Mivacurium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Mivacron: 10 mg/5 mL (5 mL); 20 mg/10 mL (10 mL)

Pharmacology

Mechanism of Action

Antagonizes acetylcholine by competitively binding to cholinergic sites on motor endplates in skeletal muscle. This inhibits contractile activity in skeletal muscle leading to muscle paralysis.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d (mean): 147 to 274 mL/kg

Metabolism

Enzymatic hydrolysis via plasma cholinesterase, inactive metabolites

Excretion

Urine (~7% as unchanged drug; Cook 1992) and bile

Onset of Action

Neuromuscular blockade: IV (dose dependent): 1.5 to 3 minutes; Elderly: 1.5 minutes slower; Children 2 to 12 years of age: Faster than adults

Peak: Neuromuscular blockade (dose dependent): IV: Children 2 to 12 years of age: Median range: 1.6 to 2.8 minutes; Adults: Median range: 2.3 to 4.9 minutes

Duration of Action

Short due to rapid hydrolysis by plasma cholinesterases; duration may be slightly longer in the elderly; may also be longer in patients with hepatic or renal impairment and patients with reduced plasma cholinesterase (pseudocholinesterase) activity; hypothermia may prolong the duration of action

Children: Clinically effective block may last 10 minutes (6 to 15 minutes) with 95% spontaneous recovery in 14 to 26 minutes

Adult: Clinically effective block may last for 15 to 20 minutes; spontaneous recovery may be 95% complete in 21 to 34 minutes (dose dependent)

Half-Life Elimination

~2 minutes

Use in Specific Populations

Special Populations: Renal Function Impairment

Duration is ~1.5 times longer in patients with ESRD.

Special Populations: Hepatic Function Impairment

Duration is ~3 times longer in patients with end-stage hepatic disease.

Special Populations: Elderly

Onset and recovery rate may be slower and duration may be longer.

Special Populations: Children

Onset and recovery rate are faster and duration is shorter in children 2 to 12 years of age. In children 2 to 12 years of age when used as adjunct to general anesthesia (nitrous oxide/oxygen/opioid), typical intermittent IV doses produced a maximum effect at a mean 1.9 minutes (range: 1.3 to 3.3 minutes) and a clinically effective blockade for a mean of 10 minutes (range: 6 to 15 minutes)

Use: Labeled Indications

Neuromuscular blockade for endotracheal intubation, surgery, or mechanical ventilation: As an adjunct to general anesthesia to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation in adequately sedated ICU patients

Note: Neuromuscular blockade does not provide pain control, sedation, or amnestic effects. Appropriate analgesic and sedative mediations should be used before and during administration of neuromuscular blockade to achieve deep sedation.

Use: Off Label

Acute respiratory distress syndromeyes

Based on the Society for Critical Care Medicine Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient, a neuromuscular blocker may be considered for short-term use (up to 48 hours) during the early course of acute respiratory distress syndrome (ARDS) in adults with PaO₂/FiO₂ <150 mmHg SCCM [Murray 2016]. Some experts recommend that neuromuscular blockers be considered for short-term use (up to 48 hours) only in patients with ARDS and severe gas exchange abnormalities (PaO₂/FiO₂ ≤120 mmHg) Siegel 2018. Note: Only cisatracurium has been studied in patients with ARDS. Whether or not other neuromuscular blockers will yield similar results is unknown.

Shivering due to therapeutic hypothermia following cardiac arrestyes

Based on the Society for Critical Care Medicine Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient, a neuromuscular blocker may be used to manage overt shivering in therapeutic hypothermia following cardiac arrest.

Contraindications

Hypersensitivity to mivacurium or any component of the formulation

Documentation of allergenic cross-reactivity for neuromuscular blockers is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

Note: Dose to effect; doses must be individualized due to interpatient variability. Ensure adequate pain control and sedation prior to and during administration of neuromuscular blockade to achieve deep sedation (SCCM [Murray 2016]).

Neuromuscular blockade for endotracheal intubation, surgery, or mechanical ventilation (as adjunct to general anesthesia): IV:

Intermittent bolus: Initial: 0.15 mg/kg over 5 to 15 seconds, or 0.2 mg/kg over 30 seconds, or 0.25 mg/kg in divided doses (0.15 mg/kg followed in 30 seconds by 0.1 mg/kg); maintenance: 0.1 mg/kg at ~15 minute intervals.

