Mivacurium (Systemic)


VA CLASSIFICATION
Primary: MS300

Commonly used brand name(s): Mivacron.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Neuromuscular blocking (paralyzing) agent—
Note: Mivacurium is a nondepolarizing neuromuscular blocking agent with a short duration of action {01} {02} {03} {04} {05} {06} {07} {08} {09} {10} {11} {12} {13} {14} {15} {16} {17} {18} {19} {50}.



Indications

Accepted

Skeletal muscle paralysis—Mivacurium is indicated as an adjunct to anesthesia to facilitate endotracheal intubation and to induce skeletal muscle relaxation in the surgical field {01} {02} {03} {04} {05} {06} {07} {08} {09} {10} {11} {12} {13} {14} {15} {16} {17} {18} {19}.

Unaccepted
Mivacurium has not been adequately studied for facilitating prolonged mechanical ventilation in intensive care patients {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Synthetic {01}.

Chemical group—
    bis-Benzylisoquinolinium diester compound {01}.
Molecular weight—
    1100.19 {01} {20}

Note: Mivacurium is a mixture of three stereoisomers, the trans-trans, cis-trans, and cis-cis diesters. The mixture contains about 57% of the trans-trans diester and about 36% of the cis-trans diester. These stereoisomers have neuromuscular blocking activities that are approximately equal to each other and to the mixture as a whole. In animals, the cis-cis diester is approximately one tenth as potent as the other stereoisomers. Interconversion of the isomers does not occur in vivo {01}.


Mechanism of action/Effect:

Mivacurium is a nondepolarizing (competitive) neuromuscular blocking agent. Nondepolarizing neuromuscular blocking agents inhibit neuromuscular transmission by competing with acetylcholine for the cholinergic receptors of the motor end plate {01} {21}, thereby reducing the response of the end plate to acetylcholine {21}. This type of neuromuscular block is usually antagonized by anticholinesterase agents {01}. Because mivacurium is hydrolyzed by plasma cholinesterase, the possibility that anticholinesterase agents might prolong, rather than reverse, the effects of mivacurium has been considered {02}. However, both neostigmine and edrophonium have been shown to reverse the effects of mivacurium, when spontaneous recovery or movement has been observed {01} {02} {03} {04}.

Neuromuscular blocking agents have no clinically significant effect on consciousness or the pain threshold {22}.


Other actions/effects:

Mivacurium may cause histamine release, especially when relatively large doses are administered rapidly, leading to a decrease in blood pressure and an increase in heart rate {01} {12} {13}.

Distribution:

Volume of distribution—0.15 (range, 0.06 to 0.24), 0.27 (range, 0.08 to 0.56), and 0.31 (range, 0.18 to 0.46) L per kg of body weight, for the trans-trans, cis-trans, and cis-cis diesters, respectively {01}.

Biotransformation:

Extensive {01} and rapid {02} {05} {06}; via enzymatic hydrolysis catalyzed by plasma cholinesterase {01} {02} {05} {06}. Biotransformation may be significantly slowed in patients with abnormal or decreased plasma cholinesterase activity, especially individuals with a homozygous atypical cholinesterase gene abnormality {37}.

Half-life:

Elimination—5 to 10 minutes, estimated using the premise that doubling the dose of a medication prolongs the duration of action by the length of its elimination half-life {05}. Half-life values of 2.3 (range, 1.4 to 3.6) and 2.1 (range, 0.8 to 4.8) minutes have been reported for the trans-trans and cis-trans stereoisomers, respectively. A value of 55 (range, 32 to 102) minutes has been reported for the cis-cis diester, but this isomer is not likely to contribute significantly to the effects of the mixture {01}. The half-life is not significantly prolonged in geriatric patients {17}.

Onset of action:


Time to achieve intubating conditions in adults:

150 mcg per kg of body weight (mcg/kg), with intravenous and/or inhalation anesthetic techniques: About 2.5 minutes {01}.

200 or 250 mcg/kg, with intravenous and/or inhalation anesthetic techniques: About 2 minutes {01} {03} {18} {19}.



Time to achieve intubating conditions in children:

200 mcg/kg, with intravenous and/or inhalation anesthetic techniques: About 2 minutes {01}.


Time to peak effect:

Note: The time to maximal suppression of the twitch response to peripheral nerve stimulation is dependent on dosage and the age of the patient. Also, administration of a volatile inhalation agent (specified below when applicable) may produce a dose-dependent decrease in the time to peak effect {23}.



Children 2 to 12 years of age:

110 to 120 mcg/kg: 2.8 (range, 1.2 to 4.6) minutes {01}.

200 mcg/kg: 1.9 (range, 1.3 to 3.3) minutes {01}.

250 mcg/kg: 1.6 (range, 1 to 2.2) minutes {01} {09}.



Nongeriatric adults with normal hepatic and renal function:

70 to 100 mcg/kg: 4.9 (range, 2 to 7.6) minutes {01}.

150 mcg/kg: 3.3 (range, 1.5 to 8.8) minutes {01} {02}.

