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  • CLASSES

    Muscle Relaxants, Peripherally Acting

    DEA CLASS

    Rx

    DESCRIPTION

    Intermediate nondepolarizing neuromuscular blocker; isomer of atracurium with 3-fold potency, but without histamine release; metabolized by Hoffman elimination to laudanosine; elimination independent of hepatic or renal function; used with general anesthesia, for endotracheal intubation, or ICU mechanical ventilation.

    COMMON BRAND NAMES

    Nimbex

    HOW SUPPLIED

    Cisatracurium/Cisatracurium Besylate/Nimbex Intravenous Inj Sol: 1mL, 2mg, 10mg

    DOSAGE & INDICATIONS

    For neuromuscular blockade, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the ICU.
    For endotracheal intubation.
    NOTE: Because of its intermediate onset of action, cisatracurium is not recommended for rapid sequence endotracheal intubation (i.e., where intubation is rapidly performed to minimize the time the airway is unprotected).
    Intravenous dosage
    Healthy Adults and Adolescents

    Doses of 0.15 to 0.2 mg/kg intravenously, as components of a propofol/nitrous oxide/oxygen induction-intubation technique, may produce generally good or excellent conditions for tracheal intubation in 2 and 1.5 minutes, respectively. The clinically effective durations of action for 0.15 mg/kg intravenously and 0.2 mg/kg intravenously during propofol anesthesia are 55 minutes (range: 44 to 74 minutes) and 61 minutes (range: 41 to 81 minutes), respectively. Lower doses may result in a longer time for the development of satisfactory intubation conditions. The presence of coinduction agents (e.g., fentanyl, midazolam) and the depth of anesthesia are factors that can influence intubation conditions. In 2 intubation studies using thiopental or propofol with midazolam and/or fentanyl as coinduction agents, excellent intubation conditions were most frequently achieved with a 0.2 mg/kg dose compared with a 0.15 mg/kg dose of cisatracurium. Doses up to 0.4 mg/kg intravenously (8 times ED95) have been administered safely to healthy adult patients and patients with serious cardiovascular disease. These doses are associated with longer clinically effective durations of action.

    Adults with myasthenia gravis

    In patients with neuromuscular disease such as myasthenia gravis, use of peripheral nerve stimulator monitoring and an initial dose of 0.02 mg/kg or less intravenously is recommended to assess the level of neuromuscular blockade and to monitor dosage requirements.

    Children 2—12 years

    0.1 to 0.15 mg/kg intravenously over 5 to 10 seconds during either halothane or opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.1 mg/kg intravenously of cisatracurium produces maximum neuromuscular block in an average of 2.8 minutes (range: 1.8 to 6.7 minutes) and clinically effective block (time to 25% recovery) for 28 minutes (range: 21 to 38 minutes). Under these conditions, 0.15 mg/kg intravenously of cisatracurium produces maximum neuromuscular block in an average of 3 minutes (range: 1.5 to 8 minutes) and clinically effective block for 36 minutes (range: 29 to 46 minutes).

    Infants and Children <= 23 months

    0.15 mg/kg intravenously over 5 to 10 seconds during either halothane or opioid anesthesia. When administered to infants 1 month to 23 months of age during stable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg intravenously of cisatracurium produces maximum neuromuscular block (time to 25% recovery) in an average of 2 minutes (range: 1.3 to 3.4 minutes) and clinically effective block for 43 minutes (range: 34 to 58 minutes). NOTE: Relative to older children, infants have a shorter onset of action and a more prolonged neuromuscular blockade after cisatracurium administration.

    To maintain neuromuscular blockade during prolonged surgical procedures.
    IV maintenance dosage
    Healthy Adults, Adolescents, and Children >= 2 years

    Maintenance doses of 0.03 mg/kg intravenous sustain neuromuscular blockade for about 20 minutes. Maintenance dosing is generally required 40 to 50 minutes after an initial dose of 0.15 mg/kg intravenously or 50 to 60 minutes after an initial dose of 0.2 mg/kg intravenously. For shorter or longer durations of action, smaller or larger maintenance doses may be administered. Cisatracurium can also be given as a continuous intravenous infusion for maintenance of neuromuscular blockade. Infusion of cisatracurium should only be initiated after spontaneous recovery from the initial bolus dose. An initial infusion rate of 3 mcg/kg/minute intravenously may be required to rapidly counteract the spontaneous recovery of neuromuscular function. Thereafter, a rate of 1 to 2 mcg/kg/minute intravenously should be adequate to maintain continuous neuromuscular blockade in the range of 89% to 99% in most pediatric and adult patients under opioid/oxygen anesthesia. Reduction of the infusion rate by 30% to 40% should be considered when cisatracurium is administered during stable isoflurane or enflurane anesthesia (with nitrous oxide/oxygen at the 1.25 MAC level). Greater reductions in the infusion rate may be required with longer durations of administration of isoflurane or enflurane.

