The clinically effective duration of action of 0.15 mg/kg MIVACRON was three times longer in eight patients with end-stage liver disease (undergoing liver transplantation) than in eight healthy patients and is likely related to the markedly decreased plasma cholinesterase activity (30% of healthy patient values) which could decrease the clearance of the trans-trans and cis-trans isomers (see PRECAUTIONS — Reduced Plasma Cholinesterase Activity).
A separate study compared the pharmacokinetics and pharmacodynamics of mivacurium in patients with mild or moderate cirrhosis to healthy adults with normal hepatic function (Table 6). Although the number of patients in each group is small, the CL values of the more potent isomers, trans-trans and cis-trans , are lower in patients with mild to moderate cirrhosis as expected based on the marked decreases in plasma cholinesterase activity in this population (see PRECAUTIONS — Reduced Plasma Cholinesterase Activity).
|Degree of Hepatic Failure|
|Parameter||Isomer||Normal Hepatic Function (n = 10)||Mild Cirrhosis (n = 5)||Moderate Cirrhosis (n = 6)|
|PlasmaClearance(mL/min/kg)||trans-trans isomer||66 (34 — 99)||43 (22 — 64)||31 (11 — 66)|
|cis-trans isomer||124‡ (57 — 218)||73 (34 — 111)||52 (18 — 128)|
|cis-cis isomer||8.6 (4.5 — 13.3)||8.6 (4.5 — 16.7)||5.6 (3.5 — 9.7)|
|Volume ofDistribution† (mL/kg)||trans-trans isomer||204‡ (94 — 269)||221 (118 — 457)||191 (74 — 273)|
|cis-trans isomer||201‡ (89 — 411)||152 (102 — 256)||111 (56 — 164)|
|Half-life (min)||trans-trans isomer||2.4‡ (1.3 — 3.9)||3.7 (1.7 — 5.1)||5.3 (1.7 — 8.5)|
|cis-trans isomer||1.2‡ (0.6 — 2.1)||1.6 (1 — 2.1)||1.9 (0.9 — 3)|
|25% to 75% Recovery Index (min)||7.3 (4.7 — 9.6)||9.5 (5.7 — 12.3)||16.4 (6.3 — 26.2)|
|* Values shown are mean (range).† Volume of distribution during the terminal elimination phase.‡ n = 9§ Not available.|
Doses of MIVACRON should be individualized and a peripheral nerve stimulator should be used to measure neuromuscular function during administration of MIVACRON in order to monitor drug effect, determine the need for additional doses, and confirm recovery from neuromuscular block.
A dose of 0.15 mg/kg MIVACRON is recommended for facilitation of tracheal intubation in patients with renal or hepatic impairment. However, the clinically effective duration of block produced by this dose may be about 1.5 times longer in patients with end-stage kidney disease and about 3 times longer in patients with end-stage liver disease than in patients with normal renal and hepatic function. Infusion rates should be decreased by as much as 50% in patients with hepatic disease depending on the degree of hepatic impairment (see PRECAUTIONS — Renal and Hepatic Disease). No infusion rate adjustments are necessary in patients with renal impairment.
The possibility of prolonged neuromuscular block following administration of MIVACRON must be considered in patients with reduced plasma cholinesterase (pseudocholinesterase) activity. MIVACRON should be used with great caution, if at all, in patients known or suspected of being homozygous for the atypical plasma cholinesterase gene (see WARNINGS). Doses of 0.03 mg/kg produced complete neuromuscular block for 26 to 128 minutes in three such patients; thus initial doses greater than 0.03 mg/kg are not recommended in homozygous patients. Infusions of MIVACRON are not recommended in homozygous patients.
MIVACRON has been used safely in patients heterozygous for the atypical plasma cholinesterase gene and in genotypically normal patients with reduced plasma cholinesterase activity. After an initial dose of 0.15 mg/kg MIVACRON, the clinically effective duration of block in heterozygous patients may be approximately 10 minutes longer than in patients with normal genotype and normal plasma cholinesterase activity. Lower infusion rates of MIVACRON are recommended in these patients (see PRECAUTIONS — Reduced Plasma Cholinesterase Activity).
As with other neuromuscular blocking agents, MIVACRON may have profound neuromuscular blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with carcinomatosis. In these or other patients in whom potentiation of neuromuscular block or difficulty with reversal may be anticipated, the initial dose should be decreased. A test dose of not more than 0.015 to 0.02 mg/kg, which represents the lower end of the dose-response curve for MIVACRON, is recommended in such patients (see PRECAUTIONS — General).
The neuromuscular blocking action of MIVACRON is potentiated by isoflurane or enflurane anesthesia. Recommended initial doses of MIVACRON (see DOSAGE AND ADMINISTRATION) may be used for intubation prior to the administration of these agents. If MIVACRON is first administered after establishment of stable-state isoflurane or enflurane anesthesia (administered with nitrous oxide/oxygen to achieve 1.25 MAC), the initial dose of MIVACRON should be reduced by as much as 25%, and the infusion rate reduced by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking action of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. The use of halothane requires no adjustment of the initial dose of MIVACRON, but may prolong the duration of action and decrease the average infusion rate by as much as 20% (see PRECAUTIONS — Drug Interactions).
When MIVACRON is administered to patients receiving certain antibiotics, magnesium salts, lithium, local anesthetics, procainamide and quinidine, longer durations of neuromuscular block may be expected and infusion requirements may be lower (see PRECAUTIONS — Drug Interactions).
When MIVACRON is administered to patients chronically receiving phenytoin or carbamazepine, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher (see PRECAUTIONS — Drug Interactions).
Severe acid-base and/or electrolyte abnormalities may potentiate or cause resistance to the neuromuscular blocking action of MIVACRON. No data are available in such patients and no dosing recommendations can be made (see PRECAUTIONS — General).
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