200 mcg/kg: 2.5 (range, 1.2 to 6) minutes {01} {02}.

250 mcg/kg: 2.3 (range, 1 to 4.8) minutes {01}.



Nongeriatric adults with end-stage renal failure undergoing renal transplantation:

150 mcg/kg (isoflurane–nitrous oxide–oxygen anesthesia): 2.6 (range, 1 to 4.5) minutes {50}.



Nongeriatric adults with end-stage hepatic disease undergoing hepatic transplantation:

150 mcg/kg (isoflurane–oxygen anesthesia): 2.1 (range, 1 to 4) minutes {50}.



Geriatric adults 68 to 77 years of age:

100 mcg/kg (isoflurane–nitrous oxide–oxygen anesthesia): 4.8 (range, 3 to 7) minutes; about 1.5 minutes longer than for nongeriatric adults receiving this dose under the same anesthetic regimen {01}.


Duration of action:

Note: Mivacurium's duration of action is dependent on the patient's age {01} {04} {11} and plasma cholinesterase activity {01} {04} {10} {11}. In addition, the duration of action is more prolonged during anesthesia with a volatile inhalation anesthetic (specified below when applicable) than during other types of anesthesia {01}. Although studies in a limited number of individuals have shown prolonged effects in patients with impaired hepatic or renal function, the contribution of these medical problems to the prolongation of effect, independent of decreased plasma cholinesterase activity and/or the anesthesia given, has not been ascertained {38}.
The duration of mivacurium's clinical effect (time to 25% spontaneous recovery) is influenced by the dose to a significantly lesser extent than that of other nondepolarizing neuromuscular blocking agents. In children, increasing the dose from 110 to 200 mcg/kg, or from 120 to 250 mcg/kg, extends the duration of clinical effect by only 2 to 4 minutes {04} {09}. In adults, the duration of clinical effect of a 200 mcg/kg dose is about 25% longer, and that of a 300 mcg/kg dose is about 50% longer, than that of a 100 mcg/kg dose {02}. In clinical studies, cumulative effects on the duration or depth of neuromuscular blockade did not occur when single supplemental doses were injected after 25% recovery from the previous dose {08} {12} or after cessation of a continuous infusion that was administered at a rate titrated to maintain 95% inhibition of the twitch response to peripheral stimulation {02} {08} {12}.



Duration of clinical effect (time for spontaneous recovery of a single-twitch response to peripheral nerve stimulation to 25% of the control value [T 25]):


Children 2 to 12 years of age—

110 to 120 mcg/kg—7 (range, 4 to 10) minutes {01}.

200 mcg/kg—10 (range, 6 to 15) minutes {01}.

250 mcg/kg—9 (range, 5 to 12) minutes {01} {09}.



Nongeriatric adults with normal hepatic and renal function—

70 to 100 mcg/kg—13 (range, 8 to 24) minutes {01}.

150 mcg/kg—16 (range, 9 to 38) minutes {01} {02}.

200 mcg/kg—20 (range, 10 to 36) minutes {01} {02}.

250 mcg/kg—23 (range, 14 to 38) minutes {01}.



Nongeriatric adults with end-stage renal disease undergoing renal transplantation—

150 mcg/kg (isoflurane–nitrous oxide–oxygen anesthesia)—30 (range, 19 to 58) minutes {01}.



Nongeriatric adults with end-stage hepatic disease undergoing hepatic transplantation—

150 mcg/kg (isoflurane–oxygen anesthesia)—57 (range, 29 to 80) minutes {01}.



Geriatric adults 68 to 77 years of age—

100 mcg/kg (isoflurane–nitrous oxide–oxygen anesthesia)—20 (range, 14 to 28) minutes {01}; about 3 minutes longer than for nongeriatric adults receiving this dose under the same anesthetic regimen {17}.




Recovery index (time for the twitch response to peripheral stimulation to increase spontaneously from 25 to 75% of the control value [T 25-75]):


Children 2 to 10 years of age—

200 mcg/kg—About 5 minutes {01}.



Nongeriatric adults with normal hepatic and renal function—

150 mcg/kg—About 6 minutes {01} {02}.

200 or 250 mcg/kg—About 7 to 8 minutes {01}.




Time to spontaneous 95% recovery of the twitch response to peripheral stimulation (T 95):


Children 2 to 12 years of age—

110 mcg/kg—About 8 minutes {04}.

200 mcg/kg—19 (range, 14 to 26) minutes {01} {04}.



Nongeriatric adults with normal hepatic and renal function—

70 to 100 mcg/kg—21 (range, 10 to 36) minutes {01}.

150 mcg/kg—26 (range, 16 to 41) minutes {01} {02}.

200 mcg/kg—31 (range, 15 to 51) minutes {01} {02}.

250 mcg/kg—34 (range, 22 to 64) minutes {01}.



Geriatric adults 65 to 80 years of age—

100 mcg/kg (isoflurane–nitrous oxide–oxygen anesthesia)—Approximately 37 minutes; about 5 minutes longer than for nongeriatric adults receiving this dose under the same anesthetic regimen {17}.




