Mivacron (Mivacurium Chloride)

MIVACRON®

Glaxo Wellcome

Mivacurium Chloride

Nondepolarizing Skeletal Neuromuscular Blocking Agent

Action And Clinical Pharmacology: Mivacurium is a short-acting, nondepolarizing skeletal neuromuscular blocking agent which is hydrolyzed by plasma cholinesterase. Mivacurium results in a blockade of neuromuscular transmission by binding competitively with cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine.

Pharmacodynamics: The time to maximum neuromuscular block is similar for mivacurium 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 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 response to ulnar nerve stimulation) of mivacurium is 0.07 mg/kg (range: 0.06 to 0.09 mg/kg) in adults receiving opioid/nitrous oxide/oxygen anesthesia. The pharmacodynamics of various doses of ³ED95 administered over 5 to 15 seconds during stable-state opioid/nitrous oxide/oxygen anesthesia are summarized in Table I. Administration of mivacurium over 60 seconds does not alter the time to maximum neuromuscular block or the duration of action.

When administered during the induction of adequate anesthesia using thiopental or propofol, nitrous oxide/oxygen, and co-induction agents such as fentanyl and/or midazolam, doses of 0.15 mg/kg (2´ED95) mivacurium administered over 5 to 15 seconds or 0.2 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. Rapid bolus administration of mivacurium at doses of 0.20 and 0.25 mg/kg should be avoided, as these doses may be associated with transient decreases in mean arterial blood pressure (MAP) and increases in heart rate (HR) in some patients (see Hemodynamics and Dosage).

Tachyphylaxis or cumulative neuromuscular blocking effects are not observed when mivacurium is administered as repeated maintenance doses or as a continuous infusion for up to 2.5 hours in ASA Physical Status I-II patients. Spontaneous recovery after infusion is independent of the duration of infusion and comparable to recovery reported for single doses. Limited data are available from patients receiving infusions of mivacurium for longer than 2.5 hours.

Mivacurium has a higher ED95 (0.1 mg/kg), faster onset, shorter duration of action, and more rapid recovery time in 2 to 12 year-old children than in adults (see Table I). Under conditions of opioid/nitrous oxide/oxygen anesthesia, the time to maximum neuromuscular block for 0.2 mg/kg mivacurium in children is approximately 80 seconds faster than the time for an equipotent dose (0.15 mg/kg) in adults. Recovery following reversal is faster in children than in adults. In children, 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 0.2 mg/kg mivacurium.

Antagonism: The neuromuscular block produced by mivacurium is readily antagonized by anticholinesterase agents. The deeper the level of neuromuscular block at reversal, the longer the time required for recovery of neuromuscular function and the greater the dose of anticholinesterase agent required. Because spontaneous recovery after mivacurium is rapid, routine reversal may not always result in a clinical benefit.

Histamine Release: Like certain other benzylisoquinoline compounds, mivacurium has a tendency to release histamine, particularly at higher doses. Plasma histamine levels generally peak within the first few minutes following the initial mivacurium bolus injection and return toward baseline by 5 minutes post-injection. In clinical trials, the histamine release response was reduced when 0.2 and 0.25 mg/kg doses were administered slowly over 30 or 60 seconds. Administration of the 0.15 mg/kg dose at injection rates slower than 5 to 15 seconds has not been studied for effects on histamine release, but may be expected to result in a diminished occurrence of this reaction.

Hemodynamics: Mivacurium-induced histamine release is sometimes associated with decreases in mean arterial blood pressure (MAP) and increases in heart rate (HR). For patients receiving bolus doses of 0.15 mg/kg mivacurium over 5 to 15 seconds during clinical trials, average mean arterial blood pressure values at the time of maximal change during the first 5 minutes post-injection were in the range of 88 to 102% of pre-injection values. At higher doses of 0.2 to 0.3 mg/kg delivered over 5 to 15 seconds, transient decreases in mean arterial blood pressure of 20% or more were reported in 45 to 85% of patients (see Adverse Effects). These decreases in mean arterial pressure were usually maximal within 1 to 3 minutes following the dose and typically resolved without treatment in an additional 1 to 3 minutes, although pharmacological intervention was occasionally necessary. Owing to the increased incidence of decreases in mean arterial blood pressure at doses of 0.2 to 0.3 mg/kg, rapid bolus administration of these doses in routine clinical practice should be avoided. Decreases in mean arterial pressure are diminished by administering mivacurium slowly over 30 to 60 seconds (see Dosage).

Children experience minimal changes in MAP or HR after administration of £0.2 mg/kg mivacurium over 5 to 15 seconds. Higher doses (³0.25 mg/kg) may be associated with transient decreases in MAP in some children.