Burn patients: Administer test dose of 0.015 to 0.02 mg/kg, then follow with appropriate dosing and monitoring.

Cardiovascular disease (clinically significant) or increased sensitivity to release of histamine (eg, asthma): Initial: ≤0.15 mg/kg over 60 seconds.

Continuous infusion: Initial: 9 to 10 mcg/kg/minute (0.54 to 0.6 mg/kg/hour) upon evidence of spontaneous recovery from initial bolus dose. Usual infusion rate: 5 to 7 mcg/kg/minute under balanced anesthesia.

Note: If continuous infusion is initiated simultaneously with the initial dose, a lower initial infusion rate should be used (eg, 4 mcg/kg/minute).

Dosage adjustment for concomitant inhalational anesthetics at steady state: Consider reduction of mivacurium continuous infusion rate by ≤35% to 40% or a reduction of bolus dose by ≤25% with concomitant isoflurane or enflurane at steady state; greater reductions may be necessary with higher concentrations of isoflurane or enflurane. Consider small reduction of mivacurium dosage with concomitant halothane administration.

Intensive care unit paralysis (eg, use for up to 48 hours in patients with early ARDS with PaO₂/FiO₂ <150, to facilitate mechanical ventilation, or for shivering from therapeutic hypothermia) (off-label dosing): IV: Initial bolus of 0.25 mg/kg, followed by 5 to 6 mcg/kg/minute (0.3 to 0.36 mg/kg/hour) (deBacker 2017)

Dosing: Geriatric

Refer to adult dosing; may require decreased infusion rates or smaller or less frequent maintenance bolus doses

Dosing: Pediatric

Note: Titrate dose to effect; dose must be individualized due to interpatient variability. Obese patients (weighing ≥30% IBW) should be dosed on IBW.

Adjunct to surgical anesthesia (neuromuscular blockade): Note: Due to pharmacodynamics differences in pediatric patients than adults, children 2 to 12 years require a higher mg/kg dose and often more frequent repeat maintenance dosing or higher continuous infusion rates.

Children 2 to 12 years:

Intermittent IV bolus: 0.2 mg/kg over 5 to 15 seconds

Continuous IV infusion: Usual dose: 14 mcg/kg/minute (0.84 mg/kg/hour); range: 5 to 31 mcg/kg/minute (0.3 to 1.86 mg/kg/hour); begin infusion upon evidence of spontaneous recovery from initial dose

Adolescents:

Intermittent IV bolus: Initial: 0.15 mg/kg over 5 to 15 seconds, or 0.2 mg/kg over 30 seconds, or a total bolus of 0.25 mg/kg divided into 2 doses (0.15 mg/kg followed in 30 seconds by 0.1 mg/kg)

Maintenance: 0.1 mg/kg at ~15-minute intervals; begin upon evidence of spontaneous recovery from initial bolus

Burn patients: Administer test dose of 0.015 to 0.02 mg/kg, then follow with appropriate dosing and monitoring

Cardiovascular disease (clinically significant) or increased sensitivity to release of histamine (eg, asthma): Initial: ≤0.15 mg/kg over 60 seconds

Continuous IV infusion: Initial: 9 to 10 mcg/kg/minute (0.54 to 0.6 mg/kg/hour); begin infusion upon evidence of spontaneous recovery from initial bolus dose. Usual infusion rate: 5 to 7 mcg/kg/minute (0.3 to 0.42 mg/kg/hour) under balanced anesthesia; range: 1 to 15 mcg/kg/minute (0.06 to 0.9 mg/kg/hour). Note: A lower initial infusion rate (eg, 4 mcg/kg/minute [0.24 mg/kg/hour]) should be used if started simultaneously with initial bolus

ICU paralysis (eg, facilitate mechanical ventilation) in select adequately sedated patients: Limited data available in ages <2 years (Martin 1999):

Infants: IV: Initial bolus: 0.2 mg/kg, followed by continuous IV infusion of 10 mcg/kg/minute (0.6 mg/kg/hour)

Children: IV: Initial bolus: 0.2 mg/kg, followed by continuous IV infusion of 16 mcg/kg/minute (0.96 mg/kg/hour)

Adolescents: IV: Initial bolus: 0.2 mg/kg, followed by continuous IV infusion of 7 mcg/kg/minute (0.42 mg/kg/hour)

Dosing adjustment for concomitant inhalational anesthetics at steady state: Children ≥2 years and Adolescents: Consider reduction of mivacurium continuous infusion rate by ≤35% to 40% and/or a reduction of bolus dose by ≤25% when administered concomitantly with isoflurane or enflurane at steady state; greater reductions may be necessary with higher concentrations of isoflurane or enflurane. Consider smaller reduction of mivacurium dosage with concomitant halothane administration.