    Adults with myasthenia gravis

    In patients with neuromuscular disease such as myasthenia gravis, use of peripheral nerve stimulator monitoring and an initial dose of 0.02 mg/kg or less intravenously is recommended to assess the level of neuromuscular blockade and to monitor dosage requirements.

    To maintain adequate neuromuscular blockade in patients undergoing coronary artery bypass surgery.
    Intravenous dosage
    Adults

    The rate of infusion of atracurium required in patients undergoing CABG surgery with induced hypothermia (25 degrees to 28 degrees C) is approximately half the drug infusion rate required during normothermia. Based on the structural similarity between cisatracurium and atracurium, a similar effect on the infusion rate of cisatracurium may be expected.

    To provide adequate neuromuscular blockade in mechanically ventilated patients in the intensive care unit.
    Intravenous dosage
    Healthy Adults

    An infusion rate of 3 mcg/kg/minute (range: 0.5 to 10.2 mcg/kg/minute) intravenously should provide adequate neuromuscular blockade. There may be wide interpatient variability in dosage requirements and these may increase or decrease with time. After recovery from neuromuscular block, readministration of a bolus dose may be necessary to quickly reestablish NMB prior to reinstitution of the infusion.

    Adults with myasthenia gravis

    In patients with neuromuscular disease such as myasthenia gravis, use of peripheral nerve stimulator monitoring and an initial dose of 0.02 mg/kg or less intravenously is recommended to assess the level of neuromuscular blockade and to monitor dosage requirements.

    For adjunct therapy in acute respiratory distress syndrome (ARDS)†.
    Intravenous dosage
    Adults

    15 mg intravenous bolus followed by 37.5 mg/hour continuous intravenous infusion for 48 hours. Alternately, 0.2 mg/kg or 50 mg intravenous bolus followed by 5 mcg/kg/minute continuous intravenous infusion with increase by 20% when train-of-four response 1 or more for 48 hours. Clinical practice guidelines recommend a short course of neuromuscular blockade (48 hours or less) for patients with early, sepsis-induced ARDS with a PaO2/FiO2 less than 150 mmHg.

    For the prevention of shaking chills† induced by therapeutic hypothermia following cardiac arrest.
    Intravenous dosage
    Adults

    Data are very limited. If muscle shivering present, 0.06 to 0.12 mg/kg/hour continuous IV infusion has been used. Outcomes specific to shivering were not assessed.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    0.4 mg/kg IV for routine intubation; individualize maintenance doses.

    Elderly

    0.4 mg/kg IV for routine intubation; individualize maintenance doses.

    Adolescents

    0.4 mg/kg IV for routine intubation; individualize maintenance doses.

    Children

    >= 2 years: 0.15 mg/kg IV for routine intubation; individualize maintenance doses.
    < 2 years: 0.15 mg/kg IV for routine intubation.

    Infants

    0.15 mg/kg IV for routine intubation.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Extending the interval between cisatracurium administration and the intubation attempt may be required to achieve adequate intubation conditions; slower times to the onset of complete neuromuscular block were observed in patients with renal dysfunction.
     
    Intermittent hemodialysis
    The effects of hemofiltration, hemodialysis, and hemoperfusion on plasma levels of cisatracurium and its metabolites are unknown.

    ADMINISTRATION

     
    NOTE: Doses of cisatracurium should be individualized. Use of a peripheral nerve stimulator will permit the most advantageous use of cisatracurium, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration.
    Only experienced clinicians, familiar with the use of neuromuscular blocking drugs, should administer or supervise the use of cisatracurium.
    Administer by rapid IV injection or by continuous IV infusion.

    Intravenous Administration

    Intravenous injection:
    Inject IV over 5—10 seconds.
     
