Description: Mivacurium is a short-acting, nondepolarizing neuromuscular blocking agent. Mivacurium is used to cause skeletal muscle relaxation as an adjunct to general anesthesia or for endotracheal intubation. Mivacurium antagonizes the action of acetylcholine by competitively binding to cholinergic receptors on the motor endplate. Compared to atracurium, another nondepolarizing agent, mivacurium has a similar onset of action, but is shorter acting. Like succinylcholine, an ultra-short acting depolarizing agent, mivacurium is metabolized by plasma cholinesterase and may have a prolonged duration of action in patients with pseudocholinesterase deficiency. The pharmacodynamic effects of mivacurium are dose-dependent. Mivacurium has histamine releasing properties, which increase with the dose and rate of IV administration. Like other neuromuscular blockers, significant variation in patient sensitivity and dosage requirements exist for mivacurium, requiring careful patient selection, dosage titration and monitoring. Mivacurium was approved by the FDA in 1992 and significant revisions were made to the safety labeling in 1998. Mechanism of Action: Mivacurium is a bezylisoquinoline nondepolarizing agent which competitively binds to nicotinic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in blockade of neuromuscular transmission. Blockade of neuromuscular transmission is antagonized by acetylcholinesterase inhibitors, such as neostigmine or edrophonium. Unlike depolarizing agents such as succinylcholine, mivacurium does not stimulate cholinergic receptors. 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. Larger doses increase the risk of developing respiratory depression due to relaxation of the intercostal muscles and diaphragm. Muscle tone returns in the reverse order. Mivacurium does not affect cardiac muscarinic receptors like pancuronium nor block ganglionic nicotinic receptors like d-tubocurarine; thereby minimizing the risk of tachycardia and hypotension. However, mivacurium does have the potential for substantial histamine release. At recommended doses, mivacurium has no significant hemodynamic effects. Increased dose, rapid rate of IV administration, or failure to individualize dosage for patient conditions may increase the risk of histamine-related adverse effects such as hypotension, tachycardia and bronchospasm. Elevations of plasma histamine levels correlate with decreased blood pressure. Like succinylcholine, patients with reduced plasma cholinesterase due to disease or medications (e.g. pseudocholinesterase deficiency) have exaggerated sensitivity to mivacurium, evidenced by prolonged neuromuscular blockade. Pharmacokinetics: Mivacurium is administered intravenously. The onset of action is about 3�6 minutes and duration lasts approximately 15�30 minutes; although substantial variability exists depending on dosage and patient characteristics. Mivacurium is a mixture of three stereoisomers, with 92�96% occurring as the trans-trans and cis-trans diesters which are equipotent in blocking neuromuscular transmission. The cis-cis diester produces minimal (<5%) neuromuscular blocking activity in humans. Like other nondepolarizing neuromuscular blockers, mivacurium is hydrophilic, has a small volume of distribution and is distributed primarily to extracellular fluids. Protein binding of mivacurium has not been evaluated due to rapid hydrolysis in plasma. Like succinylcholine, mivacurium is rapidly metabolized by plasma cholinesterase; however the resulting metabolites are inactive. Unchanged mivacurium is not significantly eliminated via the renal or biliary route. The mean elimination half-lives for the clinically significant trans-trans and cis-trans stereoisomers are 2.0 and 1.8 minutes, respectively, in adults receiving opioid/nitrous oxide/oxygen anesthesia. The low volume of distribution, short half-life and high clearance of the two potent stereoisomers of mivacurium account for its short duration of action. Patients with hepatic dysfunction have significantly increased elimination half-lives and reduced plasma clearance of the two most potent stereoisomers of mivacurium; requiring dosage adjustment. Renal impairment or failure did not alter the pharmacokinetics of the two more potent stereoisomers of mivacurium; however, did prolong the half-lives of the cis-cis isomer and the inactive metabolites of mivacurium. The mivacurium infusion rates required to maintain suppression of neuromuscular transmission were unchanged in this study. Mivacurium infusion rates do not need to be adjusted in renal dysfunction; however, the duration of block may be longer in some patients. At recommended mivacurium doses, the time to maximum neuromuscular blockade is similar to intermediate-acting agents (e.g. atracurium), but longer than the ultra-short-acting agent, succinylcholine. The clinical duration of action of mivacurium is one-third to one-half that of the intermediate-acting agents and 2 to 2.5 times that of succinylcholine. The time to maximum peak and clinical duration are dose-dependent. The average dose required to produce 95% suppression of muscular response to ulnar nerve stimulation (ED95) for mivacurium in adults receiving opioid/nitrous oxide/oxygen anesthesia is approximately 0.7 mg/kg. In children (2 to 12 years), mivacurium has a higher ED95, faster onset, and shorter duration of action than observed for adults. Higher mg/kg doses are required in children and recovery time is faster following reversal.

