Mivacron (Page 6 of 10)

Allergic Reactions

Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents. In addition, inform your patients that severe anaphylactic reactions to neuromuscular blocking agents, including MIVACRON have been reported (see CONTRAINDICATIONS).

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 0.1 to 0.2 mg/kg MIVACRON, the clinically effective duration of action was 8 minutes 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

Long-term studies in animals to evaluate carcinogenic potential of mivacurium have not been completed.

Mutagenesis

Mivacurium was non-mutagenic in the in vitro bacterial reverse mutation assay (Ames assay), the in vitro mouse lymphoma assay, the in vitro human lymphocyte assay, and the in vivo rat bone marrow cytogenetic assay.

Impairment of Fertility

Studies to evaluation the effects of mivacurium on fertility have not been completed.

Pregnancy

Risk Summary

There are no adequate and well-controlled studies of MIVACRON in pregnant women. In animal studies, subcutaneous administration of mivacurium to pregnant rats and mice during organogenesis at doses 0.16 and 0.52 times the human dose of 0.25 mg/kg did not result in any malformations or embryo toxic effects (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

There was no evidence of malformations or embryo toxicity when pregnant mice were administered 0.25 or 0.5 mg/kg mivacurium during organogenesis (0.08 and 0.16 times the human dose of 0.25 mg/kg based on body surface area). These doses were not associated with maternal toxicity.

There was no evidence of malformations or embryo toxicity when pregnant rats were administered 0.4 or 0.8 mg/kg mivacurium during organogenesis (0.26 and 0.52 times the human dose of 0.25 mg/kg based on body surface area). These doses were not associated with maternal toxicity.

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 0.2 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.

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