In patients with cardiovascular disease undergoing coronary artery bypass grafting or valve replacement procedures, mivacurium was associated with few changes in MAP or HR when administered as a 0.15 mg/kg dose over 60 seconds. Higher doses (0.2 to 0.25 mg/kg) administered over 60 seconds were associated with transient decreases in MAP in some patients. More rapid administrations of mivacurium have not been studied in this patient population.

Pharmacokinetics: The mean elimination half-life of mivacurium ranges from 1.7 to 2.6 minutes in healthy, young adults administered 0.1 to 0.25 mg/kg mivacurium. Mean plasma clearance rates range from 40 to 70 mL/min/kg and mean steady-state volume of distribution values range from 0.08 to 0.11 L/kg. The short elimination half-life and high clearance are consistent with the short duration of action of mivacurium.

Geriatrics: Pharmacokinetic parameters in 9 healthy elderly patients (68 to 77 years) administered 0.1 mg/kg mivacurium were not significantly different from those of 9 healthy young adults (21 to 47 years). However, the onset of maximum twitch suppression was delayed by approximately 1 to 2 minutes (n=8). The clinically effective duration of action of 0.1 mg/kg mivacurium averaged 3 to 4 minutes longer in elderly patients than in young adults.

Renal Impairment: Pharmacokinetic parameters were not significantly different in 9 patients with end-stage kidney disease undergoing kidney transplant surgery and 8 control patients with normal renal function. However, average times from injection of 0.15 mg/kg mivacurium to 25 and 95% recovery were longer in patients with end-stage kidney disease than in patients with normal renal function.

Hepatic Impairment: In 9 patients with end-stage liver disease undergoing liver transplant surgery, plasma clearance was approximately 50% lower than that in 8 control patients with normal hepatic function, while the elimination half-life increased to 4.4 minutes from the 1.8 minute control value. Average times from injection of 0.15 mg/kg mivacurium to 25 and 95% recovery were longer in patients with end-stage liver disease (n=8) than in patients with normal hepatic function. The longer duration of action in patients with end-stage liver disease is likely related to the markedly decreased plasma cholinesterase activity (30% of healthy patient values).

Stereochemistry: Mivacurium is a mixture of three stereoisomers: the trans-trans diester, the cis-trans diester, and the cis-cis diester. These isomers do not interconvert in vivo. The two more potent isomers, cis-trans (36% of the mixture) and trans-trans (57% of the mixture), have very high clearance rates that exceed cardiac output, reflecting the extensive metabolism by plasma cholinesterase. The volume of distribution is relatively small, reflecting limited tissue distribution secondary to the polarity and large molecular weight of mivacurium. The combination of high metabolic clearance and low distribution volume results in a short elimination half-life of approximately 2 minutes for the two active isomers. These findings are consistent with the short duration of action of mivacurium. The pharmacokinetics of these isomers appeared to be dose-proportional as the steady-state concentrations of the cis-trans and trans-trans isomers doubled when the infusion rate was increased from 5 to 10 g/kg/min.

In cats, the cis-cis isomer (6% of the mixture) has approximately one-tenth the neuromuscular blocking potency of the trans-trans and cis-trans isomers. The neuromuscular blocking potency of the cis-cis isomer in humans has not been established; however, modeling of clinical pharmacokinetic/pharmacodynamic data suggests that the cis-cis isomer produces minimal (
Metabolism and Excretion: Hydrolysis by plasma cholinesterase is the primary mechanism for inactivation of mivacurium and yields a quaternary monoester, a quaternary alcohol and a dicarboxylic acid. Tests in which these metabolites were administered to cats and dogs suggest that each metabolite is unlikely to produce significant neuromuscular, autonomic, or cardiovascular effects following administration of mivacurium. Little mivacurium is excreted unchanged in urine and bile, but urine and bile are important elimination pathways for the metabolites. In young adults, approximately 40 to 50% of an administered dose is excreted in the urine within 5 to 6 hours, while in the elderly approximately 30% of the total dose is excreted within this time span. High metabolite concentrations (412 to 1 832 times the simultaneously determined plasma concentration) were found in samples of bile approximately 70 to 90 minutes after an initial dose of mivacurium in patients undergoing cholecystectomy.

Indications And Clinical Uses: As an adjunct to general anesthesia, to facilitate non-emergency tracheal intubation and to provide skeletal muscle relaxation during surgery.