Time to spontaneous recovery of the T 4:T 1 ratio (train-of-four stimulation) to 0.75:


Children 2 to 12 years of age—

200 mcg/kg—16 (range, 12 to 23) minutes {01}.



Nongeriatric adults with normal hepatic and renal function—

70 to 100 mcg/kg—21 (range, 10 to 36) minutes {01}.

150 mcg/kg—26 (range, 15 to 45) minutes {01}.

200 mcg/kg—34 (range, 19 to 56) minutes {01}.

250 mcg/kg—43 (range, 26 to 75) minutes {01}.



Elimination:
    Renal and biliary, as inactive metabolites, following biotransformation (enzymatic hydrolysis catalyzed by plasma cholinesterase) {01}. Plasma clearances of the three stereoisomers are 53 (range, 32 to 105), 99 (range, 52 to 230), and 4.2 (range, 2.4 to 5.4) mL per kg of body weight per minute for the trans-trans, cis-trans, and cis-cis diesters, respectively {01}.


Precautions to Consider

Carcinogenicity

Studies in animals have not been done {01}.

Mutagenicity

Mivacurium displayed no mutagenicity in the Ames Salmonella test, the mouse lymphoma assay, the human lymphocyte assay, or the in vivo rat bone marrow cytogenetic assay {01}.

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies have not been done in pregnant women. However, the possibility of a prolonged response should be considered, because plasma cholinesterase activity may be reduced during pregnancy {01}.

In animal studies, no maternal or fetal toxicity or teratogenicity occurred with subcutaneous administration of maximal subparalyzing doses to nonventilated pregnant rats or mice {01}.

FDA Pregnancy Category C {01}.


Labor and delivery—

Use of mivacurium during labor, vaginal delivery, or cesarean section has not been studied. Whether administration during labor and delivery has any effects in the fetus has not been determined {01}.

In animal studies, administration of 80 or 200 mcg per kg of body weight (mcg/kg) of mivacurium to female beagles undergoing cesarean section produced negligible concentrations of mivacurium in neonatal umbilical vessel blood. No deleterious effects on the puppies were observed {01}.

Breast-feeding

It is not known whether mivacurium is distributed into human breast milk {01}.

Pediatrics

Infants and children younger than 2 years of age—Appropriate studies on the relationship of age to the effects of mivacurium in patients up to 2 years of age have not shown that mivacurium causes different, or more severe, adverse effects in infants than in children or adults {51}. No significant difference in the potency of a single dose of mivacurium was found between infants less than 6 months of age, infants 6 to 12 months of age, and older children during halothane anesthesia {51}. The effective infusion rate of mivacurium is similar in infants and children {51} {52} {68}.
Note: Mivacurium is not approved by drug regulatory agencies in the United States (i.e., the Food and Drug Administration) or Canada (i.e., the Health Protection Branch) for use in children younger than 2 years of age {01} {50}.



Children 2 to 12 years of age—Appropriate studies performed to date have not shown that mivacurium causes different, or more severe, adverse effects than have been reported in adults, or that the risk of adverse effects is increased in children {04} {09} {11}. However, the ED 95 of mivacurium (dose required to produce 95% suppression of the adductor pollicis muscle twitch response to ulnar nerve stimulation) {01} {04} {09} and the average infusion rate required to maintain a given degree of neuromuscular blockade {11} are higher in children than in adults {56} {68}. The inverse relationship between mivacurium dosage requirement and the patient's age is significant among children of different ages {11} (as well as between children and adults {09} {11}) when dosage is calculated on an mcg/kg basis, but not when it is calculated on an mcg per square meter of body surface area basis {09} {11}. Also, the onset of action of mivacurium is more rapid, and its duration of action is shorter, in children than in adults {01} {04} {09} {11} {54}. Recovery after administration of a reversal agent also occurs more rapidly in children than in adults {01} {11} {53}. Some differences between children and adults in the pharmacokinetics of mivacurium may be attributable to differences between these groups in plasma cholinesterase activity {55}.


Geriatrics


Mivacurium has been studied in geriatric patients {01} {02} {11} {12} {64}, some of whom had significant cardiovascular disease. No geriatrics-specific problems have been documented to date {02} {11} {12}. Although the duration of effect may be about 15 to 20% longer in elderly patients than in younger adults, studies have not shown significant variability in the pharmacokinetics of mivacurium (e.g., elimination half-life or clearance rate) that would account for the observed differences {01} {17} {64}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Some of the following interactions have not been documented with mivacurium. However, because they have been reported to occur with other nondepolarizing neuromuscular blocking agents, the possibility of a significant interaction with mivacurium must be considered.
Interactions reported below that may lead to enhanced neuromuscular blockade may result in prolonged paralysis, prolonged respiratory insufficiency, and/or difficulty in reversal {23}. These interactions are of minimal clinical significance while the patient is being mechanically ventilated {25}. With the exception of medications that can reduce the concentration or activity of plasma cholinesterase, these interactions may be less significant with a short-acting neuromuscular blocking agent such as mivacurium than with longer-acting agents. However, caution and careful monitoring of the patient are recommended during and following concurrent or sequential use of mivacurium with a medication that may significantly potentiate its effects, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively.

