Pharmacodynamics

The time to maximum neuromuscular block is similar for recommended doses of mivacurium chloride and intermediate-acting agents (e.g., atracurium), but longer than for the ultra-short-acting agent, succinylcholine. The clinically effective duration of action of mivacurium chloride (a mixture of three stereoisomers) is one-third to one-half that of intermediate-acting agents and 2 to 2.5 times that of succinylcholine.

The average ED95 (dose required to produce 95% suppression of the adductor pollicis muscle twitch response to ulnar nerve stimulation) of mivacurium is 0.07 mg/kg (range: 0.05 to 0.09) in adults receiving opioid/nitrous oxide/oxygen anesthesia. The pharmacodynamics of doses of mivacurium ≥ED95 administered over 5 to15 seconds during opioid/nitrous oxide/oxygen anesthesia are summarized in Table 1. The mean time for spontaneous recovery of the twitch response from 25% to 75% of control amplitude is about 6 minutes (range: 3 to 9, n=32) following an initial dose of 0.15 mg/kg mivacurium and 7 to 8 minutes (range: 4 to 24, n=85) following initial doses of 0.20 or 0.25 mg/kg mivacurium.

Volatile anesthetics may decrease the dosing requirement for mivacurium chloride and prolong the duration of action; the magnitude of these effects may be increased as the concentration of the volatile agent is increased. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 MAC [Minimum Alveolar Concentration]) may decrease the effective dose of mivacurium by as much as 25% and may prolong the clinically effective duration of action and decrease the average infusion requirement by as much as 35% to 40%. At equivalent MAC values, halothane has little or no effect on the ED50 of mivacurium, but may prolong the duration of action and decrease the average infusion requirement by as much as 20% (see CLINICAL PHARMACOLOGY: Individualization of Dosages subsection and PRECAUTIONS: Drug Interactions).

Administration of mivacurium over 30 to 60 seconds does not alter the time to maximum neuromuscular block or the duration of action. The duration of action of mivacurium may be prolonged in patients with reduced plasma cholinesterase (pseudocholinesterase) activity (see PRECAUTIONS: Reduced Plasma Cholinesterase Activity and CLINICAL PHARMACOLOGY: Individualization of Dosages subsection).

Interpatient variability in duration of action occurs with mivacurium chloride as with other neuromuscular blocking agents. However, analysis of data from 224 patients in clinical studies receiving various doses of mivacurium during opioid/nitrous oxide/oxygen anesthesia with a variety of premedicants and varying lengths of surgery indicated that approximately 90% of the patients had clinically effective durations of block within 8 minutes of the median duration predicted from the dose-response data shown in Table 1. Variations in plasma cholinesterase activity, including values within the normal range and values as low as 20% below the lower limit of the normal range, were not associated with clinically significant effects on duration. The variability in duration, however, was greater in patients with plasma cholinesterase activity at or slightly below the lower limit of the normal range.

When administered during the induction of adequate anesthesia using thiopental or propofol, nitrous oxide/oxygen, and coinduction agents such as fentanyl and/or midazolam, doses of 0.15 mg/kg (2 × ED95) mivacurium administered over 5 to 15 seconds or 0.20 mg/kg mivacurium administered over 30 seconds produced generally good-to-excellent tracheal intubation conditions in 2.5 to 3 and 2 to 2.5 minutes, respectively. A dose of 0.25 mg/kg mivacurium administered as a divided dose (0.15 mg/kg followed 30 seconds later by 0.10 mg/kg) produced generally good-to-excellent intubation conditions in 1.5 to 2 minutes after initiating the dosing regimen.

Repeated administration of maintenance doses or continuous infusion of mivacurium for up to 2.5 hours is not associated with development of tachyphylaxis or cumulative neuromuscular blocking effects in ASA Physical Status I-II patients. Based on pharmacokinetic studies in 82 adults receiving infusions of mivacurium for longer than 2.5 hours, spontaneous recovery of neuromuscular function after infusion is independent of the duration of infusion and comparable to recovery reported for single doses (Table 1).