Contra-Indications: Patients with a known hypersensitivity to this or other benzylisoquinolinium compounds or with a history (e.g., severe anaphylactoid reactions or asthma) suggesting the risk of serious adverse reactions in response to histamine release. Multiple-dose vials of Mivacron contain benzyl alcohol, while single-dose vials do not. Use from multiple-dose vials is contraindicated in patients with a known hypersensitivity to benzyl alcohol.

In newborn infants (children less than 1 month in age), benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal. I.V. preparations containing benzyl alcohol should not be used in newborns.

Manufacturers’ Warnings In Clinical States: Mivacurium should be used only by those trained in airway management and respiratory support. Equipment and personnel must be immediately available for tracheal intubation and support of ventilation, including administration of positive pressure oxygen. Adequacy of respiration must be assured through assisted or controlled ventilation. Reversal agents should be immediately available. A peripheral nerve stimulator should be employed to monitor drug response, need for additional relaxant, and adequacy of spontaneous recovery or anticholinesterase antagonism.

General: Mivacurium has no known effect on consciousness, pain threshold, or cerebration. To avoid distress to the patient, neuromuscular block should not be induced before unconsciousness.

Histamine Release: The possibility of substantial histamine release with consequent bronchospasm or anaphylaxis in sensitive individuals must be considered. Particular caution should be observed when considering the use of mivacurium in patients for whom substantial histamine release would be especially hazardous (e.g., patients with clinically significant cardiovascular disease) or in patients with any history suggesting a greater than normal sensitivity to histamine release. Release of histamine is related to the dose and speed of injection. If mivacurium is to be administered to these patients, an initial dose not exceeding 0.15 mg/kg should be administered slowly over 1 minute. Hemodynamic status should be monitored and adequate hydration assured.

Homozygotes for Atypical Plasma Cholinesterase: Mivacurium is not recommended for patients who are known or suspected to be homozygotes for the atypical plasma cholinesterase gene.

Other Diseases and Disorders: In patients who have neuromuscular diseases such as myasthenia gravis or the myasthenic (Eaton-Lambert) syndrome, small doses of neuromuscular blocking agents may have profound effects. For patients having conditions in which prolonged neuromuscular blockade is a possibility (e.g., neuromuscular disease, carcinomatosis, severe cachexia or debilitation), a peripheral nerve stimulator and use of a small test dose (0.015 to 0.02 mg/kg) may be of particular value in monitoring the response to the administration of muscle relaxants.

Mivacurium has not been studied in patients with bronchial asthma or burns or during vaginal delivery or cesarean section. The use of mivacurium in these situations is, therefore, not recommended.

Long-Term Use in the Intensive Care Unit: To reduce the possibility of prolonged neuromuscular blockade and other complications that might occur following long-term use in the ICU, mivacurium or any other neuromuscular blocking agent should be administered in carefully adjusted doses by or under the supervision of experienced clinicians who are familiar with its actions and with appropriate peripheral nerve stimulator muscle monitoring techniques.

Reversal of Neuromuscular Blockade: Evidence of spontaneous recovery from neuromuscular blockade should be observed prior to administration of reversal agents (e.g., neostigmine). The use of a peripheral nerve stimulator to evaluate recovery prior to and during reversal of neuromuscular blockade is strongly recommended.

Compatibility: Mivacurium injection is acidic (pH 3.5 to 5.5) and should not be mixed in the same syringe with highly alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions) or administered simultaneously through the same needle during i.v. infusion. In the presence of an alkaline solution, there is a risk that mivacurium may be inactivated and a free acid precipitated.

Precautions: Cardiovascular Disease: Caution should be exercised in administering mivacurium to patients with clinically significant cardiovascular disease for whom transient decreases in blood pressure would be especially hazardous. In clinical trials, mivacurium has been administered to 106 ASA III and IV patients undergoing coronary artery bypass graft (CABG) and valve replacement procedures during narcotic anesthesia. When administered as a 0.15 mg/kg bolus dose, delivered over 60 seconds, mivacurium did not result in major fluctuations in mean arterial pressure in these patients (mean values 98 to 101% of baseline at 2 minutes post-injection, range 84 to 110%). However, when mivacurium was administered at 0.2 or 0.25 mg/kg doses over 60 seconds, individual patients experienced transient episodes of marked hypotension (see Adverse Effects, Table V). More rapid rates of bolus delivery have not been tested in patients with cardiovascular disease.

In clinical trials in ASA I and II patients, a 0.15 mg/kg dose of mivacurium delivered over 5 to 15 seconds was associated with transient decreases in mean arterial pressure of 20% or more in 21% of patients.

