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Raplon

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Raplon

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CLINICAL PHARMACOLOGY

RAPLONÒ (rapacuronium bromide) for Injection is a nondepolarizing neuromuscular blocking agent with a rapid onset of action (mean onset approximately 90 seconds; range 35-219 seconds) and a dose-dependent duration of action. The recommended dose of 1.5 mg/kg in adults has a short clinical duration of action (mean duration approximately 15 minutes; range 6-30 minutes) (see

CLINICAL PHARMACOLOGY

-Clinical studies). Rapacuronium acts by competing for cholinergic recepotors at the motor end plate. Profound neuromuscular blockade induced by RAPLON (rapacuronium) Ò can be reversed by neostigmine (see CLINICAL PHRMACOLOGY-Early Reversal).

Pharmacodynamics

The neuromuscular block seen after the intravenous administration of 1.5 mg/kg RAPLON (rapacuronium) Ò (rapracuronium bromide) for Injection is primarly due to rapacuronium. Plasma levels of the major active metabolite of rapacuronium (the 3-hydroxy metabolite) are relatively low compared to the parent at a dose of 1.5 mg/kg of RAPLON (rapacuronium) Ò . Pharmacokinetic and pharmacodynamic modeling studies were conducted after the separate administration of rapacurcnium bromide and the 3-hydroxy metabolite. These studies evaluated the effect of plasma drug concentrations on the neuromuscular block achieved as measured by mechanomyography of the adductor pollicies musicle to indirect supramaximal train-of-four stimulation of the ulnar nerve. These results are shown in Tables 1 and 2 Comparison of k° ° (rate constant for the equilibration between effect compartment at 50% drug effect) values of rapacuronium and the 3-hydroxy metabolite shows that the metabolite has slower onset and a higher potency than rapacuronium bromide. However, when comparing the ED90 (dose required to produce 90% suppression of the first [T,] mechanomyographic [MMG] response of the adductor pollicis muscle to indirect supramaximal train-of-four stimulation of the ulnar nerve) of rapacuronium (0.3 mg/kg), vecuronium (0.05 mg/kg) and pancuronium (0.06 mg/kg). Rapacuronium bromide and the3-hydroxy metabolite may be viewed as low potency neuromuscular blocking drugs.

TABLE 1: Pharmacokinetic/pharmacodynamic modeling parameters of rapacuronium bromide after a slow ointravenous infusion of rapacuronium bromide in ten subjects at a median dose of 0.93 mg/kg over a median time of four minutes and forty seconds (mean (%CV)).

Parameter

 

K° ° 1/minute

0.44 (41)

Y

2.97 (23)

EC50. Mcg/mL

4.44 (33)

ED90. Mg/kg

1.03 (33)

TABLE 2: Pharmacokinetic/pharmacodynamic modeling parameters of the 3-hydroxy metabolite after a slow intavenous infusion in seven subjects of a median dose of 0.66 mg/kg over three to five minutes (mean (%CV)).

Parameter

 

K° ° . 1/minute

0.10(40)

y

4.83(44)

EC50. Mcg.mL

2.06(55)

ED90, mg/kg

0.46(33)

The ED50 for rapacuronium bromide (dose required to produce 50% suppression of the first [T1] mechanomyographic [MMG] response of the adductor pollicis muscle to indirect supramaximal train-of-four stimulation of the ulnar nerve) during opioid/nitrous oxide/oxygen anesthesia is approximately 0.3 mg/kg in adult (18 to 64 years) and geriatric (> 65 years) patients. The ED50 for rapacuronium bromide for pediatric patients (1 to 12 years) is 0.4 mg/kg and for infants (1 month to < 1 year) is 0.3mg/kg (see PRECAUTIONS, Pediatric Use).

Table 3 and 4 present the neuromuscular function parameters following an initial dose of RAPLON (rapacuronium) TM in adult patients (18 to 64 years) and geriatric patients (> 65 years).