    Continuous intravenous infusion:
    Dilute with 0.9% Sodium Chloride for injection, 5% Dextrose for injection, or 5% Dextrose and 0.9% Sodium Chloride for injection to a final concentration of 0.1—0.4 mg/mL. Adjust the rate of infusion according to patient response as determined by peripheral nerve stimulation.
    Nimbex Injection diluted to 0.1 mg/mL may be stored either under refrigeration or at room temperature for 24 hours without significant loss of potency. Dilutions to 0.1 mg/mL or 0.2 mg/mL in 5% Dextrose and Lactated Ringer's Injection may be stored under refrigeration for 24 hours.

    STORAGE

    Nimbex:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Product must be used within 21 days after removal from refrigeration to room temperature (77 degrees F)
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Cisatracurium has no known effect on consciousness, pain threshold, or cerebration. To avoid distress to the patient, neuromuscular block should not be induced before unconsciousness.
     
    Because of its intermediate onset of action, cisatracurium is not recommended for rapid sequence endotracheal intubation.

    Lung cancer, myasthenia gravis, myopathy, neuromuscular disease

    Patients with conditions that impair neuromuscular function can experience prolonged or exaggerated neuromuscular block with nondepolarizing agents. These conditions include myasthenia gravis, myasthenic syndrome associated with small cell carcinomatosis (Lambert-Eaton syndrome; originally associated with lung cancer), myopathy, or any other neuromuscular disease. Cisatracurium should be used with extreme caution in patients with these conditions; the use of a peripheral nerve stimulator and a cisatracurium dose of not more than 0.02 mg/kg is recommended to assess the level of neuromuscular block and to monitor dosage requirements. Patients with hemiparesis or paraparesis may demonstrate resistance to cisatracurium in the affected limbs. To avoid inaccurate dosing, neuromuscular monitoring should be performed on a non-paretic limb.

    Chronic obstructive pulmonary disease (COPD), pulmonary disease, respiratory depression

    Neuromuscular blocking agents can cause respiratory paralysis as a result of respiratory depression; cisatracurium should be used with caution in patients with pulmonary disease such as chronic obstructive pulmonary disease (COPD).

    Burns

    Patients with burns have been shown to develop resistance to nondepolarizing neuromuscular blocking agents, including atracurium. The extent of altered response depends upon the size of the burn and the time elapsed since the burn injury. Although cisatracurium has not been studied in burn patients, due to its structural similarity to atracurium, the possibility of increased dosage requirements and a shortened duration of action must be considered if cisatracurium is administered to burn patients.

    Acid/base imbalance, dehydration, electrolyte imbalance, hypermagnesemia, hypocalcemia, hypokalemia, hyponatremia, metabolic alkalosis, respiratory acidosis

    Pathophysiologic states that potentiate the pharmacological actions of nondepolarizing neuromuscular blockers (e.g., cisatracurium) may increase the risk of prolonged neuromuscular block. These states include dehydration, electrolyte imbalance (hypokalemia, hypocalcemia, hyponatremia or hypermagnesemia) and severe acid/base imbalance (respiratory acidosis or metabolic alkalosis).

    Intramuscular administration

    No data are available to support the use of cisatracurium by intramuscular administration.

    Malignant hyperthermia

    Patients with a familial history of malignant hyperthermia (MH) should be treated with cisatracurium with great caution. Because malignant hyperthermia can develop in patients receiving general anesthesia, with or without triggering factors (e.g. succinylcholine), this condition should be monitored for routinely in anesthetized patients. The condition can be precipitated by the use of halogenated anesthetics; and concomitant neuromuscular blocking agents may be a contributory factor.

    Labor, obstetric delivery, pregnancy

    Cisatracurium is classified as FDA pregnancy risk category B. There are no adequate and well controlled studies in pregnant women. Teratology testing in pregnant rats treated with doses of cisatracurium equivalent to 8—20 times the human ED95 revealed no maternal or fetal toxicity or teratogenic effects. However, because animal studies are not always predictive of human response, cisatracurium should only be used during pregnancy if clearly needed. Cisatracurium administration during labor and obstetric delivery has not been studied in humans. It is not known whether muscle relaxants administered during labor and obstetric delivery (vaginal) have immediate or delayed adverse effects on the fetus or increase the likelihood that resuscitation of the newborn will be necessary. The effects of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy.