Indications...Dosage For inpatients and outpatients, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide neuromuscular blockade during surgery or mechanical ventilation: Intravenous Dosage - Intermittent Injection: Adults (Otherwise Healthy): Usual initial dosage for patients without factors requiring dosage adjustment: Initially 0.15 mg/kg (based on ideal body weight) IV over 5�15 seconds. Alternatively, 0.20 mg/kg can be administered IV over 20 seconds or 0.25 mg/kg can be administered in divided doses (0.15 mg/kg followed in 30 seconds by 0.10 mg/kg). Doses above 0.15 mg/kg are either divided or administered more slowly to minimize the potential for histamine release and hypotension. In patients receiving opioid/nitrous oxide/oxygen anesthesia, initiation of maintenance dosage is generally required approximately 15, 20, and 25 minutes following initial doses of 0.15, 0.20, and 0.25 mg/kg, respectively. To maintain neuromuscular blocking effects, a continuous infusion may be administered or an IV injection of approximately 0.10 mg/kg may be repeated based on clinical goals and the response to peripheral nerve stimulation. Maintenance doses of 0.10 mg/kg each are expected to provide an additional 15 minutes of clinically effective block; for shorter or longer durations of action, smaller or larger maintenance doses may be administered. To optimize effective neuromuscular blockade with mivacurium, the amount and timing of further dosage should be adjusted according to clinical criteria and the response to peripheral nerve stimulation. Obese Adults: The dosage of mivacurium should be based on ideal body weight (IBW). Isoflurane or enflurane anesthesia: If steady-state anesthesia is already established, reduce initial dosage by up to 25%. Halothane does not require specific adjustment of the initial dosage, but a small dosage reduction may be considered; halothane may prolong the duration of block. Adults with renal or hepatic disease: Initially, <= 0.15 mg/kg (IBW) administered IV over 5�15 seconds. Adults with cardiac disease, asthma (or other sensitivity to histamine release), or undergoing cardiac surgery: Initially, <= 0.15 mg/kg (IBW) IV over 60 seconds to minimize the potential for adverse effects of histamine release in these patients. Adults with reduced plasma cholinesterase activity: Avoid use in patients homozygous for the atypical plasma cholinesterase gene; consider alternative neuromuscular blocking agents. In heterozygous patients, the initial dosage is <= 0.15 mg/kg over 5�15 seconds (prolonged blocking effects may occur; possibly 10 minutes longer than in patients with normal genotype). Adults with neuromuscular disease, who are debilitated or cachectic, or have carcinomatosis (ie. small cell carcinoma): Use great caution in these patients. The manufacturer recommends an IV test dose <= 0.015�0.020 mg/kg (IBW), followed peripheral nerve stimulator monitoring to guide further dosage. Patients with burns: An IV test dose <= 0.015�0.020 mg/kg (IBW) is recommended, followed peripheral nerve stimulator monitoring to guide further dosage. Drug interactions: Dosage requirements may be altered by drugs which potentiate or antagonize nondepolarizing neuromuscular blockers (see Drug Interactions section) Children 2�12 years of age (Otherwise Healthy): Initially, 0.20 mg/kg (IBW) IV over 5�15 seconds. This regimen provides clinically effective block in about 2 minutes (1�3 minutes) which lasts for approximately 10 minutes (6 to 15 minutes) in children receiving opioid/nitrous oxide/oxygen anesthesia. Larger mg/kg doses are required at greater frequency in children to maintain effective block. Intravenous Dosage - Continuous Infusion: Adults (Otherwise Healthy): Usual infusion rates for patients without factors requiring dosage adjustment: A continuous IV infusion rate of 4 �g/kg/minute following the initial IV injection may be used to maintain neuromuscular block. Upon evidence of early spontaneous recovery from the initial dose, the continuous infusion rate may need to be increased to 9�10 �g/kg/minute. An average infusion rate of 