NIMBEX (cisatracurium besylate) injection

NIMBEX (cisatracurium besylate) injection

NIMBEX (cisatracurium besylate) injection

NIMBEX (cisatracurium besylate) is a nondepolarizing skeletal neuromuscular blocker for intravenous administration. Compared to other neuromuscular blockers, it is intermediate in its onset and duration of action. NIMBEX contains cisatracurium besylate as the active pharmaceutical ingredient.

Cisatracurium besylate is one of 10 isomers of atracurium besylate and constitutes approximately 15% of that mixture. Cisatracurium besylate is [1R-[1α,2α(1′R*,2′R*)]]-2,2′-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium] dibenzenesulfonate. The molecular formula of the cisatracurium parent bis-cation is C53H72N2O12 and the molecular weight is 929.2. The molecular formula of cisatracurium as the besylate salt is C65H82N2O18S2 and the molecular weight is 1243.49.

INDICATIONS AND USAGE

NIMBEX 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

NIMBEX is not recommended for rapid sequence endotracheal intubation due to the time required for its onset of action.

Mechanism of Action

NIMBEX 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.

DOSAGE AND ADMINISTRATION

Important Dosage and Administration Instructions

Accidental administration of neuromuscular blocking agents may be fatal. Store NIMBEX with the cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product.

  • NIMBEX is for intravenous use only.
  • Administer NIMBEX 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 NIMBEX 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 NIMBEX.
  • The dosage information which follows is intended to serve as an initial guide for individual patients; base subsequent NIMBEX 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 NIMBEX 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 NIMBEX-induced paralysis.

Recommended NIMBEX Dose for Performing Tracheal Intubation

Tracheal Intubation in Adults: Prior to selecting the initial NIMBEX 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 NIMBEX 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.

Patients with Neuromuscular Disease: The maximum recommended initial bolus dose of NIMBEX is 0.02 mg/kg in patients withneuromuscular diseases (e.g., myasthenia gravis and myasthenic syndrome and carcinomatosis).

Geriatric Patients and Patients with End-Stage Renal Disease: Because the time to maximum neuromuscular blockade is approximately 1 minute slower ingeriatric patients compared to younger patients (and in patients with end-stage renal disease thanin patients with normal renal function), consider extending the interval between administeringNIMBEX and attempting intubation by at least 1 minute to achieve adequate intubationconditions in geriatric patients and patients with end-stage renal disease. A peripheral nervestimulator should be used to determine the adequacy of muscle relaxation for the purposes ofintubation and the timing and amounts of subsequent doses.

Tracheal Intubation in Pediatric Patients

Infants 1 to 23 Months of Age: The recommended dose of NIMBEX for intubation of pediatric patients ages 1 month to 23months is 0.15 mg/kg administered over 5 to 10 seconds. When administered during stableopioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg of NIMBEX produced maximumneuromuscular blockade in about 2 minutes (range: 1.3 to 4.3 minutes) with a clinically effectiveblock (time to 25% recovery) for about 43 minutes (range: 34 to 58 minutes).

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Pediatric Patients 2 to 12 Years of Age: The recommended weight-based bolus dose of NIMBEX for pediatric patients 2 to 12 years ofage is 0.1 to 0.15 mg/kg administered over 5 to 10 seconds. When administered during stableopioid/nitrous oxide/oxygen anesthesia, 0.1 mg/kg NIMBEX produced maximum neuromuscularblockade 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 duringstable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg NIMBEX produced maximumneuromuscular blockade in an average of about 3 minutes (range: 1.5 to 8 minutes) with aclinically effective block for 36 minutes (range: 29 to 46 minutes).

Recommended Maintenance Bolus NIMBEX 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 NIMBEX 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 NIMBEX 0.15 mg/kg;
  • 50 to 60 minutes after an initial dose of NIMBEX 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 NIMBEX. No adjustment to the initial NIMBEX maintenance bolus dose should be necessary when NIMBEX is administered shortly after initiation of volatile agents or when used in patients receiving propofol anesthesia.

Dosage in Burn Patients: Burn patients have been shown to develop resistance to nondepolarizing neuromuscular blockingagents; therefore, consider increasing the NIMBEX dosages for intubation and maintenance.

Dosage for Continuous Infusion

Continuous Infusion for Surgical Procedures in Adults and Pediatric Patients: During extended surgical procedures, NIMBEX may be administered by continuous infusion to adults and pediatric patients aged 2 or more years if patients have spontaneous recovery after the initial NIMBEX 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 NIMBEX infusion rate is 3 mcg/kg/minute. Subsequently reduce the rate to 1 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 NIMBEX 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 NIMBEX is administered during stable isoflurane anesthesia for at least 30 minutes (administered with nitrous oxide/oxygen at the 1.25 MAC level). Greater reductions in the NIMBEX infusion 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. Spontaneous recovery from neuromuscular block following discontinuation of NIMBEX 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), NIMBEX may be administered by continuous infusion to adults if a patient has spontaneous recovery of neuromuscular function after the initial NIMBEX 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 NIMBEX infusion rate in adult patients in the ICU is 3 mcg/kg/minute (range: 0.5 to 10.2 mcg/kg/minute). Use peripheral nerve stimulation to assess the level of neuromuscular blockade and to appropriately titrate the NIMBEX infusion rate.

Preparation of NIMBEX

Visually inspect NIMBEX for particulate matter and discoloration prior to administration. If a NIMBEX solution is cloudy or contains visible particulates, do not use NIMBEX. NIMBEX is a colorless to slightly yellow or greenish-yellow solution.

Discard unused portion of the 5 mL and 20 mL single-dose vials.