    Breast-feeding

    According to the manufacturer, it is not known whether cisatracurium is excreted in human milk. Caution should be exercised following administration of cisatracurium to a woman who is breast-feeding. Cisatracurium undergoes rapid and spontaneous (Hofmann elimination) degradation in the plasma with an elimination half-life of 22 minutes; metabolites are not biologically active. Atracurium also is poorly absorbed from the gastrointestinal tract. Based on these data, lactation could be allowed as soon as practically feasible after short-term use during a surgical procedure. The effects from long-term used are unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Benzyl alcohol hypersensitivity, children, neonates

    Safety and effectiveness of cisatracurium have not been studied in neonates. Tracheal intubation of children aged 1 to 4 years is facilitated more reliably when cisatracurium is used in combination with halothane than when opioids and nitrous oxide are used for induction of anesthesia. The 10 ml multiple-dose vials of Nimbex contain benzyl alcohol. In neonates or other patients with benzyl alcohol hypersensitivity, benzyl alcohol has been associated with an increased incidence of neurological and other complications, which are sometimes fatal. Single-use vials of cisatracurium do not contain benzyl alcohol.

    Neuromuscular blocking agent hypersensitivity

    Although rare, severe anaphylactic or anaphylactoid reactions to neuromuscular blockers, including cisatracurium, have been reported; some cases have been life-threatening and fatal. Precautions should be taken in patients who have experienced anaphylaxis from any neuromuscular blocking agent (i.e., neuromuscular blocking agent hypersensitivity), as cross-reactivity has been reported with this class. Immediate availability of appropriate emergency treatment for anaphylaxis is advised because of the potential for a life-threatening reaction.

    ADVERSE REACTIONS

    Severe

    bronchospasm / Rapid / 0.2-1.5
    bradycardia / Rapid / 0.4-0.4
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    laryngospasm / Rapid / Incidence not known
    apnea / Delayed / Incidence not known
    muscle paralysis / Delayed / Incidence not known

    Moderate

    hypotension / Rapid / 0.2-0.2
    wheezing / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    myasthenia / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    respiratory depression / Rapid / Incidence not known

