairment

and metabolite concentrations may be higher after long-term administration [see Warnings and

Precautions ( 5.3)] .

The mean CL values for cisatracurium ranged from 4.5 to 5.7 mL/min/kg in studies of healthy surgical

patients. The compartmental PK modeling suggests that approximately 80% of the cisatracurium CL is

accounted for by Hofmann elimination and the remaining 20% by renal and hepatic elimination. These

findings are consistent with the low magnitude of interpatient variability in CL (16%) estimated as part

of the population PK/PD analyses and with the recovery of parent and metabolites in urine.

In studies of healthy surgical patients, mean t

β values of cisatracurium ranged from 22 to 29 minutes

and were consistent with the t

β of cisatracurium in vitro (29 minutes). The mean ± SD t

β values of

laudanosine were 3.1 ± 0.4 hours in healthy surgical patients receiving cisatracurium (n = 10).

Metabolism:

The degradation of cisatracurium was largely independent of liver metabolism. Results from in vitro

experiments suggest that cisatracurium undergoes Hofmann elimination (a pH and temperature-dependent

chemical process) to form laudanosine [see Warnings and Precautions ( 5.3)] and the monoquaternary

acrylate metabolite, neither of which has any neuromuscular blocking activity. The monoquaternary

acrylate undergoes hydrolysis by non-specific plasma esterases to form the monoquaternary alcohol

(MQA) metabolite. The MQA metabolite can also undergo Hofmann elimination but at a much slower

rate than cisatracurium. Laudanosine is further metabolized to desmethyl metabolites which are

conjugated with glucuronic acid and excreted in the urine.

The laudanosine metabolite of cisatracurium has been noted to cause transient hypotension and, in

higher doses, cerebral excitatory effects when administered to several animal species. The relationship

between CNS excitation and laudanosine concentrations in humans has not been established [see

Warnings and Precautions ( 5.3)] .

During IV infusions of cisatracurium, peak plasma concentrations (C

) of laudanosine and the MQA

metabolite were approximately 6% and 11% of the parent compound, respectively. The C

values of

laudanosine in healthy surgical patients receiving infusions of cisatracurium were mean ± SD C

: 60

± 52 ng/mL.

Excretion:

Following

C-cisatracurium administration to 6 healthy male patients, 95% of the dose was recovered

in the urine (mostly as conjugated metabolites) and 4% in the feces; less than 10% of the dose was

excreted as unchanged parent drug in the urine. In 12 healthy surgical patients receiving non-

radiolabeled cisatracurium who had Foley catheters placed for surgical management, approximately

15% of the dose was excreted unchanged in the urine.

Special Populations

Geriatric Patients

The results of conventional PK analysis from a study of 12 healthy elderly patients and 12 healthy young

adult patients who received a single IV cisatracurium dose of 0.1 mg/kg are summarized in Table 7.

Plasma clearances of cisatracurium were not affected by age; however, the volumes of distribution

were slightly larger in elderly patients than in young patients resulting in slightly longer t

β values for

cisatracurium.

The rate of equilibration between plasma cisatracurium concentrations and neuromuscular blockade was

slower in elderly patients than in young patients (mean ± SD k

: 0.071 ± 0.036 and 0.105 ± 0.021

minutes

, respectively); there was no difference in the patient sensitivity to cisatracurium-induced

block, as indicated by EC

values (mean ± SD EC

: 91 ± 22 and 89 ± 23 ng/mL, respectively). These

changes were consistent with the 1-minute slower times to maximum block in elderly patients receiving

0.1 mg/kg cisatracurium, when compared to young patients receiving the same dose. The minor

differences in PK/PD parameters of cisatracurium between elderly patients and young patients were not

associated with clinically significant differences in the recovery profile of cisatracurium.

Table 7. Pharmacokinetic Parameters* of Cisatracurium in Healthy Elderly and Young Adult

Patients Following 0.1 mg/kg (2 × ED

) of Cisatracurium (Isoflurane/Nitrous Oxide/Oxygen

Anes thes ia)

Parameter

Healthy

Elderly Patients

Healthy

Young Adult Patients

Elimination Half-Life (t

β, min)

25.8 ± 3.6

22.1 ± 2.5

Volume of Distribution at Steady State

(mL/kg)

156 ± 17

133 ± 15

Plasma Clearance (mL/min/kg)

5.7 ± 1.0

5.3 ± 0.9

* Values presented are mean ± SD.

9 5

† P < 0.05 for comparisons between healthy elderly and healthy young adult patients

‡ Volume of distribution is underestimated because elimination from the peripheral compartment is

ignored.