5 to 7 �g/kg/minute is expected to maintain 89�99% neuromuscular block in adults receiving opioid/nitrous oxide/oxygen anesthesia. To optimize effective neuromuscular blockade with mivacurium, the amount and timing of further dosage should be adjusted according to clinical criteria and the response to peripheral nerve stimulation. Obese adults: Dosage rate should be based on ideal body weight (IBW). Isoflurane or enflurane anesthesia: Initial infusion rate may be reduced by <= 35�40%. Halothane anesthesia: Initial infusion rate should be reduced by <= 20%. Adults with hepatic disease: Reduce initial infusion rate, depending on the degree of hepatic impairment. Adults with renal disease: Renal disease does not require infusion adjustment; but dosage should be monitored by peripheral nerve stimulation. Adults with cardiac disease or asthma: No dosage adjustment is necessary. Adults with reduced plasma cholinesterase activity: Avoid use in patients homozygous for the atypical plasma cholinesterase gene. Heterozygous patients require reduced infusion rates. Adults with neuromuscular disease, who are debilitated or cachectic, or have carcinomatosis: Refer to dosage for intermittent injection. Adults with burns: Refer to dosage for intermittent injection. Drug interactions: Dosage requirements may be altered by drugs which potentiate or antagonize nondepolarizing neuromuscular blockers (see Drug Interactions section) Children 2�12 years of age (Otherwise Healthy): The average maintenance infusion rate is 14 (range 5�31) �g/kg/min. Doses as high as 31 �g/kg/min have been used. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment based on CrCl are not available. The initial dosage for IV injection should not exceed 0.15 mg/kg over 5�15 seconds. No specific infusion rate adjustments are necessary for patients; however, mivacurium dosage should be individualized based on the response to peripheral nerve stimulation. Intermittent hemodialysis: The effects of hemofiltration, hemodialysis, and hemoperfusion on the plasma levels of mivacurium and its metabolites are unknown.

Administration NOTE: The dosage information below is intended as a guide only. Doses of mivacurium should be individualized. Patient factors which may warrant dosage adjustment include but may not be limited to: age, significant renal, hepatic, or cardiac disease; burns, obesity, asthma, reduction in plasma cholinesterase activity, neuromuscular disease, potential for drug interactions, and use with inhalational anesthestics. Use of a peripheral nerve stimulator will permit the most advantageous use of mivacurium, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery. Only experienced clinicians, familiar with the use of neuromuscular blocking drugs, should administer or supervise the use of mivacurium. Intravenous Administration �To avoid distress to the patient, mivacurium should be administered only after unconsciousness has been induced. �Visually inspect parenteral products for particulate matter and discoloration prior to administration. Solutions which are not clear and colorless should not be used. �Administer by slow IV injection or by continuous IV infusion. The rate of IV injection should be carefully adjusted for indication, age, dosage (mg/kg), and coexisting disease states (e.g. cardiovascular disease, asthma, or history of sensitivity to histamine release). For continuous IV infusion, mivacurium may be diluted to a concentration of 0.5 mg/ml in NS, D5W, LR, D5LR, or D5NS for single patient use; discard unused admixture solution after 24 hours. The manufacturer provides infusion rate guidelines for experienced clinicians to administer undiluted mivacurium (2 mg/ml) during opioid/nitrous oxide/oxygen anesthesia. �Doses of mivacurium should be individualized. Adjust the rate of infusion according to patient response and clinical requirements. A peripheral nerve stimulator is recommended to monitor neuromuscular blocking effects. �Mivacurium should be stored at room temperature (15�25 degreesC; 59�77 degreesF). Avoid exposure to direct ultraviolet light. Do not freeze.