    Mild

    flushing / Rapid / 0.2-0.2
    rash / Early / 0.1-0.1
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    weakness / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Additive CNS depression may occur if dihydrocodeine is used concomitantly with other CNS depressants, including neuromuscular blockers.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Acetazolamide: (Moderate) Nondepolarizing neuromuscular blockers when combined with carbonic anhydrase inhibitors may lead to prolonged respiratory depression. This action is due to enhanced neural blockade as a result of potential hypokalemia from the carbonic anhydrase inhibitor. Serum potassium concentrations should be checked and adjusted prior to the administration of nondepolarizing neuromuscular blockers.
    Alfentanil: (Moderate) Concomitant use of alfentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Aliskiren; Amlodipine: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Ambenonium Chloride: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Amide local anesthetics: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Aminoglycosides: (Moderate) Aminoglycosides traditionally have been associated with neuromuscular blockade, but this event is most likely to occur when aminoglycoside solutions are used to irrigate wounds intraoperatively. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.
    Amlodipine: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Amlodipine; Atorvastatin: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Amlodipine; Benazepril: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Amlodipine; Olmesartan: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Amlodipine; Telmisartan: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Amlodipine; Valsartan: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Amphoterecin B may cause hypokalemia, which potentiates neuromuscular blockade with nondepolarizing neuromuscular blockers.
    Amphotericin B lipid complex (ABLC): (Moderate) Amphoterecin B may cause hypokalemia, which potentiates neuromuscular blockade with nondepolarizing neuromuscular blockers.
    Amphotericin B liposomal (LAmB): (Moderate) Amphoterecin B may cause hypokalemia, which potentiates neuromuscular blockade with nondepolarizing neuromuscular blockers.
    Amphotericin B: (Moderate) Amphoterecin B may cause hypokalemia, which potentiates neuromuscular blockade with nondepolarizing neuromuscular blockers.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Additive CNS depression may occur if dihydrocodeine is used concomitantly with other CNS depressants, including neuromuscular blockers.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with neuromuscular blockers can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with neuromuscular blockers can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Edrophonium: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Bacitracin: (Moderate) Systemic bacitracin may act synergistcally to increase or prolong skeletal muscle relaxation produced by neuromuscular blocking agents and/or general anesthetics. Use of topically administrated preparations containing bacitracin, especially when applied to large surface areas, may have additive nephrotoxic potential.
    Belladonna; Opium: (Moderate) Additive CNS depression may occur if opiate agonists are used concomitantly with other CNS depressants, including neuromuscular blockers.
    Benzodiazepines: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Benzonatate: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Tetracyclines may potentiate the neuromuscular effects of nondepolarizing neuromuscular blockers.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Tetracyclines may potentiate the neuromuscular effects of nondepolarizing neuromuscular blockers.
    Botulinum Toxins: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Calcium Carbonate: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Calcium Carbonate; Risedronate: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Calcium Salts: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Calcium: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Calcium; Vitamin D: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Capreomycin: (Moderate) Partial neuromuscular blockade has been reported with capreomycin after the administration of large intravenous doses or rapid intravenous infusion. Depolarizing neuromuscular blockers and non-depolarizing neuromuscular blockers could potentiate the neuromuscular blocking effect of capreomycin. If these drugs are used in combination, monitor patients for increased adverse effects.
    Carbamazepine: (Moderate) If neuromuscular blockers are administered to patients chronically receiving anticonvulsant agents such as carbamazepine, shorter durations of neuromuscular block may occur and infusion rates may be higher due to the development of resistance to muscle relaxants.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Carbonic anhydrase inhibitors: (Moderate) Nondepolarizing neuromuscular blockers when combined with carbonic anhydrase inhibitors may lead to prolonged respiratory depression. This action is due to enhanced neural blockade as a result of potential hypokalemia from the carbonic anhydrase inhibitor. Serum potassium concentrations should be checked and adjusted prior to the administration of nondepolarizing neuromuscular blockers.
    Chloroquine: (Moderate) Chloroquine may affect presynaptic and postsynaptic myoneural function and potentiate the neuromuscular blocking action of neuromuscular blockers.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Additive CNS depression may occur if dihydrocodeine is used concomitantly with other CNS depressants, including neuromuscular blockers.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Additive CNS depression may occur if dihydrocodeine is used concomitantly with other CNS depressants, including neuromuscular blockers.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Cholinesterase inhibitors: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Chromium: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Cisplatin: (Moderate) Hypokalemia potentiates the neuromuscular blockade from nondepolarizing neuromuscular blockers, including cisatracurium. Cisplatin is associated with a significant risk of hypokalemia and should be monitored closely when used with neuromuscular blockers.
    Clozapine: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Codeine: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Codeine; Phenylephrine; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants. (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Codeine; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants. (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Colistimethate, Colistin, Polymyxin E: (Moderate) Depolarizing neuromuscular blockers and non-depolarizing neuromuscular blockers can potentiate the neuromuscular blocking effect of colistimethate sodium. If these drugs are used in combination, monitor patients for increased adverse effects. Neuromuscular blockade may be associated with colistimethate sodium, and is more likely to occur in patients with renal dysfunction.