Patients with Hepatic Impairment:

Table 8 summarizes the conventional PK analysis from a study of cisatracurium in 13 patients with end-

stage liver disease undergoing liver transplantation and 11 healthy adult patients undergoing elective

surgery. The slightly larger volumes of distribution in liver transplant patients were associated with

slightly higher plasma clearances of cisatracurium. The parallel changes in these parameters resulted in

no difference in t

β values. There were no differences in k

or EC

between patient groups. 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. These minor PK differences

were not associated with clinically significant differences in the recovery profile of cisatracurium.

The t

β values of metabolites are longer in patients with hepatic disease and concentrations may be

higher after long-term administration.

Table 8. Pharmacokinetic Parameters* of Cisatracurium in Healthy Adult Patients and in Patients

Undergoing Liver Transplantation Following 0.1 mg/kg (2 × ED

) of Cisatracurium

(Isoflurane/Nitrous Oxide/Oxygen Anesthesia)

Parameter

Liver Transplant

Patients

Healthy Adult Patients

Elimination Half-Life (t

β, min)

24.4 ± 2.9

23.5 ± 3.5

Volume of Distribution at Steady State

(mL/kg)

195 ± 38

161 ± 23

Plasma Clearance (mL/min/kg)

6.6 ± 1.1

5.7 ± 0.8

* Values presented are mean ± SD.

† P < 0.05 for comparisons between liver transplant patients and healthy adult patients

‡ Volume of distribution is underestimated because elimination from the peripheral compartment is

ignored.

Patients with Renal Impairment: Results from a conventional PK study of cisatracurium in 13 healthy

adult patients and 15 patients with end-stage renal disease (ESRD) who had elective surgery are

summarized in Table 9. The PK/PD parameters of cisatracurium were similar in healthy adult patients

and ESRD patients. The times to 90% neuromuscular blockade were approximately one minute slower

in ESRD patients following 0.1 mg/kg cisatracurium. There were no differences in the durations or

rates of recovery of cisatracurium between ESRD and healthy adult patients.

The t

β values of metabolites are longer in patients with ESRD and concentrations may be higher after

long-term administration.

Population PK analyses showed that patients with creatinine clearances ≤ 70 mL/min had a slower rate

of equilibration between plasma concentrations and neuromuscular block than patients with normal renal

function; this change was associated with a slightly slower (~ 40 seconds) predicted time to 90% T

suppression in patients with renal impairment following 0.1 mg/kg cisatracurium. There was no

clinically significant alteration in the recovery profile of cisatracurium in patients with renal

impairment. The recovery profile of cisatracurium is unchanged in the presence of renal or hepatic

failure, which is consistent with predominantly organ-independent elimination.

Table 9. Pharmacokinetic Parameters* for Cisatracurium in Healthy Adult Patients and in

9 5

Patients With End-Stage Renal Disease (ESRD) Who Received 0.1 mg/kg (2 × ED

) of

Cisatracurium (Opioid/Nitrous Oxide/Oxygen Anesthesia)

Parameter

Healthy Adult Patients

ESRD Patients

Elimination Half-Life (t

β, min)

29.4 ± 4.1

32.3 ± 6.3

Volume of Distribution at Steady State

(mL/kg)

149 ± 35

160 ± 32

Plasma Clearance (mL/min/kg)

4.66 ± 0.86

4.26 ± 0.62

* Values presented are mean ± SD.

† Volume of distribution is underestimated because elimination from the peripheral compartment is

ignored.

Intensive Care Unit (ICU) Patients:

The PK of cisatracurium and its metabolites were determined in six ICU patients who received

cisatracurium and are presented in Table 10. The relationships between plasma cisatracurium

concentrations and neuromuscular blockade have not been evaluated in ICU patients.

Limited PK data are available for ICU patients with hepatic or renal impairment who received

cisatracurium. Relative to cisatracurium-treated ICU patients with normal renal and hepatic function,

metabolite concentrations (plasma and tissues) may be higher in cisatracurium-treated ICU patients with

renal or hepatic impairment [see Warnings and Precautions ( 5.3)] .

Table 10. Parameter Estimates* for Cisatracurium and Metabolites in ICU Patients After Long-

Term (24-48 Hour) Administration of Cisatracurium

Parameter

Cisatracurium (n = 6)

Parent Compound

CL (mL/min/kg)

7.45 ± 1.02

β(min)

26.8 ± 11.1

Vβ (mL/kg)

280 ± 103

Laudanosine

(ng/mL)

707 ± 360

β (hrs)

6.6 ± 4.1

MQA metabolite

(ng/mL)

152-181

β (min)

26-31

* Presented as mean ± standard deviation

† Volume of distribution during the terminal elimination phase, an underestimate because elimination

from the peripheral compartment is ignored.