» Aminoglycosides{01}{23}{24} , possibly including oral neomycin (if significant quantities are absorbed by patients with renal function impairment) or
Anesthetics, parenteral-local{01}{23}{24} (large doses leading to significant plasma concentrations) or
Bacitracin or{01}
» Capreomycin or{25}
» Citrate-anticoagulated blood (massive transfusions) or{25}
» Clindamycin or{01}{23}
Colistin or{01}{23}{24}
Colistimethate sodium or{01}{24}
Lidocaine (systemic use, with intravenous doses > 5 mg/kg) or{25}
» Lincomycin or{01}{23}{24}
» Polymyxins or{01}{23}{24}
Procaine (systemic use) or{25}
Tetracyclines or{01}{23}{24}
Trimethaphan (large doses){23}{25}    (neuromuscular blocking activity of these medications may be additive to that of neuromuscular blocking agents; reversal agents have sometimes been ineffective in reversing neuromuscular blockade potentiated by aminoglycosides, clindamycin, lincomycin, or polymyxins {24})


Analgesics, opioid (narcotic), especially those commonly used as adjuncts to anesthesia{25}    (central respiratory depressant effects of opioid analgesics may be additive to the respiratory insufficiency induced by neuromuscular blocking agents)

    (concurrent use of a neuromuscular blocking agent prevents or reverses muscle rigidity induced by sufficiently high doses of most opioid analgesics, especially alfentanil, fentanyl, or sufentanil)


Anesthetics, hydrocarbon inhalation, such as:
Chloroform
Cyclopropane
Desflurane{47}
Enflurane{63}
Ether
Halothane{63}
Isoflurane{63}
Methoxyflurane
Trichloroethylene    (neuromuscular blocking activity of inhalation hydrocarbon anesthetics, especially desflurane, enflurane, or isoflurane, may be additive to that of nondepolarizing neuromuscular blocking agents, with the degree of potentiation being increased as the concentration of the anesthetic is increased; a reduction of mivacurium dosage may be necessary when it is given after steady-state anesthesia with one of these anesthetics has been established; with enflurane or isoflurane anesthesia, it is recommended that mivacurium dosage be decreased by about 25% for initial single doses and about 35 to 40% for administration by continuous infusion {01} {13} {14} {15} {16} {63}; although specific recommendations for altering mivacurium dosage during desflurane anesthesia are not currently available, desflurane has been shown to decrease the ED 95 of other nondepolarizing neuromuscular blocking agents [specifically, atracurium and pancuronium] by approximately 50% {47})

    (halothane potentiates the effects of mivacurium to a lesser extent than enflurane or isoflurane {01}; prior halothane administration may not decrease initial mivacurium dosage requirements {01} {19}, but halothane may decrease maintenance dose [infusion rate] requirements by about 20% {01} {11} {63}, decrease mivacurium's onset of action {09}, and prolong mivacurium's duration of action {01} {09} {19})


Antihypertensives or other hypotension-inducing medications or
Bradycardia-inducing medications    (although histamine release induced by rapid injection of large doses of mivacurium may increase heart rate, this effect is generally of brief duration {01} {12} {13}, so that mivacurium should not significantly counteract bradycardia induced by other medications or vagal stimulation {01}; however, mivacurium-induced histamine release may cause a temporary decrease in blood pressure, and it is possible that the risk of severe hypotension may be increased in patients receiving other hypotension-inducing medications; therefore, the incidence and/or severity of these effects may be higher with mivacurium than with a neuromuscular blocking agent that has significant vagolytic activity, especially in patients with compromised cardiac function and in patients receiving 2 or more medications that may decrease heart rate and/or blood pressure [e.g., benzodiazepines, beta-adrenergic blocking agents, calcium channel blocking agents, opioid analgesics] prior to and/or during surgery {25})


Antimyasthenics or
Edrophonium    (these agents antagonize the effects of nondepolarizing neuromuscular blocking agents; parenteral neostigmine, pyridostigmine, or edrophonium are indicated to reverse neuromuscular blockade following surgery, if necessary {01} {25})

    (neuromuscular blocking agents may antagonize the effects of antimyasthenics on skeletal muscle; temporary dosage adjustment may be required to control symptoms of myasthenia gravis following surgery {25})


Any medication that may reduce plasma cholinesterase concentrations or activity, such as:
Cytotoxic antineoplastic agents{23}{39}{40}
» Demecarium
» Echothiophate
» Insecticides, neurotoxic, recent exposure to, possibly including large quantities of topical malathion
» Isoflurophate
Metoclopramide{23}{40}
Phenelzine
Procaine (systemic){23}{40}    (reduction of plasma concentrations or activity of cholinesterase, the enzyme that catalyzes hydrolysis of mivacurium, to 50% or less of normal {39}, may enhance and prolong mivacurium's effects {01}; reduction of plasma cholinesterase activity may persist for weeks or months after therapy with demecarium, echothiophate, or isoflurophate has been discontinued)