Dosing: Obesity

Dose obese patients (weight ≥30% more than IBW) based on IBW.

Reconstitution

May prepare an infusion solution (final concentrations: 0.5 mg/mL) by admixing with an appropriate diluent (eg, NS, D5W, D5NS, LR, D5LR). Do not mix with alkaline solutions having a pH >8.5 (eg, barbiturates).

Administration

IV: For IV administration only. May administer as IV bolus and/or continuous infusion.

Storage

Store intact vials at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Do not freeze. Mivacurium diluted to 0.5 mg/mL in D5W, D5NS, NS, LR, or D5LR in PVC bags is stable at 5°C to 25°C (41°F to 77°F) for up to 24 hours. Discard unused portion.

Drug Interactions

Acetylcholinesterase Inhibitors: May diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Aminoglycosides: May enhance the respiratory depressant effect of Neuromuscular-Blocking Agents. Monitor therapy

Bacitracin (Systemic): May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Botulinum Toxin-Containing Products: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Bromperidol: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Calcium Channel Blockers: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Capreomycin: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Cardiac Glycosides: Neuromuscular-Blocking Agents may enhance the arrhythmogenic effect of Cardiac Glycosides. Monitor therapy

Clindamycin (Topical): May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Colistimethate: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Consider therapy modification

Corticosteroids (Systemic): Neuromuscular-Blocking Agents (Nondepolarizing) may enhance the adverse neuromuscular effect of Corticosteroids (Systemic). Increased muscle weakness, possibly progressing to polyneuropathies and myopathies, may occur. Consider therapy modification

Cyclophosphamide: May increase the serum concentration of Mivacurium. Monitor therapy

CycloSPORINE (Systemic): May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Echothiophate Iodide: May increase the serum concentration of Mivacurium. Monitor therapy

Estrogen Derivatives: May increase the serum concentration of Mivacurium. Monitor therapy

Fosphenytoin-Phenytoin: May diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Fosphenytoin-Phenytoin may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Fosphenytoin-Phenytoin may decrease the serum concentration of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Inhalational Anesthetics: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Ketorolac (Nasal): May enhance the adverse/toxic effect of Neuromuscular-Blocking Agents (Nondepolarizing). Specifically, episodes of apnea have been reported in patients using this combination. Monitor therapy

Ketorolac (Systemic): May enhance the adverse/toxic effect of Neuromuscular-Blocking Agents (Nondepolarizing). Specifically, episodes of apnea have been reported in patients using this combination. Monitor therapy

Lincosamide Antibiotics: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Lithium: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Local Anesthetics: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Exceptions: Benzocaine; Benzydamine; Cocaine (Topical); Dibucaine; Dyclonine; Ethyl Chloride; Hexylresorcinol; Lidocaine (Ophthalmic); Lidocaine (Topical); Pramoxine; Proparacaine; Tetracaine (Ophthalmic); Tetracaine (Topical). Monitor therapy

Loop Diuretics: May diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Loop Diuretics may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Magnesium Salts: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Minocycline (Systemic): May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Phenelzine: May increase the serum concentration of Mivacurium. Monitor therapy

Pholcodine: May enhance the adverse/toxic effect of Neuromuscular-Blocking Agents. Specifically, anaphylaxis has been reported. Monitor therapy

Polymyxin B: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Consider therapy modification

Procainamide: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

QuiNIDine: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

QuiNINE: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Avoid combination

Sertraline: May increase the serum concentration of Mivacurium. Monitor therapy

Spironolactone: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Tetracyclines: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Trimebutine: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Vancomycin: May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Adverse Reactions

>10%: Cardiovascular: Flushing (16% to 25%)

1% to 10%: Cardiovascular: Hypotension (<1% to 4%; dosage and time dependent)