TABLE 3: Neuromuscular Function Parameters (Mean SD)) Following and Initial Dose of RAPLON (rapacuronium) TM in Adults (18 to 64 years)

Dosage

Time to Maximum Blocka (sec)

Maximum Blockb (%)

Clinical Duration (min)c

25%-75% T1 Recovery Index (min)

Time to 70% T4/T1 recovered (min)

RAPLON (rapacuronium) Ò

1.5 mg/kg

88 (47)

(n=32)

99 (2)

(n=49)

15 (5)

(n=57)

9 (5)

(n=38)

34 (15)

(n=47)

a=time from injection to maximum block (peak effect)

b=(100-%T1 control at peak effect)

c=time from injection to return to 25 % of control T1

d=time from injection to recovery of 70% T4/T1

In U.S. clinical trials, in adult patients (18 to 64 years), the mean (SD) time to maximum block

[time from injection to maximum block (peak effect)] following an initial 2.5 mg/kg dose of

RAPLON (rapacuronium) Ò was 72 (24) seconds (n=19). The mean (SD) clinical duration (time from injection to return to 25% of control T,) in adult patients was 24 (8) minutes (n=45) with a mean (SD) 25 %-75%T, recovery index of 13 (7) minutes (n=23) and a mean (SD) time to 70% T,/T,).

TABLE 4: Neuromuscular Function Parameters (Mean (SD) Following an Initial Dose of RAPLON (rapacuronium) Ò in Geriatric Patients (2 65 years)

Dosage

Time to Maximum Blocka (sec)

Maximum Blockb (%)

Clinical Durationc (min)

25%-74%T1 Recovery Index (min)

Time to 70%T4/T1 recoveryc (min)

RAPLONÒ

1.5 mg/kg

89 (6)

(n=6)

98 (5)

(n=17)

17 (5)

(n=16)

11 (6)

(n=4)

36 (5)

(n=12)

a=time from injection to maximum block (peat effect)

b= (100.% T1 control at peak effect)

c=time from injection to return to 25% of control T1

d=time from injection to recovery of 70% T4/T1

in U.S. clinical trials, in geriatric patients (≥

65 years), the mean (SD) time to maximum block [[time

from injection to maximum block (peak effect)] following an initial 2.5 mg/kg dose of RAPLON (rapacuronium) Ò was 51 (21) seconds (n=4). The mean (SD) clinical duration (time from injection to return to 25% of control T1) was 43 (37) minutes (n=13) with a mean (SD) 25%-75%T1 recovery index of 17 (16) minutes (n=3) and a mean (SD) time to 70%T4/T1 recovery (n=9) of 76 (20) minutes (time from injection to recovery of 70% T4/T1).

Table 5 presents the neuromuscular function parameters following an initial dose of RAPLON (rapacuronium) Ò in pediatric patients under halothane anesthesia.

TABLE 5" Neuromuscular Function Parameters Following an Initial Dose of RAPLON (rapacuronium) Ò in Pediatric patients (1 month to ≥ 12 years)

Age Group

Dosage

Time to Maximum Blocka (sec)

Maximum Blockb (%)

Clinical Durationc (min)

25%-75%T1 Recovery Index (min)

Time to 70%T4/T1 recoveryc (min)

Infants (1mo

to < 2yrs)

RAPLON Ò 1 mg/kg (n=14)

88 (73)

96 (12)

9 (3)

(n=13)

7 (4)

(n=9)

20 (7)

(n=12)

RAPLONÒ 2 mg/kg (n=16)

84 (66)

99 (3)

16 (7)

13 (11)

(n=8)

34 (13)

Children

(2 to 12yrs)

RAPLONÒ 2 mg/kg (n=23)

53 (16)

100 (1)

14 (7)

6 (4)

(n=19)

26 (9)

(n=21)

RAPLONÒ 3 mg/kg (n=21)

67 (44)

100 (2)

18 (3)

(n=20)

11 (6)

(n=12)

37 (9)

(n=19)

a=time from injection to maximum block (peak effect)

b=(100. % T1 control at peak effect)

c= time from injection to return to 25% of control T1

d= time from injection to recovery of 70% T4/T1

Cardiac Patients

Hemodynamic parameters were assessed in patients with coronary artery and valvular disease receiving 1.5 mg/kg of RAPLON (rapacuronium) Ò in one European (n=18) placebo controlled trial. Overall, there were mild to moderate changes in hemodynamic parameters (e.g., mean arterial pressure, heart rate, mean pulmonary artery pressure, pulmonary capilary wedge pressure, central venous pressure, cardiac index , and systemic vascular resistance index) measured invasively, in cardiac patients (valvular disease or coronary artery disease) receiving 1.5 mg/kg RAPLON (rapacuronium) TM