Mivacurium chloride was administered as an infusion for as long as 4 to 6 hours in 20 adult patients and 19 geriatric patients. In most patients, after a brief period of adjustment, the rate of mivacurium required to maintain 89% to 99% T1 suppression remained relatively constant over time. There was a subset of patients in each group whose infusion rates did not stabilize quickly and decreased (by ≥30%) over the period of infusion. The rate of spontaneous recovery in these patients was comparable with that of patients having stable infusion rates and not dependent on the duration of infusion. These patients, however, tended to have higher infusion requirements (i.e., >8 mcg/kg/min) during the first 30 minutes of infusion than patients with stable infusion rates, although their final infusion rates were similar to those with stable infusion rates. There were no clinically important differences in infusion rate requirements between geriatric and young patients (see Pharmacokinetics: Special Populations: Geriatric Patients).

The neuromuscular block produced by mivacurium chloride is readily antagonized by anticholinesterase agents. As seen with other nondepolarizing neuromuscular blocking agents, the more profound the neuromuscular block at the time of reversal, the longer the time and the greater the dose of anticholinesterase agent required for recovery of neuromuscular function.

In children (2 to 12 years), mivacurium has a higher ED95 (0.10 mg/kg), faster onset, and shorter duration of action than in adults. The mean time for spontaneous recovery of the twitch response from 25% to 75% of control amplitude is about 5 minutes (n=4) following an initial dose of 0.20 mg/kg mivacurium. Recovery following reversal is faster in children than in adults (Table 1).

Hemodynamics

Administration of mivacurium in doses up to and including 0.15 mg/kg (2 × ED95) over 5 to 15 seconds to ASA Physical Status I-II patients during opioid/nitrous oxide/oxygen anesthesia is associated with minimal changes in mean arterial blood pressure (MAP) or heart rate (HR) (Table 2).

Higher doses of ≥0.20 mg/kg (≥3 × ED95) may be associated with transient decreases in MAP and increases in HR in some patients. These decreases in MAP are usually maximal within 1 to 3 minutes following the dose, typically resolve without treatment in an additional 1 to 3 minutes, and are usually associated with increases in plasma histamine concentration. Decreases in MAP can be minimized by administering mivacurium over 30 to 60 seconds (see CLINICAL PHARMACOLOGY: Individualization of Dosages subsection and PRECAUTIONS: General).

Analysis of 426 patients in clinical studies receiving initial doses of mivacurium up to and including 0.30 mg/kg during opioid/nitrous oxide/oxygen anesthesia showed that high initial doses and a rapid rate of injection contributed to a greater probability of experiencing a decrease of ≥30% in MAP after administration of mivacurium. Obese patients also had a greater probability of experiencing a decrease of ≥30% in MAP when dosed on the basis of actual body weight, thereby receiving a larger dose than if dosed on the basis of ideal body weight (see CLINICAL PHARMACOLOGY): Individualization of Dosages subsection and PRECAUTIONS: General).

Children experience minimal changes in MAP or HR after administration of doses of mivacurium up to and including 0.20 mg/kg over 5 to 15 seconds, but higher doses (≥0.25 mg/kg) may be associated with transient decreases in MAP (Table 2).

Following a dose of 0.15 mg/kg mivacurium administered over 60 seconds, adult patients with significant cardiovascular disease undergoing coronary artery bypass grafting or valve replacement procedures showed no clinically important changes in MAP or HR. Transient decreases in MAP were observed in some patients after doses of 0.20 to 0.25 mg/kg mivacurium administered over 60 seconds. The number of patients in whom these decreases in MAP required treatment was small.

Pharmacokinetics

Mivacurium chloride is a mixture of isomers which do not interconvert in vivo. The cis-trans and trans-trans isomers (92% to 96% of the mixture) are equipotent. The steady-state concentrations of the cis-trans and trans-trans isomers doubled after the infusion rate was increased from 5 to 10 mcg/kg/min, indicating that their pharmacokinetics is dose-proportional.