‡ n = 2, range presented

Pediatric Population: The population PK/PD of cisatracurium were described in 20 healthy pediatric

patients ages 2 to 12 years during halothane anesthesia, using the same model developed for healthy

adult patients. The CL was higher in healthy pediatric patients (5.89 mL/min/kg) than in healthy adult

patients (4.57 mL/min/kg) during opioid anesthesia. The rate of equilibration between plasma

concentrations and neuromuscular blockade, as indicated by k

, was faster in healthy pediatric patients

receiving halothane anesthesia (0.1330 minutes

) than in healthy adult patients receiving opioid

anesthesia (0.0575 minutes

). The EC

in healthy pediatric patients (125 ng/mL) was similar to the

value in healthy adult patients (141 ng/mL) during opioid anesthesia. The minor differences in the

PK/PD parameters of cisatracurium were associated with a faster time to onset and a shorter duration of

9 5

cisatracurium-induced neuromuscular blockade in pediatric patients.

Sex and Obesity:

Although population PK/PD analyses revealed that sex and obesity were associated with effects on the

PK and/or PD of cisatracurium; these PK/PD changes were not associated with clinically significant

alterations in the predicted onset or recovery profile of cisatracurium.

Use of Inhalation Agents:

The use of inhalation agents was associated with a 21% larger V

, a 78% larger k

, and a 15% lower

for cisatracurium. These changes resulted in a slightly faster (~ 45 seconds) predicted time to

90% T

suppression in patients who received 0.1 mg/kg cisatracurium during inhalation anesthesia than

in patients who received the same dose of cisatracurium during opioid anesthesia; however, there were

no clinically significant differences in the predicted recovery profile of cisatracurium between patient

groups.

Drug Interaction Studies

Carbamazepine and phenytoin:

The systemic clearance of cisatracurium was higher in patients who were on prior chronic

anticonvulsant therapy of carbamazepine or phenytoin [see Warning and Precautions ( 5.9) and Drug

Interactions ( 7.1)] .

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 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 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).

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 doses of 0.15 mg/kg

and in 97/110 (88%) patients in 1.5 minutes following cisatracurium doses of 0.2 mg/kg.

In Study 1, the clinically effective duration of action for 0.15 mg/kg and 0.2 mg/kg cisatracurium 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 doses of 0.25 mg/kg and 0.4 mg/kg were evaluated in 30 patients under

opioid/nitrous oxide/oxygen anesthesia and provided 78 (66-86) and 91 (59-107) 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 in 51 patients (see Table 11).

Table 11. Intubating Conditions at 120 Seconds after Cisatracurium Administration with

Thiopental Anesthesia in Adult Surgery Patients in Study 4

Cisatracurium 0.15 mg/kg

(n = 26)

Cisatracurium 0.20 mg/kg

(n = 25)

Excellent and Good

95% CI

76,100

88,100

Excellent

Good

* 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.

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.

Study 5 evaluated intubating conditions after 3 and 4 × ED

(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 after 90 seconds. Table 12 displays

these results.

Table 12. Intubating Conditions at 90 Seconds after Cisatracurium Administration with

Thiopental or Propofol Anesthesia in Study 5

Intubating

Condition

Cisatracurium

0.15 mg/kg

with Propofol

(n = 31)

Cisatracurium

0.15 mg/kg

with Thiopental

(n = 31)

Cisatracurium

0.20 mg/kg

with Propofol

(n = 30)

Cisatracurium

0.20 mg/kg

with Thiopental

(n = 28)

Excellent and

Good

95% CI

85,100

80,100

84,100

90,100

Excellent

Good

* 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.

Excellent intubating conditions were more frequently observed with the 0.2 mg/kg dose when intubation

was attempted 90 seconds following cisatracurium.

14.2 Skeletal Muscle Relaxation for Intubation of Pediatric Patients

The efficacy of cisatracurium 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 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 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 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 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

Cisatracurium 0.15

mg/kg

1-11 mo.

Cisatracurium 0.15

mg/kg

1-4 years

Cisatracurium 0.15

mg/kg

5-12 years

Halothane

Anes thes ia

(n=30)

Thiopentone/

Fentanyl

Anesthesia

(n=30)

Halothane

Anes thes ia

(n=30)

Thiopentone/

Fentanyl

Anesthesia

(n=30)

Halothane

Anes thes ia

(n=30)

Thiopentone/

Fentanyl

Anesthesia

(n=30)

Excellent and

Good

100%

100%

Excellent

100%

Good

Poor

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

* 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.