Contraindications NOTE: Mivacurium does not cause sedation or analgesia and should be administered only after unconsciousness has been induced. Doses of mivacurium should be individualized. Use of a peripheral nerve stimulator will permit the most advantageous use of mivacurium, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery. 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 (Eaton Lambert syndrome; originally associated with lung cancer), myopathy, or any other neuromuscular disease. Mivacurium should be used with extreme caution in patients with these conditions. Pathophysiologic states that potentiate the pharmacological actions of nondepolarizing neuromuscular blockers 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). Mivacurium should be used with caution in patients with reduced plasma cholinesterase activity (also see Drug Interactions); prolonged and exaggerated neuromuscular blockade may occur due to decreased elimination of mivacurium. Reduced plasma cholinesterase activity may occur in patients with genetic pseudocholinesterase deficiency, malignant tumors, infections, anemia, decompensated heart disease, peptic ulcer, myxedema, hepatic disease or renal disease. Mivacurium should be avoided in patients who are homozygous for the atypical plasma cholinesterase gene; three such patients demonstrated markedly prolonged neuromuscular block at one-fifth the usual dose of mivacurium. The effective duration of mivacurium blockade was prolonged by about 1.5 times longer in patients with end-stage kidney disease and approximately 3 times longer in patients with end-stage hepatic disease. Patients with renal disease generally do not require adjustments of the maintenance infusion rate of mivacurium, but some patients may have a prolonged duration of neuromuscular blockade or slower recovery. Patients with hepatic dysfunction have significantly increased elimination half-lives of the two more potent stereoisomers of mivacurium. Decreased maintenance infusion rates are required in patients with liver disease, depending on the degreee of hepatic impairment. Mivacurium should be used with caution in any condition in which a significant release of histamine may be contraindicated (e.g., cardiac disease or asthma). Mivacurium has substantial potential to produce histamine release; with increased risk for hypotension and tachycardia in patients with cardiac disease. Histamine release and the risk of hypotension increases with higher mivacurium dosages or rates of IV injection. Histamine release can also result in excessive salivation, which may exacerbate asthma or bronchospasm. Obese patients are more likely to experience clinically significant transient hypotension than non-obese patients when mivacurium is based on actual rather than ideal body weight. Mivacurium is minimally lipophilic and distributes primarily to extracellular fluid. Dosage should be adjusted based on ideal body weight in obesity. Mivacurium has not been studied in burn patients. Patients with significant burns may develop resistance to nondepolarizing neuromuscular blockers, via upregulation of aceylcholine receptors at the neuromuscular junction. Theoretically, this could increase the dosage requirements for mivacurium, however burn patient may also have reduced plasma cholinesterase activity which could prolong the actions of mivacurium. Therefore, the manufacturer recommends a test dose of mivacurium followed by dosage which is guided by peripheral nerve stimulator monitoring. Neuromuscular blocking agents can cause respiratory paralysis as a result of respiratory depression and should be used with caution in patients with pulmonary disease such as COPD. High dose corticosteroid therapy has resulted in persistent paralysis with myopathy in some patients receiving concomitant therapy with nondepolarizing neuromuscular blockers. This reaction has primarily been reported with steroidal neuromuscular blockers (e.g. vecuronium and pancuronium); the exact mechanism is not known. Patients with a familial history of malignant hyperthermia (MH) should be treated 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. Mivacurium has not been studied in MH-susceptible patients; however, malignant hyperthermia did not develop in a study of mivacurium in MH-susceptible pigs. The multiple dose vials of mivacurium contain benzyl alcohol which can cause adverse effects in neonates or in other patients with a benzyl alcohol hypersensitivity. The single dose vials lack benzyl alcohol. Mivacurium is rated as FDA pregnancy risk category C. There are no adequate, well-controlled trials in pregnant women; mivacurium should be used in pregnancy only when the potential benefit outweighs the potential risk to the fetus. Pregnancy may also reduce plasma cholinesterase activity, which could reduce the clearance of mivacurium. Mivacurium should be used with caution in women who are breast-feeding. It is not known if any of the mivacurium stereoisomers are excreted in breast milk.