    Collagenase: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Corticosteroids: (Moderate) Caution and close monitoring are advised if corticosteroids and neuromuscular blockers are used together, particularly for long periods, due to enhanced neuromuscular blocking effects. In such patients, a peripheral nerve stimulator may be of value in monitoring the response. Concurrent use may increase the risk of acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.
    Cyclophosphamide: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    Cyclosporine: (Moderate) Cyclosporine may potentiate the action of nondepolarizing neuromuscular blockers. Prolonged neuromuscular blockade has been reported in patients receiving cyclosporine who receive neuromuscular blockers as part of surgical anesthesia. Monitor patients for recurrent neuromuscular blockade and respiratory depression; extended ventilatory support may be required.
    Demeclocycline: (Moderate) Tetracyclines may potentiate the neuromuscular effects of nondepolarizing neuromuscular blockers.
    Dextromethorphan; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants.
    Dextromethorphan; Quinidine: (Major) Quinidine can potentiate the effects of neuromuscular blockers. Neostigmine will not reverse these effects. Respiratory support may be necessary if quinidine is given concomitantly or shortly after a neuromuscular blocking agent.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Additive CNS depression may occur if dihydrocodeine is used concomitantly with other CNS depressants, including neuromuscular blockers.
    Diltiazem: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Donepezil: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Donepezil; Memantine: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Doxycycline: (Moderate) Tetracyclines may potentiate the neuromuscular effects of nondepolarizing neuromuscular blockers.
    Edrophonium: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Enalapril; Felodipine: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Ester local anesthetics: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Local anesthetics interfere with the release of acetylcholine and thus, can produce neuromuscular blockade. Potentiation of neuromuscular blockade by a local anesthetic can occur with either depolarizing or nondepolarizing neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Estrogens: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Felodipine: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Fentanyl: (Moderate) Although adequate sedation and analgesia must accompany the use of neuromuscular blockers, coadministration of opioids such as fentanyl, may enhance neuromuscular blockade and produce an increased degree of respiratory depression, hypotension, or sedation. Monitor patients for signs of respiratory depression or sedation that may be greater than otherwise expected. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Fosphenytoin: (Moderate) Chronic antiepileptic drug therapy with phenytoin may antagonize the effects of nondepolarizing neuromuscular blockers. This interaction lengthens the onset and shortens the duration of neuromuscular blockade. The exact mechanism for this interaction is unknown, but could involve neuromuscular and hepatic enzyme induction effects of phenytoin.
    Galantamine: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    General anesthetics: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Hetastarch; Dextrose; Electrolytes: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Hydromorphone: (Moderate) Concomitant use of hydromorphone with other central nervous system (CNS) depressants, such as skeletal muscle relaxants, can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Furthermore, opioid analgesics such as hydromorphone may enhance the action of neuromuscular blockers and produce an excessive degree of respiratory depression. Careful monitoring of a patient's respiratory rate and oxygenation is imperative. Prior to concurrent use of hydromorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Indapamide: (Moderate) Concomitant administration of indapamide to patients receiving nondepolarizing neuromuscular blockers can cause prolonged neuromuscular blockade due to indapamide-induced hypokalemia. Serum potassium concentrations should be determined and adjusted prior to initiation of neuromuscular blockade therapy.
    Irinotecan Liposomal: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Irinotecan: (Moderate) Monitor for altered clinical response to neuromuscular blockers if coadministration with irinotecan is necessary. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs. According to the manufacturer of irinotecan, an interaction with neuromuscular blocking agents cannot be ruled out.
    Isradipine: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Ketorolac: (Moderate) Ketorolac may enhance the muscle-relaxant effect of nondepolarizing neuromuscular blockers. Caution should be exercised during concomitant administration of ketorolac with these agents.
    Levomethadyl: (Moderate) Concomitant use of levomethadyl with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Levorphanol: (Moderate) Additive CNS depression may occur if opiate agonists are used concomitantly with other CNS depressants, including neuromuscular blockers.
    Lincosamides: (Moderate) Lincosamides can potentiate the action of neuromuscular blockers, leading to skeletal muscle weakness, respiratory depression, or paralysis. Concurrent use during surgery or during the postoperative period requires close monitoring.
    Lithium: (Moderate) Lithium may potentiate the effects of nondepolarizing neuromuscular blockers. Monitor for prolonged paralysis or toxicity.
    Loop diuretics: (Moderate) Furosemide-induced hypokalemia can potentiate neuromuscular blockade with nondepolarizing neuromuscular blockers. In addition, furosemide may antagonize the skeletal muscle relaxing effect of tubocurarine and can potentiate neuromuscular blockade following succinylcholine administration.
    Magnesium: (Moderate) Parenteral magnesium salts can enhance the neuromuscular blocking effects of neuromuscular blockers. Caution should be exercised when using these agents concurrently.
    Mepenzolate: (Moderate) CNS depression can be increased when mepenzolate is combined with other CNS depressants such as neuromuscular blockers.