The cis-cis isomer (6% of the mixture) has approximately one-tenth the neuromuscular blocking potency of the trans-trans and cis-trans isomers in cats. Neuromuscular blocking effects due to the cis-cis isomer cannot be ruled out in humans; however, modeling of clinical pharmacokinetic-pharmacodynamic data suggests that the cis-cis isomer produces minimal (<5%) neuromuscular block during a 2-hour infusion. In studies of ASA Physical Status I-II patients receiving infusions of mivacurium lasting as long as 4 to 6 hours, the 5% to 25% and the 25% to 75% recovery indices were independent of the duration of infusion, suggesting that the cis-cis isomer does not affect the rate of post-infusion recovery.

General

Although mivacurium chloride (a mixture of three stereoisomers) is not a potent histamine releaser, the possibility of substantial histamine release must be considered. Release of histamine is related to the dose and speed of injection.

Caution should be exercised in administering mivacurium chloride to patients with clinically significant cardiovascular disease and patients with any history suggesting a greater sensitivity to the release of histamine or related mediators (e.g., asthma). In such patients, the initial dose of mivacurium should be 0.15 mg/kg or less, administered over 60 seconds; assurance of adequate hydration and careful monitoring of hemodynamic status are important (see CLINICAL PHARMACOLOGY: Hemodynamics and Individualization of Dosages).

Obese patients may be more likely to experience clinically significant transient decreases in MAP than non-obese patients when the dose of mivacurium is based on actual rather than ideal body weight. Therefore, in obese patients, the initial dose should be determined using the patient's ideal body weight (see CLINICAL PHARMACOLOGY: Hemodynamics and Individualization of Dosages).

Recommended doses of mivacurium have no clinically significant effects on heart rate; therefore, mivacurium will not counteract the bradycardia produced by many anesthetic agents or by vagal stimulation.

Neuromuscular blocking agents may have a profound effect in patients with neuromuscular diseases (e.g., myasthenia gravis and the myasthenic syndrome). In these and other conditions in which prolonged neuromuscular block is a possibility (e.g., carcinomatosis), the use of a peripheral nerve stimulator and a dose of not more than 0.015 to 0.020 mg/kg mivacurium is recommended to assess the level of neuromuscular block and to monitor dosage requirements (see CLINICAL PHARMACOLOGY: Individualization of Dosages).

Mivacurium chloride has not been studied in patients with burns. Resistance to nondepolarizing neuromuscular blocking agents may develop in patients with burns, depending upon the time elapsed since the injury and the size of the burn. Patients with burns may have reduced plasma cholinesterase activity which may offset this resistance (see CLINICAL PHARMACOLOGY: Individualization of Dosages).

Acid-base and/or serum electrolyte abnormalities may potentiate or antagonize the action of neuromuscular blocking agents. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy (see CLINICAL PHARMACOLOGY: Individualization of Dosages).

No data are available to support the use of mivacurium chloride by intramuscular injection.

Renal and Hepatic Disease

The possibility of prolonged neuromuscular block must be considered when mivacurium is used in patients with renal or hepatic disease (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Most patients with chronic hepatic disease such as hepatitis, liver abscess, and cirrhosis of the liver exhibit a marked reduction in plasma cholinesterase activity. Patients with acute or chronic renal disease may also show a reduction in plasma cholinesterase activity (see CLINICAL PHARMACOLOGY: Individualization of Dosages).

Reduced Plasma Cholinesterase Activity

The possibility of prolonged neuromuscular block following administration of mivacurium chloride must be considered in patients with reduced plasma cholinesterase (pseudocholinesterase) activity.

Plasma cholinesterase activity may be diminished in the presence of genetic abnormalities of plasma cholinesterase (e.g., patients heterozygous or homozygous for the atypical plasma cholinesterase gene), pregnancy, liver or kidney disease, malignant tumors, infections, burns, anemia, decompensated heart disease, peptic ulcer, or myxedema. Plasma cholinesterase activity may also be diminished by chronic administration of oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors and by irreversible inhibitors of plasma cholinesterase (e.g., organophosphate insecticides, echothiophate, and certain antineoplastic drugs).