Mivacurium has no clinically significant effect on heart rate at recommended doses and will not counteract the bradycardia produced by many anesthetic agents or by vagal stimulation.

Long-Term Use in the Intensive Care Unit: No information is available concerning the efficacy and safety of long-term (days to weeks) i.v. mivacurium infusion to facilitate mechanical ventilation in the intensive care unit (ICU).

In rare cases, long-term use of other neuromuscular blocking drugs to facilitate mechanical ventilation in ICU settings has been associated with prolonged paralysis and/or skeletal muscle weakness that is first noted during attempts to wean patients from the ventilator. In such patients, neuromuscular blockade may have been enhanced by acid-base or electrolyte imbalances, hypoxic episodes of varying duration, extreme debilitation, and/or concurrent treatment with broad spectrum antibiotics, narcotics and/or steroids. Additionally, patients immobilized for extended periods frequently develop symptoms consistent with disuse muscle atrophy. The recovery picture may vary from regaining movement and strength in all muscles to initial recovery of movement of the facial muscles and small muscles of the extremities then to the remaining muscles. In rare cases recovery may require an extended period of time or even rehabilitation. Therefore, when long-term mechanical ventilation is indicated, the risk-benefit ratio of neuromuscular blockade must be considered.

Whenever the use of mivacurium or any neuromuscular blocking agent is contemplated in the ICU, it is recommended that a peripheral nerve stimulator be used to continuously monitor neuromuscular transmission during administration and recovery. Additional doses of mivacurium or any other neuromuscular blocking agent should not be given before there is a definite response to T1 or to the first twitch. If no response is elicited, the infusion should be discontinued until a response returns.

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 pseudocholinesterase activity which may offset this resistance. Mivacurium has not been studied in patients with burns, but use of a test dose (0.015 to 0.02 mg/kg) is recommended.

Acid-Base or Electrolyte Abnormalities: Acid-base and/or electrolyte abnormalities may antagonize or potentiate the action of neuromuscular blocking agents. For example, hyperkalemia has been reported to antagonize nondepolarizing agents while hypokalemia has been associated with an enhancement of their activity.

Histamine Release: In 11 patients administered a 0.15 mg/kg bolus dose of mivacurium over 5 to 15 seconds, mean plasma histamine levels were increased 1.6-fold (range: 0.5 to 4-fold) at 2 minutes post-injection and returned to near baseline levels at 5 minutes post-injection. At a dose of 0.2 mg/kg delivered over 5 to 15 seconds, mean histamine levels were typically increased 3- to 6-fold at 2 minutes post-injection. When administration of the drug was slowed to 30 seconds, the 0.2 mg/kg dose typically resulted in a 2-fold increase in histamine levels. Slow bolus injections should be considered whenever the risk of histamine release is to be minimized.

I.M. Use: No data are available to support the use of mivacurium by i.m. injection.

Renal and Hepatic Disease: The effects of renal and hepatic dysfunction on the action of mivacurium have been studied in a small number of patients with end-stage kidney (n=9) or liver disease (n=8) undergoing transplantation surgery. For kidney transplant patients, the mean 25 and 95% recovery times were increased by 1.6 and 1.9 times, respectively, over the values obtained in elective surgery patients (n=8). For liver transplant patients, both of these recovery times were tripled. The possibility of prolonged neuromuscular block must be considered when mivacurium is used in patients with renal or hepatic disease. Chronic hepatic diseases such as hepatitis, liver abscess, and cirrhosis of the liver are commonly associated with pronounced reductions in plasma cholinesterase activity. Acute or chronic renal disease may also be associated with reduced plasma cholinesterase activity.

Plasma Cholinesterase Deficiency: The possibility of prolonged neuromuscular block following the administration of mivacurium must be considered in patients with reduced plasma cholinesterase (pseudocholinesterase: PsChE) activity.

PsChE activity may be diminished in the presence of genetic abnormalities of PsChE (e.g., patients heterozygous or homozygous for atypical PsChE), pregnancy, liver or kidney disease, malignant tumors, infections, burns, anemia, decompensated heart disease, peptic ulcer or myxedema. PsChE activity may also be diminished by chronic administration of oral contraceptives, glucocorticoids, or certain MAO inhibitors and by irreversible inhibitors of PsChE (e.g., organophosphate insecticides, echothiophate, and certain antineoplastic drugs). Consideration should be given to administration of a test dose of mivacurium in patients suspected of having a clinically significant reduction of PsChE activity.

Mivacurium has been used safely in patients heterozygous for the atypical plasma cholinesterase gene. In patients with the heterozygous genotype (1 in 40 patients), the mean clinically effective duration of action of 0.1 and 0.2 mg/kg doses is increased by approximately 50%.