NIMBEX 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 NIMBEX solutions either in a refrigerator or at room temperature for 24 hours without significant loss of potency.

NIMBEX 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 NIMBEX solution under refrigeration for no more than 24 hours.

Do not dilute NIMBEX in Lactated Ringer’s Injection, USP due to chemical instability.

Drug Compatibility

NIMBEX 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

NIMBEX is acidic (pH = 3.25 to 3.65) and may not be compatible with alkaline solution having a pH greater than 8.5 (e.g., barbiturate solutions). Therefore, do not administer NIMBEX and alkaline solutions simultaneously in the same intravenous line.

NIMBEX is not compatible with propofol injection or ketorolac injection for Y-site administration. Compatibility studies with other parenteral products have not been conducted.

CONTRAINDICATIONS

  • NIMBEX is contraindicated in patients with known hypersensitivity to cisatracurium. Severe anaphylactic reactions to NIMBEX have been reported
  • The use of 10 mL NIMBEX 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

WARNINGS AND PRECAUTIONS

Residual Paralysis: NIMBEX 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. To prevent complications resulting from NIMBEX-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.

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 NIMBEX (10 mL multiple-dose vials). This warning is not applicable to the 5 mL and 20 mL NIMBEX 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 NIMBEX vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including NIMBEX (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.

The use of 10 mL NIMBEX 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.

Risk of Seizure: Laudanosine, an active metabolite of NIMBEX, has been shown to cause seizures in animals. NIMBEX-treated patients with renal or hepatic impairment may have higher metabolite concentrations (including laudanosine) than patients with normal renal and hepatic function Therefore, patients with renal or hepatic impairment receiving extended administration of NIMBEX may be at higher risk of seizures.

The level of neuromuscular blockade during long-term NIMBEX administration should be monitored with a nerve stimulator to titrate NIMBEX administration to the patients’ needs and limit exposure to toxic metabolites.

Hypersensitivity Reactions Including Anaphylaxis: Severe hypersensitivity reactions, including fatal and life-threatening anaphylactic reactions, have been reported. There have been reports of wheezing, laryngospasm, bronchospasm, rash and itching following NIMBEX 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.

Risk of Death Due to Medication Errors: Administration of NIMBEX 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.

Risks Due to Inadequate Anesthesia: Neuromuscular blockade in the conscious patient can lead to distress. Use NIMBEX in the presence of appropriate sedation or general anesthesia. Monitor patients to ensure that the level of anesthesia is adequate.

Risk for Infection: The 20 mL vial of NIMBEX 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).

Potentiation of Neuromuscular Blockade: Certain drugs may enhance the neuromuscular blocking action of NIMBEX including inhalational anesthetics, antibiotics, magnesium salts, lithium, local anesthetics, procainamide and quinidine.

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 NIMBEX dosage.

Resistance to Neuromuscular Blockade with Certain Drugs: Shorter durations of neuromuscular block may occur and NIMBEX infusion rate requirements may be higher in patients chronically administered phenytoin or carbamazepine. 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 NIMBEX dosage.

Malignant Hyperthermia (MH): NIMBEX 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.

DRUG INTERACTIONS

Succinylcholine: The use of succinylcholine prior to NIMBEX 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 NIMBEX. This may potentiate the neuromuscular blockade.

Antibiotics: May prolong the neuromuscular blockade action of NIMBEX. Examples: aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, sodium colistimethate

Local anesthetics: May prolong the neuromuscular blockade action of NIMBEX

Magnesium salts: May prolong the neuromuscular blockade action of NIMBEX

Procainamide: May prolong the neuromuscular blockade action of NIMBEX

Lithium: May prolong the neuromuscular blockade action of NIMBEX

Quinidine: May prolong the neuromuscular blockade action of NIMBEX

USE IN SPECIFIC POPULATIONS

Pregnancy: The 10 mL NIMBEX multiple-dose vials contain the preservative benzyl alcohol. Therefore, if NIMBEX is needed during pregnancy, consider using a benzyl alcohol-free formulation (i.e., 5mL and 20 mL NIMBEX single-dose vials). Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs.

There are no available clinical trial data on cisatracurium use in pregnancy to evaluate a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal studies conducted in rats administered cisatracurium besylate during organogenesis (Gestational Day 6 to 15) 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.

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Labor or Delivery: The action of neuromuscular blocking agents may be enhanced by magnesium salts administeredfor the management of preeclampsia or eclampsia of pregnancy.

Lactation: The 10 mL NIMBEX multiple-dose vials contains the preservative benzyl alcohol. Therefore, if NIMBEX is needed during lactation, consider using a benzyl alcohol-free formulation (i.e., 5 mL and 20 mL NIMBEX single-dose vials). Because benzyl alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs.

There are no data on the presence of cisatracurium besylate in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NIMBEX and any potential adverse effects on the breastfed child from NIMBEX or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of NIMBEX 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.

The safety and effectiveness of NIMBEX have not been established in pediatric patients less than 1 month of age.

Geriatric Use: Of the total number of subjects (135) in clinical studies of NIMBEX, 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.

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 NIMBEX and attempting intubation by at least 1 minute to achieve adequate intubation conditions.

Patients with Renal Impairment: The time to 90% neuromuscular blockade was 1 minute slower in patients with end-stage renaldisease than in patients with normal renal function. Therefore, consider extending the interval between administering NIMBEX and attempting intubation by at least 1 minute to achieve adequate intubation conditions.

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 NIMBEX. These minor differences in pharmacokinetics were not associated with clinically significant differences in the recovery profile of NIMBEX.

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. NIMBEX 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 NIMBEX is administered to burn patients.

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

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

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