Mivacurium chloride has been used safely in patients heterozygous for the atypical plasma cholinesterase gene. At doses of 0.10 to 0.20 mg/kg mivacurium chloride, the clinically effective duration of action was 8 to 11 minutes longer in patients heterozygous for the atypical gene than in genotypically normal patients.

As with succinylcholine, patients homozygous for the atypical plasma cholinesterase gene (one in 2500 patients) are extremely sensitive to the neuromuscular blocking effect of mivacurium chloride. In three such adult patients, a small dose of 0.03 mg/kg (approximately the ED10-20 in genotypically normal patients) produced complete neuromuscular block for 26 to 128 minutes. Once spontaneous recovery had begun, neuromuscular block in these patients was antagonized with conventional doses of neostigmine. One adult patient, who was homozygous for the atypical plasma cholinesterase gene, received a dose of 0.18 mg/kg mivacurium and exhibited complete neuromuscular block for about 4 hours. Response to post-tetanic stimulation was present after 4 hours, all four responses to train-of-four stimulation were present after 6 hours, and the patient was extubated after 8 hours. Reversal was not attempted in this patient.

Malignant Hyperthermia (MH)

In a study of MH-susceptible pigs, mivacurium chloride did not trigger MH. Mivacurium chloride has not been studied in MH-susceptible patients. Because MH can develop in the absence of established triggering agents, the clinician should be prepared to recognize and treat MH in any patient undergoing general anesthesia.

Long-Term Use in the Intensive Care Unit (ICU)

No data are available on the long-term use of mivacurium chloride in patients undergoing mechanical ventilation in the ICU.

Drug Interactions

Although mivacurium chloride (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between mivacurium chloride and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of mivacurium chloride.

The use of mivacurium chloride before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied.

There are no clinical data on the use of mivacurium chloride with other nondepolarizing neuromuscular blocking agents.

Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 MAC) decrease the ED50 of mivacurium by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of mivacurium by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of mivacurium may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50, but may prolong the duration of action and decrease the average infusion requirement by as much as 20%.

Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as mivacurium chloride include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of mivacurium chloride may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase (see PRECAUTIONS: Reduced Plasma Cholinesterase Activity subsection).

Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of mivacurium chloride are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and fertility studies have not been performed. Mivacurium chloride was evaluated in a battery of four short-term mutagenicity tests. It was non-mutagenic in the Ames Salmonella assay, the mouse lymphoma assay, the human lymphocyte assay, and the in vivo rat bone marrow cytogenetic assay.

Pregnancy

Labor and Delivery

The use of mivacurium chloride during labor, vaginal delivery, or cesarean section has not been studied in humans and it is not known whether mivacurium chloride administered to the mother has effects on the fetus. Doses of 0.08 and 0.20 mg/kg mivacurium given to female beagles undergoing cesarean section resulted in negligible levels of the stereoisomers in mivacurium chloride in umbilical vessel blood of neonates and no deleterious effects on the puppies.

Nursing Mothers

It is not known whether any of the stereoisomers of mivacurium are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised following administration of mivacurium chloride to a nursing woman.

Pediatric Use

Mivacurium chloride has not been studied in pediatric patients below the age of 2 years (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION for clinical experience and recommendations for use in children 2 to 12 years of age).

Geriatric Use

Mivacurium chloride was safely administered during clinical trials to 64 geriatric (≥65 years) patients, including 31 patients with significant cardiovascular disease (see PRECAUTIONS: General subsection). In general, the clearances of mivacurium chloride are most likely lower, the duration may be longer, the rate of recovery may be slower, therefore, mivacurium chloride requirements may be lower in geriatric patients (see CLINICAL PHARMACOLOGY: Special Populations: Geriatric Patients)

