Administration of MIVACRON in doses up to and including 0.15 mg/kg (2 x 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).
|% of Patients With ≥ 30% Change|
|Initial Dose of MIVACRON* (mg/kg)||Dec||Inc||Dec||Inc|
|0.07 to 0.1||[n = 49]||0%||2%||0%||0%|
|0.15||[n = 53]||4%||4%||4%||2%|
|0.2†||[n = 53]||30%||0%||0%||8%|
|0.25†||[n = 44]||39%||2%||0%||14%|
|Children 2 to 12 years|
|0.11 to 0.12||[n = 17]||0%||6%||0%||0%|
|0.2||[n = 17]||0%||0%||0%||0%|
|0.25||[n = 8]||13%||0%||0%||0%|
|* Doses administered over 5 to 15 seconds.† 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.)|
Higher doses of greater than or equal to 0.2 mg/kg (greater than or equal to 3 x 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 MIVACRON 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 MIVACRON up to and including 0.3 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 greater than or equal to 30% in MAP after administration of MIVACRON. Obese patients also had a greater probability of experiencing a decrease of greater than or equal to 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 MIVACRON up to and including 0.2 mg/kg over 5 to 15 seconds, but higher doses (greater than or equal to 0.25 mg/kg) may be associated with transient decreases in MAP (Table 2).
Following a dose of 0.15 mg/kg MIVACRON 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 0.2 to 0.25 mg/kg MIVACRON administered over 60 seconds. The number of patients in whom these decreases in MAP required treatment was small.
MIVACRON 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.
|Parameter||trans-trans isomer||cis-trans isomer|
|Elimination Half-life (t½ min)||2 (1-3.6)||1.8 (0.8-4.8)|
|Volume of Distribution‡ (mL/kg)||147 (67-254)||276 (79-772)|
|Plasma Clearance (mL/min/kg)||53 (26-98)||99 (44-199)|
|* Values shown are mean (range).† Ages 31 to 48 years.‡ Volume of distribution during the terminal elimination phase.|
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 (less than 5%) neuromuscular block during a 2-hour infusion. In studies of ASA Physical Status I-II patients receiving infusions of MIVACRON 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.
The volume of distribution of cis-trans and trans-trans isomers in healthy surgical patients is relatively small, reflecting limited tissue distribution (Table 3). The volume of distribution of cis-cis isomers is also small and averaged 335 mL/kg (range 192 to 523) in the 18 healthy surgical patients whose data are displayed in Table 3. The protein binding of mivacurium has not been determined due to its rapid hydrolysis by plasma cholinesterase.
Enzymatic hydrolysis by plasma cholinesterase is the primary mechanism for inactivation of mivacurium and yields a quaternary alcohol and a quaternary monoester metabolite. Tests in which these two metabolites were administered to cats and dogs suggest that each metabolite is unlikely to produce clinically significant neuromuscular, autonomic, or cardiovascular effects following administration of MIVACRON.
The mean ± S.D. in vitro t½ values of the trans-trans and the cis-trans isomers were 1.3 ± 0.3 and 0.8 ± 0.2 minutes, respectively, in human plasma from healthy male (n = 5) and female (n = 5) volunteers. The mean in vivo t½ values for the more potent trans-trans and cis-trans isomers in healthy surgical patients (Table 3) were similar to those found in vitro , suggesting that hydrolysis by plasma cholinesterase is the predominant elimination pathway for these isomers. The mean ± S.D. in vitro t½ of the less potent cis-cis isomer was 276 ± 130 minutes, while the mean ± S.D. in vivo t½ for the cis-cis isomer in healthy surgical patients was 53 ± 20 minutes. These data suggest that in vivo , pathways other than hydrolysis by plasma cholinesterase contribute to the elimination of the cis-cis isomer.
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