    Meperidine: (Moderate) Concomitant use of meperidine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Meperidine; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants. (Moderate) Concomitant use of meperidine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Methadone: (Moderate) Concomitant use of methadone with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of methadone on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Methazolamide: (Moderate) Nondepolarizing neuromuscular blockers when combined with carbonic anhydrase inhibitors may lead to prolonged respiratory depression. This action is due to enhanced neural blockade as a result of potential hypokalemia from the carbonic anhydrase inhibitor. Serum potassium concentrations should be checked and adjusted prior to the administration of nondepolarizing neuromuscular blockers.
    Methohexital: (Moderate) Methohexital may enhance the neuromuscular activity of neuromuscular blocking agents, prolonging neuromuscular blockade.
    Minocycline: (Moderate) Tetracyclines, such as minocycline, may potentiate the neuromuscular effects of nondepolarizing neuromuscular blockers. Additionally, injectable minocycline contains magnesium sulfate heptahydrate, which can also enhance the neuromuscular blocking effects of neuromuscular blockers. Caution should be exercised when using these agents concurrently.
    Morphine: (Moderate) Concomitant use of morphine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of morphine on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Morphine; Naltrexone: (Moderate) Concomitant use of morphine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of morphine on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants like neuromuscular blockers can potentiate the effects of nabilone on respiratory depression.
    Nalbuphine: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Neostigmine: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Nicardipine: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Nimodipine: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Nisoldipine: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Oxymorphone: (Moderate) Additive CNS depression may occur if opiate agonists are used concomitantly with other CNS depressants, including neuromuscular blockers.
    Pantothenic Acid, Vitamin B5: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Perindopril; Amlodipine: (Minor) Calcium-channel blockers may prolong neuromuscular blockade.
    Phenylephrine; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants.
    Phenytoin: (Moderate) Chronic antiepileptic drug therapy with phenytoin may antagonize the effects of nondepolarizing neuromuscular blockers. This interaction lengthens the onset and shortens the duration of neuromuscular blockade. The exact mechanism for this interaction is unknown, but could involve neuromuscular and hepatic enzyme induction effects of phenytoin.
    Physostigmine: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Polymyxin B: (Moderate) Systemic Polymyxin B can increase the neuromuscular blockade effects of neuromuscular blockers. Polymyxin B affects both pre- and post-synaptic myoneural areas by inhibiting release of acetylcholine pre-synaptically and/or blocking acetylcholine activity post-synaptically. Thus, polymyxin B acts synergistically with these agents, increasing or prolonging the skeletal muscle relaxation of neuromuscular blockers. If polymyxin B is used postoperatively, neuromuscular blockade may recur and may cause respiratory paralysis. Concomitant use should be avoided if possible.
    Polymyxins: (Moderate) Depolarizing neuromuscular blockers and non-depolarizing neuromuscular blockers can potentiate the neuromuscular blocking effect of colistimethate sodium. If these drugs are used in combination, monitor patients for increased adverse effects. Neuromuscular blockade may be associated with colistimethate sodium, and is more likely to occur in patients with renal dysfunction.
    Procainamide: (Moderate) Patients taking procainamide who require depolarizing neuromuscular blocking agents may require less than usual doses, due to procainamide effects of reducing acetylcholine release. In addition, procainamide appears to potentiate or prolong the effects of nondepolarizing neuromuscular blockers. Patients receiving procainamide following surgery should be monitored for potential prolongation of neuromuscular blockade.
    Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants.
    Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Pyridostigmine: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Quinidine: (Major) Quinidine can potentiate the effects of neuromuscular blockers. Neostigmine will not reverse these effects. Respiratory support may be necessary if quinidine is given concomitantly or shortly after a neuromuscular blocking agent.
    Quinine: (Moderate) Quinine can potentiate the pharmacologic effects of neuromuscular blockers.
    Remifentanil: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Rivastigmine: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Sedating H1-blockers: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including neuromuscular blockers.
    Skeletal Muscle Relaxants: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    Sufentanil: (Moderate) High doses of neuromuscular blockers may produce increases in heart rate during sufentanil-oxygen anesthesia. Bradycardia and hypotension have also been reported with concomitant use of neuromuscular blockers during sufentanil-oxygen anesthesia; this effect may be more pronounced in the presence of beta-blockers and/or calcium-channel blockers.
    Tacrine: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Tapentadol: (Moderate) Additive CNS depressive effects are expected if tapentadol is used in conjunction with other CNS depressants including neuromuscular blockers. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered.
    Tetracycline: (Moderate) Tetracyclines may potentiate the neuromuscular effects of nondepolarizing neuromuscular blockers.
    Thalidomide: (Moderate) Thalidomide and other agents that slow cardiac conduction such as neuromuscular blockers should be used cautiously due to the potential for additive bradycardia.
    Thiazide diuretics: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Thiopental: (Moderate) Thiopental may enhance the neuromuscular activity of neuromuscular blocking agents, prolonging neuromuscular blockade.
    Trandolapril; Verapamil: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly verapamil and diltiazem. It may be necessary to decrease the dosage of verapamil when it is administered to patients receiving non-depolarizing or polarizing neuromuscular blockers.
    Vancomycin: (Moderate) Vancomycin may potentiate the neuromuscular effects of neuromuscular blockers.
    Verapamil: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly verapamil and diltiazem. It may be necessary to decrease the dosage of verapamil when it is administered to patients receiving non-depolarizing or polarizing neuromuscular blockers.