Observed in Clinical Trials

Mivacurium chloride (a mixture of three stereoisomers) was well tolerated during extensive clinical trials in inpatients and outpatients. Prolonged neuromuscular block, which is an important adverse experience associated with neuromuscular blocking agents as a class, was reported as an adverse experience in three of 2074 patients administered mivacurium chloride. The most commonly reported adverse experience following the administration of mivacurium chloride was transient, dose-dependent cutaneous flushing about the face, neck, and/or chest. Flushing was most frequently noted after the initial dose of mivacurium and was reported in about 25% of adult patients who received 0.15 mg/kg mivacurium over 5 to 15 seconds. When present, flushing typically began within 1 to 2 minutes after the dose of mivacurium and lasted for 3 to 5 minutes. Of 105 patients who experienced flushing after 0.15 mg/kg mivacurium, two patients also experienced mild hypotension that was not treated, and one patient experienced moderate wheezing that was successfully treated.

Overall, hypotension was infrequently reported as an adverse experience in the clinical trials of mivacurium. One of 332 (0.3%) healthy adults who received 0.15 mg/kg mivacurium over 5 to 15 seconds and none of 37 cardiac surgery patients who received 0.15 mg/kg mivacurium over 60 seconds were treated for a decrease in blood pressure in association with the administration of mivacurium. One to two percent of healthy adults given ≥0.20 mg/kg mivacurium over 5 to 15 seconds, 2% to 3% of healthy adults given 0.20 mg/kg over 30 seconds, none of 100 healthy adults given 0.25 mg/kg as a divided dose (0.15 mg/kg followed in 30 seconds by 0.10 mg/kg), and 2% to 4% of cardiac surgery patients given ≥0.20 mg/kg over 60 seconds were treated for a decrease in blood pressure. None of the 63 children who received the recommended dose of 0.20 mg/kg mivacurium was treated for a decrease in blood pressure in association with the administration of mivacurium.

The following adverse experiences were reported in patients administered mivacurium (all events judged by investigators during the clinical trials to have a possible causal relationship):

Observed in Clinical Practice

Based on initial clinical practice experience in patients who received mivacurium chloride, spontaneously reported adverse events are uncommon. Some of these events occurred at recommended doses and required treatment.

Antagonism of Neuromuscular Block

ANTAGONISTS (SUCH AS NEOSTIGMINE) SHOULD NOT BE ADMINISTERED WHEN COMPLETE NEUROMUSCULAR BLOCK IS EVIDENT OR SUSPECTED. THE USE OF A PERIPHERAL NERVE STIMULATOR TO EVALUATE RECOVERY AND ANTAGONISM OF NEUROMUSCULAR BLOCK IS RECOMMENDED.

Administration of 0.030 to 0.064 mg/kg neostigmine or 0.5 mg/kg edrophonium at approximately 10% recovery from neuromuscular block (range: 1 to 15) produced 95% recovery of the muscle twitch response and a T4/T1 ratio ≥75% in about 10 minutes. The times from 25% recovery of the muscle twitch response to T4/T1 ratio ≥75% following these doses of antagonists averaged about 7 to 9 minutes. In comparison, average times for spontaneous recovery from 25% to T4/T1 ≥75% were 12 to 13 minutes.

Patients administered antagonists should be evaluated for adequate clinical evidence of antagonism, e.g., 5-second head lift and grip strength. Ventilation must be supported until no longer required.

Antagonism may be delayed in the presence of debilitation, carcinomatosis, and the concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular block or separately cause respiratory depression (see PRECAUTIONS: Drug Interactions). Under such circumstances the management is the same as that of prolonged neuromuscular block (see OVERDOSAGE).

Adults

Children

Infusion Rate Tables

For adults and children the amount of infusion solution required per hour depends upon the clinical requirements of the patient, the concentration of mivacurium in the infusion solution, and the patient's weight. The contribution of the infusion solution to the fluid requirements of the patient must be considered.

Table 8 provides guidelines for delivery in mL/hr (equivalent to microdrops/min when 60 microdrops= 1 mL) of mivacurium chloride injection, equivalent to 2 mg/mL mivacurium.

Mivacurium Chloride Injection Compatibility and Admixtures

Store under refrigeration between 2°C and 8°C (36°F and 46°F). Avoid exposure to direct ultraviolet light. Retain in carton until time of use. DO NOT FREEZE