a=p< 0.03 for comparisons with each early reversal with neostigmine

b=(p=NS)

Hemodynamics

After the administration of RAPLON^TM (rapacuronium bromide) for Injection, dose-related increase in heart rate were observed, peaking within the first few minutes after RAPLON^TM administration. These changes in heart rate were generally mild to moderate and were stable or near baseline levels within 5 to 10 minutes of RAPLON^TM administration. After the administration of RAPLON^TM, dose-related decreases in mean arterial pressure (MAP) were observed. Decreases in MAP occurred after all doses of RAPLON^TM. These changes were observed to peak within 5 minutes after the administration of RAPLON^TM, returning toward baseline by 10 minutes.

Increase in heart rate and decreases in mean blood pressure were also observed in the pediatric population. In neonates, infants, and children treated with RAPLON^TM, the observed changes of increased heart rate and decreased mean blood pressure were generally small in magnitude (see CLINICAL PHARMAOLOGY, Clinical Studies).

Dose-and duration-related adverse ECG changes were observed in non clinical studies in dogs. These changes included prolongation of the QT interval after dosing 2 times per week over 4 weeks, at a total dosage of 18 mg/kg/day given in 3 divided doses, and prolongation of QT interval, sinus arrhythmia, lengthened PR intervals, P wave widening, and AV dissociation following a bolus dose of 27 mg/kg given at 30 minutes after an uneventful first dose of 13.5 mg/kg. In the cat, night bundle branch block pattern and prolonged PR intervals were observed following a bolus dose of 26 mg/kg given at 30 minutes after an uneventful first dose of 13 mg/kg Therefore, potential adverse ECG effects in humans should be considered when RAPLON^TM is given in a high bolus dose or following prolonged infusion.

Electrocardiogram parameters (QT, QT_C, and RR intervals) were assessed in patients during a 15 minute observation period after receiving 1.5 mg/kg RAPLON^TM (n=18) and placebo (n=16) in a European study. Mean QT interval decreases up to 0.015 second from baseline were observed in the RAPLON^TM group while small increases of up to 0.082 second were observed in the placebo group. Mean changes in the QT_C interval during the 15-minute period ranged from a decrease of 0.025 second to an increase of 0.052 second from baseline in the RAPLON^TM group compared to increases of up to 0.04 second in the placebo group. Mean changes in the RR interval ranged from 0.101 to 0.024 second in the RAPLON^TM group and up to 0.113 second in the placebo group. The clinical significance of these changes is unknown.

Histamine Release

Plasma histamine release was assessed following administration of RAPLON^TM (rapacuronium bromide) for Injection (1.0,2.0, and 3.0 mg/kg) in a US study (n=46). Increases in plasma histamine levels peaked at 1 minute following 2.0 and 3.0 mg/kg of RAPLON^TM. The elevation in histamine levels was dose-related; 1/16, 2/15, and 6/15 subjects in the 1.0 mg/kg. 2.0 mg/kg, and 3.0 mg/kg groups, respectively, demonstrated clinically significant elevations of histamine levels (clinical significance defined as > 1 ng/mL or 100% increase from baseline). Two of six patients in the 3.0 mg/kg group with clinically significant elevations of histamine levels had >30% increase in heart rate and >30% decrease in blood pressure after the administration of RAPLON^TM.

Events possibly related to histamine release (e.g., erythema, bronchospasm) occurred in 29 (5.1%) of 564 adult patients in US studies and in 43 (6.8%) of 736 adult patients in European studies.

Intraocular Pressure

In a clinical study, intraocular pressure following a single bolus dose of 1.5 mg/kg of RAPLON^TM (rapacuronium bromide) for Injection (n=8) decreased by a maximum of 15% at 3 minutes.

Data from the in vivo pharmacokinetic studies were used to develop population estimates of the parameters for the subpopulations represented (e.g., geriatric, pediatric, renal insufficiency, and hepatic insufficiency). These population-based estimates and a measure of the estimated variability are contained in the following sections.

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