Calcium channel blocking agents{23}{24}{27}    (although an interaction with mivacurium has not been documented, verapamil and nifedipine have been shown to potentiate the effects of several other neuromuscular blocking agents; also, difficulty in reversing verapamil-potentiated neuromuscular blockade with a single dose of neostigmine has been reported)


Calcium salts{25}    (calcium salts may reverse the effects of nondepolarizing neuromuscular blocking agents)


Carbamazepine and/or{01}{28}
Phenytoin{01}{23}{28}{29}{30}    (although an interaction with mivacurium has not been documented, resistance to the effects of other nondepolarizing neuromuscular agents has occurred in patients receiving chronic carbamazepine and/or phenytoin therapy, leading to a lengthening of the time needed to achieve adequate skeletal muscle relaxation and to significantly accelerated recovery from an initial or supplemental dose)


Dantrolene or{23}{41}
Furosemide or{23}{41}
Lithium or{01}{23}{24}
Magnesium salts, parenteral, or{01}{23}{24}
» Procainamide or{01}{24}
» Quinidine{01}{23}{24}    (these medications may enhance and/or prolong the effects of neuromuscular blocking agents)


Neuromuscular blocking agents, other    (prior administration of succinylcholine [for endotracheal intubation] has caused potentiation of some of the other nondepolarizing neuromuscular blocking agents; although the effect of succinylcholine administration on subsequent administration of mivacurium has not been studied, it is recommended that mivacurium not be administered until after spontaneous recovery from succinylcholine has begun {01})

    (use of subparalyzing doses of mivacurium prior to succinylcholine, to attenuate some of succinylcholine's adverse effects, has not been studied {01})

    (administration of mivacurium after administration of atracurium, pancuronium, rocuronium, or vecuronium results in a longer duration of action of mivacurium {57} {58} {59} {60} {61} {62}; this effect may be the most pronounced in geriatric patients, and least pronounced in children {65})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Note: Medical problems that may lead to enhanced neuromuscular blockade may result in prolonged paralysis, prolonged respiratory impairment, and/or difficulty in reversal. With the exception of medical conditions associated with a reduction of the concentration or activity of plasma cholinesterase, such medical problems may be less troublesome with a short-acting neuromuscular blocking agent such as mivacurium than with longer-acting agents. However, some patients may require unexpectedly prolonged monitoring and ventilatory assistance postoperatively.


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Genetic abnormality, homozygous for atypical cholinesterase gene    (patients with homozygous atypical cholinesterase gene abnormality are extremely sensitive to the effects of mivacurium; in three such patients, a dose of only 30 mcg/kg produced complete neuromuscular block lasting from 26 to 128 minutes, although administration of conventional doses of neostigmine after spontaneous recovery began effectively antagonized the remaining block; in a fourth patient, a dose of 180 mcg/kg produced complete neuromuscular block for about 4 hours, and the patient was not extubated until 8 hours after administration [reversal was not attempted]; it is recommended that an alternative nondepolarizing neuromuscular blocking agent be used instead {37})


Risk-benefit should be considered when the following medical problems exist
Allergy, including asthma, or other conditions predisposing to complications associated with histamine release or
Cardiovascular disease or other conditions in which histamine release–induced hypotension or tachycardia would be particularly hazardous    (it is recommended that initial dosage of mivacurium not exceed 150 mcg/kg, administered over 60 seconds, to decrease the risk of histamine release–related adverse effects {01})


Burns    (although resistance to the effects of nondepolarizing neuromuscular blocking agents has been reported in burn patients {01} {23}, the reduction in plasma cholinesterase activity that may occur in burn patients may prolong the effect of mivacurium {01} {42}; because the effect of mivacurium in these patients may be unpredictable, it is recommended that the response to a test dose of 15 to 20 mcg/kg, as determined via peripheral nerve stimulation, be used as a guide to appropriate dosage {01})


Carcinoma, bronchogenic, or other malignancy    (the duration of action of nondepolarizing neuromuscular agents may be prolonged in patients with bronchogenic carcinoma {24}; also, the reduction in plasma cholinesterase activity that may occur in patients with malignancy {01} {23} may prolong the effect of mivacurium {01})


Dehydration or{28}
Electrolyte or acid-base imbalance{01} , especially:
Hypokalemia    (action of neuromuscular blocking agents may be altered {01}; neuromuscular blockade is usually counteracted by alkalosis and enhanced by acidosis, but mixed imbalances may be present, leading to unpredictable responses {22}; also, the reduction in plasma cholinesterase activity that may occur in dehydrated patients {25} may prolong the effect of mivacurium {01})

    (serum potassium determinations may be advisable prior to administration of a nondepolarizing neuromuscular blocking agent, because hypokalemia tends to enhance the blockade produced by these medications; adjustment of dosage of the neuromuscular blocking agent, or correction of potassium concentration prior to administration, may be needed {31})


