WARNINGS
MIVACRON SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED DOSAGE BY OR UNDER THE SUPERVISION OF EXPERIENCED CLINICIANS WHO ARE FAMILIAR WITH THE DRUG'S ACTIONS AND THE POSSIBLE COMPLICATIONS OF ITS USE. THE DRUG SHOULD NOT BE ADMINISTERED UNLESS PERSONNEL AND FACILITIES FOR RESUSCITATION AND LIFE SUPPORT (TRACHEAL INTUBATION, ARTIFICIAL VENTILATION, OXYGEN THERAPY), AND AN ANTAGONIST OF MIVACRON ARE IMMEDIATELY AVAILABLE. IT IS RECOMMENDED THAT A PERIPHERAL NERVE STIMULATOR BE USED TO MEASURE NEUROMUSCULAR FUNCTION DURING THE ADMINISTRATION OF MIVACRON IN ORDER TO MONITOR DRUG EFFECT, DETERMINE THE NEED FOR ADDITIONAL DRUG, AND CONFIRM RECOVERY FROM NEUROMUSCULAR BLOCK.
MIVACRON HAS NO KNOWN EFFECT ON CONSCIOUSNESS, PAIN THRESHOLD, OR CEREBRATION. TO AVOID DISTRESS TO THE PATIENT, NEUROMUSCULAR BLOCK SHOULD NOT BE INDUCED BEFORE UNCONSCIOUSNESS.
MIVACRON IS METABOLIZED BY PLASMA CHOLINESTERASE AND SHOULD BE USED WITH GREAT CAUTION, IF AT ALL, IN PATIENTS KNOWN TO BE OR SUSPECTED OF BEING HOMOZYGOUS FOR THE ATYPICAL PLASMA CHOLINESTERASE GENE.
MIVACRON Injection is acidic (pH 3.5 to 5.0) and may not be compatible with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions).
Multiple-dose vials of MIVACRON contain benzyl alcohol. In newborn infants, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal. Single-use vials do not contain benzyl alcohol (see PRECAUTIONS - Pediatric Use).
PRECAUTIONS
General
Although MIVACRON (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 MIVACRON 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 MIVACRON 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 MIVACRON 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 MIVACRON have no clinically significant effects on heart rate; therefore, MIVACRON 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 MIVACRON is recommended to assess the level of neuromuscular block and to monitor dosage requirements (see CLINICAL PHARMACOLOGY - Individualization of Dosages).
MIVACRON 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 MIVACRON by intramuscular injection.
Renal and Hepatic Disease
The possibility of prolonged neuromuscular block must be considered when MIVACRON 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 MIVACRON 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).
MIVACRON has been used safely in patients heterozygous for the atypical plasma cholinesterase gene. At doses of 0.10 to 0.20 mg/kg MIVACRON, 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 MIVACRON. 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 MIVACRON 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, MIVACRON did not trigger MH. MIVACRON 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 MIVACRON in patients undergoing mechanical ventilation in the ICU.
Drug Interactions
Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON 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 MIVACRON.
The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied.
There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents.
Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 MAC) decrease the ED50 of MIVACRON 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 MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON 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 MIVACRON 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 MIVACRON 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 MIVACRON 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. MIVACRON 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
Teratogenic Effects
Pregnancy Category C
Teratology testing in nonventilated pregnant rats and mice treated subcutaneously with maximum subparalyzing doses of MIVACRON revealed no maternal or fetal toxicity or teratogenic effects. There are no adequate and well-controlled studies of MIVACRON in pregnant women. Because animal studies are not always predictive of human response, and the doses used were subparalyzing, MIVACRON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The use of MIVACRON during labor, vaginal delivery, or cesarean section has not been studied in humans and it is not known whether MIVACRON administered to the mother has effects on the fetus. Doses of 0.08 and 0.20 mg/kg MIVACRON given to female beagles undergoing cesarean section resulted in negligible levels of the stereoisomers in MIVACRON 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 MIVACRON to a nursing woman.
Pediatric Use
MIVACRON 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
MIVACRON 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 MIVACRON are most likely lower, the duration may be longer, the rate of recovery may be slower, therefore, MIVACRON requirements may be lower in geriatric patients (see CLINICAL PHARMACOLOGY - Special Populations - Geriatric Patients).
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