14.3 Skeletal Muscle Relaxation in ICU Patients

Long-term infusion (up to 6 days) of cisatracurium during mechanical ventilation in the ICU was

evaluated in two studies.

Study 8 was a randomized, double-blind study using presence of a single twitch during train-of-four

(TOF) monitoring to regulate dosage. Patients treated with cisatracurium (n = 19) recovered

neuromuscular function (T4:T1 ratio ≥ 70%) following termination of infusion in approximately 55

minutes (range: 20 to 270).

In Study 9, cisatracurium patients recovered neuromuscular function in approximately 50 minutes (range:

20 to 175; n = 34).

16 HOW SUPPLIED/STORAGE AND HANDLING

Cisatracurium Besylate Injection, USP is a clear solution supplied as follows:

Strength

(mg of cisatracurium)

Containers

NDC#

Pres ervative

10 mg/5 mL (2 mg/mL)

Single-dose vials

57884-3061-1

Does not contain benzyl

alcohol

20 mg/10 mL (2 mg/mL)

Multiple-dose vials

57884-3062-1

Contains 0.9% w/v

benzyl alcohol [see

Warnings and

Precautions ( 5.2)]

200 mg/20 mL (10

mg/mL)

Single-dose vials

57884-3063-1

Does not contain benzyl

alcohol

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 from refrigeration to room temperature

storage conditions (25°C/77°F), use Cisatracurium Besylate Injection, USP within 21 days, even if re-

refrigerated.

17 PATIENT COUNSELING INFORMATION

Hypersensitivity Reactions Including Anaphylaxis

Advise the caregiver and/or family that severe hypersensitivity reactions have occurred with

Cisatracurium Besylate Injection, USP [see Warnings and Precautions ( 5.4)] .

Manufactured by:

Jiangsu Hengrui Medicine Co., Ltd.

Lianyungang, Jiangsu 222047, China

Distributed by:

eVenus Pharmaceutical Laboratories, Inc.

506 Carnegie Center, Suite 100, Princeton, NJ 08540, USA

Revised: October 2018

14VUF01

Principal Display Panel

NDC57884-3061-1

Cisatracurium Besylate Injection, USP

For Intravenous Injection

5 mL Single Dose Vial

10 mg/5 mL*

(2 mg/mL)

Rx only

Principal Display Panel

NDC57884-3063-1

Cisatracurium Besylate Injection, USP

For Intravenous Injection

20 mL Single Dose Vial

200 mg/20 mL*

(10 mg/mL)

Rx only

CISATRACURIUM BESYLATE

cisatracurium besylate injection

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:578 8 4-30 6 3

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

CISATRACURIUM BESYLATE (UNII: 8 0 YS8 O1MBS) (CISATRACURIUM - UNII:QX6 2KLI41N)

CISATRACURIUM

10 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

BENZENESULFO NIC ACID (UNII: 6 8 59 28 Z18 A)

WATER (UNII: 0 59 QF0 KO0 R)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:578 8 4-30 6 3-1

1 in 1 CARTON

0 9 /19 /20 17

1

20 mL in 1 VIAL; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 49 6 0

0 9 /19 /20 17

CISATRACURIUM BESYLATE

cisatracurium besylate injection

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:578 8 4-30 6 1

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

CISATRACURIUM BESYLATE (UNII: 8 0 YS8 O1MBS) (CISATRACURIUM - UNII:QX6 2KLI41N)

CISATRACURIUM

2 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

BENZENESULFO NIC ACID (UNII: 6 8 59 28 Z18 A)

WATER (UNII: 0 59 QF0 KO0 R)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:578 8 4-30 6 1-1

1 in 1 CARTON

0 1/27/20 17

1

5 mL in 1 VIAL; Type 0 : No t a Co mbinatio n Pro duct

Jiangsu Hengrui Medicine Co., Ltd.

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 49 6 0

0 1/27/20 17

Labeler -

Jiangsu Hengrui Medicine Co., Ltd. (654147255)

Registrant -

Jiangsu Hengrui Medicine Co., Ltd. (654147255)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Jiangsu Hengrui Medicine Co ., Ltd.

4212518 6 8

manufacture(578 8 4-30 6 1, 578 8 4-30 6 3)

Revised: 10/2018

Similar products

Search alerts related to this product

Share this information