As with succinylcholine, patients homozygous for atypical PsChE (1 in 2 500 patients) are extremely sensitive to the neuromuscular blocking effect of mivacurium. In 4 of these patients, a small dose of 0.03 mg/kg produced complete neuromuscular block for 26 to 128 minutes. Once spontaneous recovery had begun, neuromuscular block produced by mivacurium in patients homozygous for atypical PsChE could be antagonized with conventional doses of neostigmine. In 1 adult patient who was homozygous for the atypical plasma cholinesterase gene, a 0.18 mg/kg dose of mivacurium produced complete neuromuscular blockade for about 4 hours. Recovery of all 4 responses to train-of-four stimulation occurred after 6 hours and extubation was performed after 8 hours.

Malignant Hyperthermia: Multiple factors in anesthesia practice are suspected of triggering malignant hyperthermia (MH), a potentially fatal hypermetabolic state of skeletal muscle. Halogenated anesthetic agents and succinylcholine are recognized as the principal pharmacologic triggering agents in MH-susceptible patients; however, since MH can develop in the absence of established triggering agents, the clinician should be prepared to recognize and treat MH in any patient scheduled for general anesthesia. In a study of 8 MH-susceptible pigs, mivacurium did not trigger MH. Mivacurium has not been studied in MH-susceptible patients.

Drug Interactions: Mivacurium has been administered safely following succinylcholine-facilitated tracheal intubation. 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. No information is available on the administration of mivacurium, prior to succinylcholine, to attenuate some of the side effects of succinylcholine (e.g., muscle pain and fasciculations). The administration of mivacurium in conjunction with other non-depolarizing neuromuscular blocking agents, simultaneously or consecutively, has been reported to produce neuromuscular blockade of a degree and duration exceeding that which might be expected from an equipotent total dose of mivacurium. Any synergistic effect may vary between different drug combinations.

A depolarizing muscle relaxant such as succinylcholine should not be administered to prolong the neuromuscular blocking effects of nondepolarizing agents, as this may result in a prolonged and complex block which can be difficult to reverse with anticholinesterase drugs.

Based on data from 2 studies of adult patients receiving isoflurane (n=34) or enflurane (n=32) anesthesia, these agents may decrease the ED50 doses of mivacurium by as much as 25%. Mivacurium bolus doses in the recommended therapeutic range are not potentiated by halogenated anesthetics in a consistent or clinically significant manner. In some clinical studies, infusion requirements were approximately 30% lower during steady-state anesthesia with enflurane or isoflurane than during opioid/nitrous oxide/oxygen anesthesia. Halothane has little or no effect on the ED50 of mivacurium, but may prolong its duration of action and decrease the average infusion requirement in adult patients.

Drugs that may enhance the neuromuscular blocking action of nondepolarizing agents such as mivacurium include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin and sodium colistimethate), magnesium salts, lithium salts, local anesthetics, procainamide and quinidine. The neuromuscular blocking effects of mivacurium may also be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, pancuronium or certain MAO inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase (e.g., organophosphate insecticides, echothiophate, and certain antineoplastic drugs).

Pregnancy: (Teratogenic Effects): Teratology testing in nonventilated pregnant rats and mice revealed no maternal or fetal toxicity or teratogenic effects. However, as mivacurium was administered by the s.c. route at sub-paralyzing doses, the relevance of these studies to the clinical use of the drug cannot be assessed. Because animal reproduction studies have not been performed under conditions that would approximate those of clinical use, mivacurium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no studies of mivacurium in pregnant women.

Labor and Delivery: The use of mivacurium during labor, vaginal delivery or cesarean section has not been studied in humans. Doses of 0.08 and 0.2 mg/kg mivacurium given to 3 female beagles undergoing cesarean section resulted in negligible levels of mivacurium in umbilical vessel blood of neonates and no deleterious effects on the puppies. In humans, it is not known whether mivacurium administered to the mother has effects on the fetus. The possibility that a forceps delivery will be necessary may increase. The possibility of respiratory depression in the neonate should be considered following deliveries during which a neuromuscular blocking agent has been administered. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy.

Lactation: It is not known whether mivacurium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mivacurium is administered to a nursing woman.

Children: For children 2 to 12 years of age, see Pharmacology and Dosage. The safety and efficacy of mivacurium in children below the age of 2 years have not been established.

Geriatrics: Mivacurium has been administered to elderly patients ³65 years of age (n=64), including patients with significant cardiovascular disease (n=31) (see Cardiovascular Disease). The duration of neuromuscular block may be slightly longer in elderly patients (see Pharmacology).