    PREGNANCY AND LACTATION

    Pregnancy

    Cisatracurium is classified as FDA pregnancy risk category B. There are no adequate and well controlled studies in pregnant women. Teratology testing in pregnant rats treated with doses of cisatracurium equivalent to 8—20 times the human ED95 revealed no maternal or fetal toxicity or teratogenic effects. However, because animal studies are not always predictive of human response, cisatracurium should only be used during pregnancy if clearly needed. Cisatracurium administration during labor and obstetric delivery has not been studied in humans. It is not known whether muscle relaxants administered during labor and obstetric delivery (vaginal) have immediate or delayed adverse effects on the fetus or increase the likelihood that resuscitation of the newborn will be necessary. The effects of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy.

    MECHANISM OF ACTION

    Like other nondepolarizing agents, cisatracurium binds competitively to (but does not activate) nicotinic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in blockade of neuromuscular transmission. Skeletal muscle relaxation proceeds in a predictable order, starting with muscles associated with fine movements, e.g., eyes, face, and neck. These effects are followed by muscle relaxation of the limbs, chest, and abdomen and, finally, the diaphragm. The effects of cisatracurium are antagonized by acetylcholinesterase inhibitors such as neostigmine. Cisatracurium has no dose-related effects on mean arterial blood pressure (MAP) or heart rate following doses ranging from 2—8 times ED95 (> 0.1 to > 0.4 mg/kg) in healthy adult patients or in patients with serious cardiovascular disease. Unlike atracurium, cisatracurium does not cause dose-related elevations in histamine plasma concentrations.

    PHARMACOKINETICS

    Cisatracurium is administered intravenously. The volume of distribution is limited by its large molecular weight and high polarity. The binding of cisatracurium to plasma proteins has not been successfully studied due to its rapid degradation at physiologic pH. Cisatracurium undergoes organ-independent Hofmann elimination (a pH and temperature-dependent chemical process) to form the monoquaternary acrylate metabolite and laudanosine, neither of which has any neuromuscular blocking activity. The monoquaternary acrylate metabolite undergoes hydrolysis by non-specific plasma esterases to form the monoquaternary alcohol (MQA) metabolite. Laudanosine is further metabolized to desmethyl metabolites which are conjugated with glucuronic acid and excreted in the urine. Mean clearance values for cisatracurium range 4.5—5.7 mL/min/kg in healthy surgical patients. Pharmacokinetic modeling suggests that 80% of the clearance is accounted for by Hofmann elimination and the remaining 20% by renal and hepatic elimination. Approximately 95% of a dose is recovered in the urine (mostly as conjugated metabolites) and 4% in the feces; less than 10—15% of the dose is excreted as unchanged drug. The mean elimination half-life of cisatracurium is 22—29 minutes. The mean elimination half-life for laudanosine is 3.1 hours.

    Intravenous Route

    During IV infusions of cisatracurium, peak plasma concentrations of laudanosine and the MQA metabolite are approximately 6% and 11% of the parent compound, respectively. Peak concentrations of laudanosine are significantly lower in healthy surgical patients receiving infusions of cisatracurium than in patients receiving infusions of atracurium (Cmax = 60 ng/mL vs 342 ng/mL). The average ED95 (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—0.053) in adults receiving opioid/nitrous oxide/oxygen anesthesia. The average ED95 for atracurium under similar conditions is 0.17 mg/kg. After a cisatracurium dose of 0.1 mg/kg (2 times ED95), time to 90% block is 3.3 minutes (range: 1—8.7 min) and time to 95% recovery is about 64 minutes (range: 25—93 min). In adult patients, the time to maximum block is up to 2 minutes longer for equipotent doses of cisatracurium compared to atracurium. The clinically effective duration of action and rate of spontaneous recovery from equipotent doses of cisatracurium and atracurium are similar. For cisatracurium, the rate of spontaneous recovery of neuromuscular function after infusion is independent of the duration of the infusion and comparable to the rate of recovery following initial doses. In one study in which cisatracurium or vecuronium infusion was administered for up to 6 days during mechanical ventilation in the ICU, patients treated with cisatracurium recovered neuromuscular function following termination of the infusion in about 55 minutes (range: 20—270 min); those treated with vecuronium recovered in 178 minutes (range: 40 min to 33 hours).