Mivacron

MIVACRON- mivacurium chloride solution
AbbVie Inc.

This drug should be administered only by adequately trained individuals familiar with its actions, characteristics, and hazards.

DESCRIPTION

MIVACRON (mivacurium chloride) is a short-acting, nondepolarizing skeletal muscle relaxant for intravenous (IV) administration. Mivacurium chloride is [R -[R *,R *-(E)]]-2,2′-[(1,8-dioxo-4-octene-1,8-diyl)bis(oxy-3,1-propanediyl)]bis[1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]isoquinolinium] dichloride. The molecular formula is C58 H80 Cl2 N2 O14 and the molecular weight is 1100.18. The structural formula is:

Mivacron structure
(click image for full-size original)

The partition coefficient of the compound is 0.015 in a 1-octanol/distilled water system at 25°C.

Mivacurium chloride is a mixture of three stereoisomers: (1R ,1′R , 2S , 2′S ), the trans-trans diester; (1R ,1′R , 2R , 2′S ), the cis-trans diester; and (1R ,1′R , 2R , 2′R ), the cis-cis diester. The trans-trans and cis-trans stereoisomers comprise 92% to 96% of mivacurium chloride and their neuromuscular blocking potencies are not significantly different from each other or from mivacurium chloride. The cis-cis diester has been estimated from studies in cats to have one-tenth the neuromuscular blocking potency of the other two stereoisomers.

MIVACRON Injection is a sterile, non-pyrogenic solution (pH 3.5 to 5) in Water for Injection. Each mL of MIVACRON solution contains 2 mg mivacurium, equivalent to 2.14 mg mivacurium chloride. Hydrochloric acid may have been added to adjust pH.

CLINICAL PHARMACOLOGY

MIVACRON (a mixture of three stereoisomers) binds competitively to cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in a block of neuromuscular transmission. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine.

Pharmacodynamics

The time to maximum neuromuscular block is similar for recommended doses of MIVACRON and intermediate-acting agents (e.g., atracurium), but longer than for the ultra-short-acting agent, succinylcholine. The clinically effective duration of action of MIVACRON (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 MIVACRON is 0.07 mg/kg (range: 0.05 mg/kg to 0.09 mg/kg) in adults receiving opioid/nitrous oxide/oxygen anesthesia. The pharmacodynamics of doses of MIVACRON greater than or equal to ED95 administered over 5 to 15 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 minutes, n = 32) following an initial dose of 0.15 mg/kg MIVACRON and 7 to 8 minutes (range: 4 to 24 minutes, n = 85) following initial doses of 0.2 or 0.25 mg/kg MIVACRON.

Volatile anesthetics may decrease the dosing requirement for MIVACRON 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 MIVACRON 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 MIVACRON, 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).

Table 1. Pharmacodynamic Dose Response During Opioid/Nitrous Oxide/Oxygen Anesthesia
Time to Spontaneous Recovery
Initial Dose of MIVACRON* (mg/kg) Time to Maximum Block (min) 5% Recovery (min) 25% Recovery (min) 95% Recovery§ (min) T4 /T 1 Ratio ≥ 75%§ (min)
Adults
0.07 to 0.1 [n = 47] 4.9 (2-7.6) 11 (7-19) 13 (8-24) 21 (10-36) 21 (10-36)
0.15 [n = 50] 3.3 (1.5-8.8) 13 (6-31) 16 (9-38) 26 (16-41) 26 (15-45)
0.2|| [n = 50] 2.5 (1.2-6) 16 (10-29) 20 (10-36) 31 (15-51) 34 (19-56)
0.25|| [n = 48] 2.3 (1-4.8) 19 (11-29) 23 (14-38) 34 (22-64) 43 (26-75)
Children 2 to 12 Years
0.11 to 0.12 [n = 17] 2.8 (1.2-4.6) 5 (3-9) 7 (4-10)
0.2 [n = 18] 1.9 (1.3-3.3) 7 (3-12) 10 (6-15) 19 (14-26) 16 (12-23)
0.25 [n = 9] 1.6 (1-2.2) 7 (4-9) 9 (5-12)
* Doses administered over 5 to 15 seconds.† Values shown are medians of means from individual studies (range of individual patient values).‡ Clinically effective duration of neuromuscular block.§ Data available for as few as 40% of adults in specific dose groups and for 22% of children in the 0.2 mg/kg dose group due to administration of reversal agents or additional doses of MIVACRON prior to 95% recovery or T4 /T1 ratio recovery to greater than or equal to 75%.|| Rapid administration not recommended due to possibility of decreased blood pressure. Administer 0.2 mg/kg over 30 seconds; administer 0.25 mg/kg as divided dose (0.15 mg/kg followed 30 seconds later by 0.1 mg/kg). (See DOSAGE AND ADMINISTRATION.)

Administration of MIVACRON over 30 to 60 seconds does not alter the time to maximum neuromuscular block or the duration of action. The duration of action of MIVACRON 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 MIVACRON as with other neuromuscular blocking agents. However, analysis of data from 224 patients in clinical studies receiving various doses of MIVACRON 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 co-induction agents such as fentanyl and/or midazolam, doses of 0.15 mg/kg (2 x ED95 ) MIVACRON administered over 5 to 15 seconds or 0.2 mg/kg MIVACRON 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 MIVACRON administered as a divided dose (0.15 mg/kg followed 30 seconds later by 0.1 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 MIVACRON 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 MIVACRON 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).

MIVACRON 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 MIVACRON 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 greater than or equal to 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., greater than 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 MIVACRON 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), MIVACRON has a higher ED95 (0.1 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 0.2 mg/kg MIVACRON. Recovery following reversal is faster in children than in adults (Table 1).

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