Obesity: Ideal body weight should be considered in dosage calculations for obese patients with appropriate attention to the attendant risk of underdosing. Severe obesity may pose airway or ventilatory problems before, during, or after the use of nondepolarizing neuromuscular blockers.

Increased Volume of Distribution: The onset of action of neuromuscular blocking agents may be delayed in patients in whom the volume of distribution is increased as a result of old age, edematous states, or cardiovascular disease. In these patients, more time should be permitted for the drug to achieve its maximal effect.

Hypothermia: Hypothermia (25 to 28°C) has been associated with a decreased requirement for nondepolarizing neuromuscular blocking agents.

Adverse Reactions: Mivacurium was well tolerated during extensive clinical trials. Prolonged neuromuscular block, which is an important adverse experience associated with neuromuscular blocking agents as a class, was reported as an adverse experience in 3 of 2 074 patients administered mivacurium. In 2 074 patients administered mivacurium in clinical trials, the following adverse experiences were reported (all events judged by investigators during the clinical trials to have a possible causal relationship): incidence >1%: Cardiovascular: flushing (15%). Incidence
Skin flushing, erythema, urticaria, hypotension, tachycardia, wheezing, or bronchospasm associated with the use of mivacurium have been attributed to histamine release. Histamine release is dose related and more common following the rapid administration of initial doses of 0.2 mg/kg or more and can be reduced by injecting mivacurium slowly over 30 to 60 seconds or in divided doses over 30 seconds.

The most commonly reported adverse experience was transient, dose-related cutaneous flushing about the face, neck and/or chest. In clinical trials, flushing was reported in approximately 25% of adult patients who received 0.15 mg/kg over 5 to 15 seconds. Flushing reactions typically had an onset time of 1 to 2 minutes and a duration of 3 to 5 minutes.

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. Treatment for a decrease in blood pressure was reported in 1 to 2% of healthy adults given 0.2 mg/kg mivacurium over 5 to 15 seconds, 2 to 3% of healthy adults given 0.2 mg/kg over 30 seconds, none of 100 healthy adults given 0.25 mg/kg as a divided dose (0.15 mg/kg followed 30 seconds later by 0.1 mg/kg), and 2 to 4% of cardiac surgery patients given ³0.2 mg/kg over 60 seconds. None of 63 children who received the recommended dose of 0.2 mg/kg mivacurium was treated for a decrease in blood pressure in association with the administration of mivacurium.

Observed During Clinical Practice: General: allergic reactions, anaphylactoid reactions (very rarely, severe anaphylactic or anaphylactoid reactions) have been reported. Musculoskeletal: diminished drug effect, prolonged drug effect, re-paralysis following initial cholinesterase-induced reversal. Cardiovascular: hypotension, flushing, edema, angioedema, tachycardia, bradycardia, cardiovascular collapse, cardiac arrest, arrhythmias. Respiratory: bronchospasm, laryngospasm, wheezing. Integumentary: rash, erythema, urticaria.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The possibility of iatrogenic overdosage can be minimized by carefully monitoring the muscle twitch response to peripheral nerve stimulation. Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway and controlled ventilation until recovery of normal respiration is assured. Once evidence of spontaneous recovery from neuromuscular block is observed, further recovery may be facilitated by administration of an anticholinesterase agent (e.g., neostigmine or edrophonium) in conjunction with an appropriate anticholinergic agent. Overdosage may increase the risk of histamine release and hemodynamic side effects, especially decreases in blood pressure. If needed, cardiovascular support may be provided by proper positioning of the patient, fluid administration and/or vasopressor agent administration. A peripheral nerve stimulator should be used to monitor recovery.

Antagonism of Neuromuscular Blockade: Anticholinesterase agents should be used to antagonize neuromuscular blockade only after spontaneous recovery of the muscle twitch response has begun. Antagonists should not be administered if complete neuromuscular blockade is evident or suspected. Owing to the rapid spontaneous recovery from mivacurium-induced neuromuscular blockade, the use of anticholinesterase reversal agents may not always represent a clinically significant advantage in terms of recovery time. However, mivacurium-induced neuromuscular blockade can be antagonized by anticholinesterase agents once spontaneous recovery has begun. As with other nondepolarizing neuromuscular blocking agents, the time required for anticholinesterase-mediated recovery is longer for reversals attempted at deeper levels of blockade.