Interactions Inhaled general anesthetics decrease the dose requirement and prolong the neuromuscular blocking action of mivacurium; with the greatest interaction observed with isoflurane and enflurane compared to halothane. Inhalational anesthetics act synergistically with competitive neuromuscular blockers by stabilizing the postjunctional membrane. Cholinesterase inhibitors such as neostigmine and edrophonium, may be used to antagonize the neuromuscular blocking effects of mivacurium. These agents should not be used when complete neuromuscular block is evident or suspected. Once evidence of neuromuscular recovery is observed, further recovery may be facilitated by administration of neostigmine or edrophonium. Calcium salts may antagonize the neuromuscular blocking effects of mivacurium. Antibiotics, local anesthetics, and cardiovascular drugs which independently induce neuromuscular blockade may potentiate the neuromuscular effects of nondepolarizing agents. These agents include aminoglycosides, tetracyclines, clindamycin, lincomycin, streptomycin, vancomycin, bacitracin, polymyxin B, capreomycin, colistin, colistimethate, lidocaine, procaine, procainamide and quinidine. Some evidence exists that calcium-channel blockers prolong neuromuscular blockade, but further data are required to confirm this observation. Chronic antiepileptic drug therapy with carbamazepine or 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/or hepatic enzyme induction effects of phenytoin and carbamazepine. The effects of these agents on mivacurium are unknown, but higher infusion rate requirements may be anticipated. Drugs that reduce the plasma concentrations or the activity of plasma cholinesterase may potentiate the neuromuscular blocking actions of mivacurium, which is eliminated by plasma cholinesterase. These agents include chronic administration of oral contraceptives, poisoning with organophosphate insecticides, certain neoplastic drugs (e.g. thiotepa) and echothiophate. Lithium and magnesium salts may potentiate the effects of nondepolarizing neuromuscular blockers. Hypokalemia potentiates neuromuscular blockade with nondepolarizing neuromuscular blockers. Drugs which are associated with a significant risk of hypokalemia should be monitored closely when used with neuromuscular blockers. Drugs which should be monitored for hypokalemia and possible potentiation of neuromuscular blockade include but are not limited to: amphotericin B, cisplatin, corticosteroids, loop diuretics, and thiazide diuretics. Mivacurium in combination with other nondepolarizing neuromuscular blockers may have additive or synergistic effects. The early phase I depolarizing blockade of succinylcholine may be antagonized by nondepolarizing neuromuscular blockers. However, if prolonged administration of succinylcholine results in a nondepolarized block; then the combination of succinylcholine with nondepolarizing neuromuscular blockers can result in augmented blockade. Mivacurium has been administered safely following succinylcholine tracheal intubation; however, evidence of spontaneous recovery from succinylcholine should be established before administering mivacurium. The effects of botulinum toxin type A or botulinum toxin type B can be potentiated by neuromuscular blockers or other drugs that interfere with neuromuscular transmission.

Adverse Reactions Prolonged neuromuscular blockade can occur with mivacurium, and result in muscle paralysis, apnea, or respiratory depression with hypoxemia. Patients at risk for prolonged neuromuscular blockade with mivacurium include those with conditions or receiving medications that impair the underlying neuromuscular function, reduce plasma cholinesterase activity, or potentiate the pharmacological actions of nondepolarizing neuromuscular blockers. Refer to the Contraindications/Precautions and Drug Interactions sections for more specific information. Histamine releasing effects of mivacurium may frequently result in dose-dependent cutaneous flushing (16%). Transient flushing is commonly seen on the face, neck and/or chest. The incidence of flushing is increased with rapid IV administration (e.g. 25% when an initial dose of 0.15 mg/kg was injected over 5�15 seconds in adult patients). Less common effects (<1%) which are potentially related to histamine release include hypotension, sinus tachycardia, cardiac arrhythmias, urticaria, bronchospasm, and wheezing. Hypotension occurs infrequently (< 1%), but the incidence increases in patients with cardiac disease or in patients receiving increased dosage or rate of IV administration. Patients with cardiac disease or undergoing cardiac surgery should receive an injection of mivacurium over 60 seconds to minimize cardiovascular potential adverse effects. Hypotension which required treatment occurred in 2 to 4% of cardiac surgery patients receiving 0.20 mg/kg or more of mivacurium injected IV over 60 seconds. Severe hypotension is rare, however, can occur with overdosage or rapid IV administration rates. Cardiovascular support may be provided by proper patient positioning, fluid administration, and/or vasopressor administration. Other potential adverse events include injection site reaction and maculopapular rash. Other uncommon adverse effects (<1%) with a possible causal relationship include sinus bradycardia, dizziness, and muscle spasms. Since mivacurium does not affect heart rate at recommended doses, unopposed sinus bradycardia may occur in anesthetized patients due to vagal stimulation or specific anesthetic agents. Malignant hyperthermia (MH) did not develop in a study of mivacurium in MH-susceptible pigs; however mivacurium has not been studied in MH-susceptible patients. Because malignant hyperthermia can develop in patients receiving general anesthesia, with or without triggering factors (e.g. succinylcholine), anesthesized patients should be monitored routinely for this condition.

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