<1%, postmarketing, and/or case reports: Anaphylactoid reaction, anaphylaxis, bradycardia, bronchospasm, cardiac arrhythmia, delayed recovery from neuromuscular block (prolonged effect), dizziness, drug tolerance (diminished effect), erythema, hypersensitivity reaction, hypoxemia, injection site reaction, muscle spasm, phlebitis, skin rash, tachycardia, urticaria, wheezing

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis: Severe anaphylactic reactions have been reported (some life-threatening and fatal). Appropriate emergency treatment (including epinephrine 1 mg/mL) should be immediately available during use. Use caution in patients with previous anaphylactic reactions to other neuromuscular-blocking agents.
• Bradycardia: Does not counteract bradycardia produced by anesthetics/vagal stimulation.
• Neuromuscular cross-sensitivity: Cross-sensitivity with other neuromuscular-blocking agents may occur; use extreme caution in patients with previous anaphylactic reactions.

Disease-related concerns:

• Burn injury: Resistance may occur in burn patients (≥20% of total body surface area), usually several days after the injury, and may persist for several months after wound healing (Han 2009). These patients may require increased doses or patients may also have reduced plasma cholinesterase activity, requiring dose reduction.
• Cardiovascular disease: Use with caution in patients with clinically significant cardiovascular disease; reduce initial dosage and inject slowly (over 60 seconds). Carefully monitor hemodynamic status and maintain adequate hydration in these patients.
• Conditions that may antagonize neuromuscular blockade (decreased paralysis): Respiratory alkalosis, hypercalcemia, demyelinating lesions, peripheral neuropathies, denervation, and muscle trauma may result in antagonism of neuromuscular blockade (ACCM/SCCM/ASHP [Murray 2002]; Greenberg 2013; Miller 2010; Naguib 2002).
• Conditions that may diminish plasma cholinesterase activity: Plasma cholinesterase genetic abnormalities, malignant tumors, infections, anemia, decompensated heart disease, peptic ulcer, and myxedema may diminish plasma cholinesterase activity and result in prolonged neuromuscular blockade.
• Conditions that may potentiate neuromuscular blockade (increased paralysis): Electrolyte abnormalities (eg, severe hypocalcemia, severe hypokalemia, hypermagnesemia), neuromuscular diseases, metabolic acidosis, respiratory acidosis, Eaton-Lambert syndrome and myasthenia gravis may result in potentiation of neuromuscular blockade (Greenberg 2013; Miller 2010; Naguib 2002).
• Renal impairment: Use with caution in patients with renal impairment; prolonged neuromuscular block may occur. Reduced plasma cholinesterase activity may occur in patients with renal disease.
• Hepatic impairment: Use with caution in patients with hepatic impairment; prolonged neuromuscular block may occur. Markedly reduced plasma cholinesterase activity may occur in patients with chronic hepatic disease.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in the elderly; effects and duration are more variable.
• Immobilized patients: Resistance may occur in patients who are immobilized.
• Homozygous for atypical plasma cholinesterase gene: Use with extreme caution if at all in patients homozygous for the atypical plasma cholinesterase gene; extremely sensitive to the neuromuscular blocking effect of mivacurium.

Other warnings/precautions:

• Appropriate use: Maintenance of an adequate airway and respiratory support is critical. All patients should receive eye care including liberal use of lubricating drops, gel, or ointment and eyelids should remain closed during continuous neuromuscular blockade to protect against damage to the cornea (ulceration and drying).
• Experienced personnel: Should be administered by adequately trained individuals familiar with its use.
• Histamine release: Use with caution in patients in whom substantial histamine release would be potentially hazardous (eg, asthma); reduce initial dosage and inject slowly (over 60 seconds). Carefully monitor hemodynamic status and maintain adequate hydration in these patients.
• Risk of medication errors: Accidental administration may be fatal. Confirm proper selection of intended product, store vial so the cap and ferrule are intact and the possibility of selecting the wrong product is minimized, and ensure that the intended dose is clearly labeled and communicated, when applicable.

Monitoring Parameters

Vital signs (heart rate, blood pressure, respiratory rate); degree of muscle paralysis (eg, presence of spontaneous movement, ventilator asynchrony, shivering, and consider use of a peripheral nerve stimulator with train of four monitoring along with clinical assessments)

Pregnancy

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Plasma cholinesterase concentrations are decreased in pregnancy; neuromuscular blockade may be prolonged and intensified. Use in cesarean section has been reported; adjustment of the dose may be necessary (Kim 1999).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience flushing (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.