» Familial periodic paralysis, hypokalemic or hyperkalemic, or{23}{43}
» Muscular dystrophy or{44}{45}
» Myasthenia gravis{01}{23}{43} or
» Myasthenic syndrome (Eaton-Lambert syndrome){01}{23}{43} or
» Other neuromuscular disease leading to muscle weakness{44}    (risk of severe and prolonged muscle paralysis or weakness is increased; neuromuscular blocking agents are best avoided in patients with familial periodic paralysis or myasthenia gravis [and may not be needed in patients with myasthenia gravis if a volatile anesthetic with potent relaxant properties, such as enflurane or isoflurane, is administered in sufficient quantities] {23}; if a neuromuscular blocking agent is needed for these patients, mivacurium may be preferable to longer-acting agents, but caution is recommended {01} {10}; patient response to a test dose of 15 to 20 mcg/kg, as determined via peripheral nerve stimulation, should be used as a guide to appropriate dosage {01})


» Genetic abnormality, heterozygous for atypical cholinesterase gene{01}{23}{25}{66} , or
Other conditions in which plasma cholinesterase activity may be substantially reduced, such as:
Anemia, severe{01}{25}
Exposure to neurotoxic insecticides or other cholinesterase inhibitors{23}{25}
Hepatic disease, severe or chronic, including hepatic cirrhosis{01}{23}{25}
Malnutrition{25}
Pregnancy{01}{23}{25}    (effects of mivacurium may be enhanced and/or prolonged {01} {10}, especially when plasma cholinesterase activity is reduced to 50% or less of normal {39}; in most patients, the time to 25% recovery of the twitch response to peripheral stimulation [T 25] is prolonged [by 8 to 11 minutes following doses of 100 to 200 mcg/kg in patients with heterozygous gene abnormality, compared with genotypically normal patients] {01}, but not the time from 25% to 75% recovery [T 25-75] {10}; although mivacurium has been used safely in patients with reduced plasma cholinesterase activity {01} {10}, it is recommended that the response to a test dose of 15 to 20 mcg/kg, as determined via peripheral nerve stimulation, be used as a guide to appropriate dosage {45})


Hypothermia    (intensity and duration of action of nondepolarizing neuromuscular blocking agents may be increased {32})


Obesity    (the risk of a > 30% decrease in mean arterial blood pressure is increased in obese patients receiving doses calculated on the basis of actual body weight; it is recommended that dosage for these patients be calculated on the basis of ideal body weight {01})


Pulmonary function impairment or
Respiratory depression    (risk of additive respiratory depression or impairment {25})


Sensitivity to mivacurium{01}


Side/Adverse Effects

Note: Mivacurium failed to trigger malignant hyperthermia in a study in malignant hyperthermia–susceptible swine. Whether mivacurium may precipitate malignant hyperthermia in susceptible humans has not been assessed {01}.
Bradycardia may occur during mivacurium-assisted anesthesia, but is not likely to be a direct effect of the medication. Because mivacurium (unlike gallium and pancuronium) {25} does not have vagolytic activity, it does not counteract bradycardia induced by other medications (e.g., anesthetics, opioid analgesics) or vagal stimulation {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Hypotension{01}

Incidence rare (1% or less)
    
Bronchospasm{01}
    
cardiac arrhythmia{01}
    
erythema{01}
    
hypoxemia{01}
    
injection site reaction{01}
    
phlebitis{01}
    
skin rash{01}
    
tachycardia{01}
    
urticaria{01}
    
wheezing{01}
Note: Hypotension, tachycardia, bronchospasm, and/or wheezing may result from mivacurium-induced histamine release, which may occur when large initial doses of the medication are administered rapidly {69}. In most patients, these effects last only a few minutes and do not require treatment {01} {06} {12} {13} {17} {18} {69}. In clinical trials, hypotension requiring treatment occurred in 1 to 2% of patients receiving > 200 mcg per kg of body weight (mcg/kg) of mivacurium over 5 to 15 seconds, and 2 to 4% of cardiac surgery patients receiving > 200 mcg/kg over 60 seconds, but did not occur with doses of 150 mcg/kg or less {01}.
Hypotension may also occur during mivacurium-assisted surgery because mivacurium does not counteract the hypotensive effects of other medications or vagal stimulation {01}.





Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare
    
Dizziness{01}
    
muscle spasm{01}



Those not indicating need for medical attention
Incidence more frequent
    
Flushing{01} —incidence 15 to 20%
Note: Flushing occurs mostly when initial doses of 150 mcg/kg or higher are administered over 5 to 15 seconds. It usually appears within 1 to 2 minutes after administration and persists for 3 to 5 minutes {01}.