Administration of 0.03 to 0.064 mg/kg neostigmine or 0.5 mg/kg edrophonium to adults at approximately 10% recovery from neuromuscular block (range: 1 to 15%) produced 95% recovery of the muscle twitch response and a T4/T1 ratio of 75% in about 10 minutes. The time from 25% recovery of the muscle twitch response to T4/T1 ratios of ³75% under these conditions of antagonism averaged about 7 to 9 minutes. In comparison, average times for spontaneous recovery from 25% to a T4/T1 ratio of ³75% were 12 to 13 minutes.

Patients 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. Conditions that may be associated with delayed antagonism include debilitation, carcinomatosis, concomitant use of certain broad spectrum antibiotics, or use of anesthetic agents or other drugs that enhance neuromuscular blockade or depress respiration.

Dosage And Administration: To avoid distress to the patient, mivacurium should not be administered before unconsciousness has been induced. It should not be mixed in the same syringe, or administered simultaneously through the same needle, with alkaline solutions (e.g., barbiturate solutions).

Mivacurium should be administered i.v. only. Do not administer mivacurium by the i.m. route. The dosage information provided below is intended as a guide only. The 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. Dosage requirements may vary and dosage should be individualized. The duration of action of mivacurium may be increased in elderly patients or in patients with renal or hepatic disease. In patients known or suspected of having a significant reduction in plasma cholinesterase activity, consideration should be given to the administration of a small test dose of mivacurium (see Precautions).

When using mivacurium or other neuromuscular blocking agents to facilitate tracheal intubation, it is important to recognize that the most important factors affecting intubation are the depth of general anesthesia and the level of neuromuscular block. Satisfactory intubating conditions can usually be achieved before complete neuromuscular block is attained if there is adequate anesthesia.

When using a stimulator to monitor onset of neuromuscular block, clinical studies have shown that all 4 twitches of the train-of-four response may be present, with little or no fade, at the times recommended for intubation. Therefore, as with other neuromuscular blocking agents, it is important to use other criteria, such as clinical evaluation of the status of relaxation of jaw muscles and vocal cords, in conjunction with peripheral muscle twitch monitoring, to guide the appropriate time of intubation.

The onset of conditions suitable for tracheal intubation occurs earlier after a conventional intubating dose of succinylcholine than after recommended doses of mivacurium.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Adults: Initial Bolus Doses: Doses of 0.15 mg/kg administered over 5 to 15 seconds, 0.2 mg/kg administered over 30 seconds, or 0.25 mg/kg administered in divided doses (0.15 mg/kg followed 30 seconds later by 0.1 mg/kg) are recommended for facilitation of non-emergency tracheal intubation for most patients.

The purpose of slowed or divided dosing of mivacurium at doses above 0.15 mg/kg is to minimize the transient decreases in blood pressure, and other symptoms of histamine release, observed in some patients given these doses over 5 to 15 seconds (see Pharmacology, Precautions and Adverse Effects). The quality of intubation conditions does not significantly differ for the times and doses of mivacurium, but the onset of suitable intubation conditions may be reached earlier with higher doses. The choice of a particular dose and regimen should be based on individual circumstances and patient requirements (see Precautions).

In patients for whom a sudden decrease in blood pressure may prove hazardous (e.g., patients with significant cardiovascular disease) or with any history suggesting a greater sensitivity to histamine release, the dose of mivacurium should be 0.15 mg/kg administered over 60 seconds (see Precautions). No data are available on the use of doses of mivacurium above 0.15 mg/kg in patients with clinically significant kidney or liver disease.

In patients receiving opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg mivacurium typically produces 96 to 100% maximal twitch suppression (range: 53 to 100%) in 3 to 7 minutes (range: 2 to 11 min). Clinically effective neuromuscular block generally lasts for 15 to 20 minutes (range: 8 to 38 min) and spontaneous recovery may be expected to be 95% complete in 25 to 30 minutes (range: 14 to 74 min).

A dose of 0.1 mg/kg produces a mean 96 to 100% maximal twitch suppression in about 4 minutes during balanced anesthesia with a mean clinically effective duration of action of approximately 15 minutes (range: 8 to 24 min).

The expected duration of clinically effective block and the time to 95% spontaneous recovery following 0.2 mg/kg mivacurium are approximately 20 and 30 minutes, respectively, and following 0.25 mg/kg mivacurium are approximately 25 and 35 minutes. Initiation of maintenance dosing during opioid/nitrous oxide/oxygen anesthesia is generally required approximately 15, 20, and 25 minutes following initial mivacurium doses of 0.15, 0.20, and 0.25 mg/kg, respectively. Maintenance doses of 0.1 mg/kg administered to patients at approximately 10% twitch recovery each provide approximately 13 minutes (range: 10 to 19 min) of 95% twitch suppression. For a shorter or longer duration of action, smaller or larger maintenance doses may be administered. 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 (see Pharmacology).