Overdose
For specific information on the agents used in the management of mivacurium overdose, see:
   • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Edrophonium (Systemic) monograph;
   • Glycopyrrolate in Anticholinergics/Antispasmodics (Systemic) monograph; and/or
   • Neostigmine in Antimyasthenics (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

For treatment of overdose


Specific treatment:
Because of mivacurium's short duration of action, administration of a reversal agent may not be necessary, or may not speed recovery to a clinically significant extent {02} {12}. However, an anticholinesterase agent, e.g., neostigmine or edrophonium, may be administered if needed. Use of an antagonist is an adjunct to, and not a substitute for, measures to ensure adequate ventilation. Ventilatory assistance must be continued until the patient can maintain an adequate ventilatory exchange unassisted {25}. A suitable antimuscarinic agent (e.g., atropine, glycopyrrolate) should be administered prior to or concurrently with the antagonist to counteract its muscarinic side effects {25} {34} {35}. It is recommended that reversal agents be administered only after some spontaneous recovery, as demonstrated using a peripheral nerve stimulator, has taken place. In adults, doses of 30 to 64 mcg/kg of neostigmine or 500 mcg/kg of edrophonium, administered at 10% recovery from neuromuscular block, generally produce 95% recovery of the single twitch response, and 75% recovery of the T 4:T 1 ratio (train-of-four stimulation), in about 10 minutes {01}. In children younger than 12 years of age, 300 mcg/kg of edrophonium, administered at 11% or more recovery, produces 95% recovery of the single twitch response in less than 4 minutes {04}. However, recovery may be delayed if the reversal agent is administered in the presence of medications or medical conditions that tend to prolong the effects of mivacurium {01}.



Monitoring:
Determining the degree of the neuromuscular blockade with a peripheral nerve stimulator {25}.



Supportive care:
For hypotension or other adverse hemodynamic effects—Cardiovascular support, e.g., fluid administration, proper positioning of the patient, and/or administration of a vasopressor may be needed {01}.

For apnea or prolonged paralysis—Maintaining an adequate airway and assisting or controlling ventilation. If prolonged paralysis occurs, checking the patient's plasma cholinesterase activity (via determination of dibucaine number and activity) {37}. If the patient's cholinesterase activity is found to be significantly reduced, continued respiratory support, rather than administration of a reversal agent, is recommended {44}.



General Dosing Information
Neuromuscular blocking agents have no clinically significant {30} effect on consciousness or the pain threshold; therefore, when used as an adjunct to surgery, they should always be used with adequate anesthesia {01} or sedation {33}.

Because neuromuscular blocking agents suppress respiration, they should be used only by individuals experienced in tracheal intubation, artificial respiration, and the administration of oxygen under positive pressure; facilities for these procedures should be immediately available {01}.

Mivacurium is intended for intravenous administration only {01}.

The stated doses are intended as a guideline. Actual dosage must be individualized. It is recommended that a peripheral nerve stimulator be used to monitor response, need for additional doses, and reversal {01}.

The ED 95 (dose required to produce maximum [95%] suppression of the adductor pollicis muscle twitch response to ulnar nerve stimulation) is about 70 (range, 60 to 90) mcg per kg of body weight (mcg/kg) in adults {01} and about 100 to 110 mcg/kg in children 2 to 12 years of age (opioid–nitrous oxide–oxygen anesthesia) {01} {04} {09} {11}.

A reduction in initial and maintenance doses of a nondepolarizing neuromuscular blocking agent may be required when it is administered after steady-state anesthesia has been established with a volatile (hydrocarbon) inhalation anesthetic. Halothane may cause less potentiation of mivacurium than desflurane {47}, enflurane {01}, or isoflurane {01}.

A reduction of initial dosage may be advisable for patients in whom histamine release may be hazardous; patients with decreased plasma cholinesterase activity, hepatic or renal disease, burns, severe electrolyte abnormalities, or neuromuscular disease; and other patients in whom there is a risk of potentiation of neuromuscular blockade or difficulty with reversal. Supplemental doses should be titrated according to patient response {01}. A slower rate of administration (i.e., administration of initial doses over 30 to 60 seconds) {01} {06} {14} {17} {18} and/or pretreatment with antihistamines (both H 1- and H 2-receptor blockers) {06} may also decrease the risk to patients who may be harmed by histamine release.

For obese patients (> 30% above ideal body weight for height), dosage of mivacurium should be calculated on the basis of ideal body weight {01}.


Parenteral Dosage Forms

MIVACURIUM INJECTION

Note: Mivacurium injection contains mivacurium chloride, but the dosing and strengths are expressed in terms of mivacurium base.


Usual adult dose
Skeletal muscle paralysis


Initial (for endotracheal intubation and surgical relaxation):
Intravenous, 150 {01} to 200 {42} {48} {49} mcg (0.15 to 0.2 mg) per kg of body weight, administered over five to fifteen seconds, to provide intubating conditions in about two to two and one-half minutes and about fifteen to twenty minutes of clinically effective neuromuscular block (opioid–nitrous oxide–oxygen anesthesia) {01}.

Note: Satisfactory intubating conditions are attained more slowly when initial doses lower than 150 mcg per kg of body weight are administered {01}.
For patients with cardiovascular disease or other patients who may be especially sensitive to histamine release, it is recommended that initial doses of 150 mcg per kg of body weight, or lower, be administered over at least sixty seconds. In most other patients, higher initial doses may be administered when a more rapid onset of action is needed, although the risk of inducing hypotension in some patients must be kept in mind {01}. However, administration of higher initial doses may not reduce the onset of action sufficiently to permit emergency intubation {39}. Initial doses higher than 250 mcg (0.25 mg) per kg of body weight are not recommended {46}.
Initial dosage may be decreased by 25% or more when mivacurium is administered after anesthesia with enflurane or isoflurane has been established {01}. The need for a reduction in initial dosage should also be anticipated after anesthesia with desflurane has been established, but studies to determine the extent to which dosage should be reduced have not been done {47}. A reduction in the initial mivacurium dose may not be needed after anesthesia with halothane has been established {01}.