Continuous Infusion: Continuous infusion of mivacurium may be used to maintain neuromuscular block. Upon early evidence of spontaneous recovery from the intial dose, an infusion rate of 9 to 10 g/kg/min counteracts the rapid spontaneous recovery of neuromuscular function in most patients. If continuous infusion is initiated simultaneously with the administration of an initial bolus dose, a lower initial infusion rate should be used (e.g., 4 g/kg/min). In either case, the initial infusion rate should be adjusted according to the response to peripheral nerve stimulation and to clinical criteria. On average, an infusion rate of 6 to 7 g/kg/min (range: 1 to 15 g/kg/min) may be expected to maintain neuromuscular block within the range of 89 to 99% for extended periods in adults receiving opioid/nitrous oxide/oxygen anesthesia. Upon cessation of infusions delivered at these rates, 25% recovery can generally be expected in about 6 to 9 minutes (range: 2 to 45 min) and 95% recovery in 16 to 24 minutes (range: 8 to 34 min).

Children: Mivacurium has not been studied in children under 2 years of age.

Initial Bolus Doses: Dosage requirements for mivacurium on a mg/kg basis are higher in children than in adults. Onset and recovery of neuromuscular block occur more rapidly in children than in adults (see Pharmacology).

The recommended initial dose of mivacurium in children 2 to 12 years of age is 0.2 mg/kg. The use of mivacurium to facilitate endotracheal intubation in children has not been studied. In 18 pediatric patients, an initial dose of 0.2 mg/kg produced maximum block of 95 to 100% in an average of 1.9 minutes (range: 1 to 3 min) and clinically effective block for 10 minutes (range: 6 to 15 min) during stable opioid/nitrous oxide/oxygen anesthesia. Under the same anesthetic conditions, doses of 0.11 to 0.12 mg/kg produced maximum neuromuscular block of 89 to 100% in an average of 2.8 minutes (range 1 to 5 min) and clinically effective block for an average of 7 minutes (range: 4 to 10 min) in 17 pediatric patients. Maintenance doses may be required more frequently in children than in adults. Administration of mivacurium doses above the recommended range (>0.2 mg/kg) is associated with transient decreases in MAP in some children.

Continuous Infusion: Children require higher mivacurium infusion rates than adults. During opioid/nitrous oxide/oxygen anesthesia the infusion rate required to maintain 89 to 99% neuromuscular block averages 14 g/kg/min (range: 5 to 31 g/kg/min). Following cessation of infusion, 25% recovery can typically be expected in 3 to 4 minutes (range: 2 to 11 min) and 95% recovery in 11 to 12 minutes (range 6 to 17 min). The principles for infusion of mivacurium in adults (see above) are also applicable to 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.

Parenteral Products: Mivacron injection should not be mixed with highly alkaline solutions (e.g., barbiturate solutions).

Mivacron injection is compatible with: 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, 5% Dextrose and 0.9% Sodium Chloride Injection USP, Lactated Ringer’s Injection USP and 5% Dextrose in Lactated Ringer’s Injection.

These solutions may be administered simultaneously with Mivacron injection or used to prepare admixtures of Mivacron injection (e.g., 0.5 mg/mL). Compatibility studies with other parenteral products have not been done.

Dilution Stability: Mivacron injection diluted to 0.5 mg mivacurium per mL in the above mentioned diluents is physically and chemically stable when stored in PVC (polyvinyl chloride) bags at room temperature for up to 24 hours. All solutions should be visually inspected for particulate matter and discoloration prior to i.v. administration whenever solution and container permit. Solutions that are not clear and colorless should not be used. Aseptic techniques should be used to avoid microbial contamination of the admixture. Admixtures of Mivacron injection should be prepared for single-patient use only and used within 24 hours of preparation. The unused portion of the admixture should be discarded.

Availability And Storage: Each mL of sterile, nonpyrogenic solution contains: mivacurium chloride equivalent to mivacurium 2 mg in water for injection, pH 3.5 to 5.5. Hydrochloric acid may have been added to adjust pH. Multiple dose vials contain benzyl alcohol 0.9% w/v. Single dose vials of 10 mL, trays of 10. Multiple dose vials of 20 mL, trays of 10. Multiple dose vials of 50 mL, boxes of 1. Store at room temperature of 15 to 25°C. Do not freeze.

MIVACRON® Glaxo Wellcome Mivacurium Chloride Nondepolarizing Skeletal Neuromuscular Blocking Agent

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