Maintenance:
Intravenous, to be administered after the twitch response to a previous dose has returned to about 10 to {46} 25% of the control value, or after reappearance of the second twitch response to train-of-four stimulation {36}—About 100 mcg (0.1 mg) per kg of body weight, to provide about fifteen additional minutes of clinically effective block (opioid–nitrous oxide–oxygen anesthesia). Smaller or larger doses may be given as needed to provide shorter or longer durations of action {01}.

Note: Maintenance dosage requirements may be reduced by 25% or more when enflurane or isoflurane is being administered, and by a smaller amount when halothane is being administered {01}. The need for a reduction in maintenance dosage should also be anticipated when desflurane is being administered, but studies to determine the extent to which dosage should be reduced have not been done {47}.
Maintenance doses of mivacurium injection may also be given by intravenous infusion {01}.




Usual pediatric dose
Skeletal muscle paralysis


Infants and children 2 months to 2 years of age:
Initial—Intravenous, 200 to 250 mcg (0.2 to 0.25 mg) per kg of body weight, administered over five to fifteen seconds, to provide maximum blockade in about two minutes and about ten minutes of clinically effective block with intravenous and/or inhalation anesthesia {51} {56}.

Maintenance—Intravenous, as required by clinical circumstances and the desired duration of clinically effective block. Additional doses may be required more frequently than in adults. In a clinical trial in infants the mean mivacurium requirement for 95% neuromuscular block was 820 ± 300 mcg per kg of body weight per hour {52}, and the mean mivacurium requirement for 50% neuromuscular block was 320 ± 150 mcg per kg of body weight per hour {52}.

Note: Mivacurium is not approved by drug regulatory agencies in the United States (i.e., the Food and Drug Administration) or Canada (i.e., the Health Protection Branch) for use in children younger than 2 years of age {01} {50}.




Children 2 to 12 years of age:
Initial—Intravenous, 200 {01} to 250 {42} {48} mcg (0.2 to 0.25 mg) per kg of body weight, administered over five to fifteen seconds, to provide maximum blockade in about two minutes and about ten minutes of clinically effective block (opioid–nitrous oxide–oxygen anesthesia) {01}.

Maintenance—Intravenous, as required by clinical circumstances and the desired duration of clinically effective block. Additional doses may be required more frequently than in adults {01}.



Note: In two studies, the duration of clinical effect of mivacurium with nitrous oxide–halothane–oxygen anesthesia was not significantly different from that produced by the same dose of mivacurium under nitrous oxide–opioid–oxygen anesthesia {04} {09}.
Maintenance doses of mivacurium injection may also be given by intravenous infusion {01}.


Strength(s) usually available
U.S.—


2 mg per mL (Rx) [Mivacron]{01}

Canada—


2 mg per mL (Rx) [Mivacron]{50}

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F), protected from exposure to direct ultraviolet light and from freezing, unless otherwise specified by manufacturer.

Stability:
Mivacurium injection is physically and chemically stable for up to 24 hours when diluted to 500 mcg (0.5 mg) per mL with 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 0.9% sodium chloride injection, lactated Ringer's injection, or 5% dextrose in lactated Ringer's injection and stored in polyvinyl chloride bags at 5 to 25 °C (41 to 77 °F) {01}. After preparation, the diluted solution should be used within 24 hours. Also, the solution should be used for one patient only, and unused portions discarded {01}.

Mivacurium is compatible for Y-site administration with alfentanil, droperidol, fentanyl, midazolam, and sufentanil {01}.

Incompatibilities:
Mivacurium injection should not be admixed with other medications (except for preparation of an infusion solution using a diluent listed under Stability , above). Mivacurium injection is acidic (pH 3.5 to 5.0) and may not be compatible with alkaline solutions (pH > 8.5), such as barbiturate solutions {01}.



Revised: 12/03/1998



References
  1. Mivacron package insert (Glaxo Wellcome—US), Rev 8/98, Rec 9/98.
  1. Savarese JJ, Ali HH, Basta SJ, et al. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). Anesthesiology 1988; 68: 723-32.
  1. Goldhill DR, Whitehead JP, Emmott RS, et al. Neuromuscular and clinical effects of mivacurium chloride in healthy adult patients during nitrous oxide–enflurane anaesthesia. Br J Anaesth 1991; 67: 289-95.
  1. Goudsouzian NG, Alifimoff JK, Eberly C, et al. Neuromuscular and cardiovascular effects of mivacurium in children. Anesthesiology 1989; 70: 237-42.
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  1. Panelist comments; Doxacurium drafts 7/91 and 10/91.
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