Obese Patients

Obese patients with a body mass index (BMI) >30kg/m2 were compared to normal weight subjects in a European study in which they received 1.5 mg/kg of RAPLON (rapacuronium) TM as part of a rapid sequence induction of anesthesia using either fentanyl/thiopental or alfentanil/propofol. Patients were dosed based on actual body weight. Acceptable (excellent or good) intubating conditions following 1.5 mg/kg of RAPLON (rapacuronium) TM were similar in obese (86% under fentanyl/thiopental, 92% under alfentanil/propofol) and normal weight subjects (87% under fentanyl/thiopental, 91% under alfentanil/propofol) at 60 seconds. The percent of excellent scores under fentanyl/thiopental of alfentanil/propofol were 48% and 65%, respectively in obese patients, and 44% and 52%, respectively, in normal weight patients.

Repeat Dosing in Adults

In three controlled clinical trials, after an initial intubating dose a RAPLON (rapacuronium) TM of 1.5 mg/kg. 3 additional doses of 0.5 to 0.55 mg/kg were administered at 25% recovery of T1 or at the reappearance of T3(n=76). The duration of action of maintenance doses of 0.5 to 0.55 mg/kg ranged from 3 to 35 minutes. A statistically significant increase in the duration of action of RAPLON (rapacuronium) TM was noted with subsequent maintenance doses (See Table 6).

Table 6: Clinical Duration (25% Recovery of T1) of Maintenance Doses of Raplon (rapacuronium) (minutes) following an initial intubating dose of 1.5 mg/kg

Study 1 Raplon 0.55 mg/kg

Study 2 Raplon 0.5 mg/kg

Study Raplon 0.5 mg/kg

Dose No.1

(n=15)

(n=28)

(n=33)

Mean (SD)

7(3)

12(3)

13(3)

Median

6

12

13

Range

3-12

6-19

7-20

Dose No.2

(n=15)

(n=28)

(n=33)

Mean (SD)

8(2)

14(4)

15(5)

Median

8

14

14

Range

5-12

6-22

8-29

Dose No. 3

(n=14)

(n-15)

 

Mean (SD)

8(2)

15(5)

 

Median

8

15

 

Rasnge

5-13

6-35

 

Early Reversal

Administration of neostigmine (50 or 70 mcg/kg at 2 or 5 min) at profound neuromuscular block (>90%) following administration of either 1.5 or 2.5 mg/kg of RAPLONTM (rapacuronium bromide) for Injection in adults reduced the recovery time by approximately 50%. After early reversal with neostigmine, a decrease in neuromuscular function did not occur over the clinical trial period.

Table 7 presents the recovery parameters following reversal of profound block from a US study of adult patients. Anesthesia consisted of premedication with midazolam, induction with fentanyl and propofol, and maintenance with N2O supplemented with fentanyl and propofol.

TABLE 7: Recovery Profile Following Neostigmine Reversal at Profound RAPLON (rapacuronium) TM-induced Block (> 90%) in Adults (18 to 64 years)

RAPLONTM Dose

Neostigmine Dose

Time of Neostigmine Administration

Clinical Duration (min)

25%-75% T1 Recovery Index (min)

Time to 70% T4/T1 recovery (min)

Time to 80% T4/T1 recovery (min)

 

1.5 mg/kg

None

N/A (n=11)

17(5)a

12(5)a

38(10)a

43(12)a

50mcg/kg

2 min (n=7)

8(1)

5(1)

17(4)

20(5)

5 min (n=12)

9(1)

5(3)

17(3)

19(4)

70mcg/kg

2 min (n=10)

8(1)

7(4)

15(3)

21(7)

5 min (n=9)

9(1)

6(2)

19(8)

24(8)

 

2.5 mg/kg

None

N/A (n=10)

24(5)a

15(6)a

56(13)a

60(11)a

50 mcg/kg

2 min(n=12)

12(2)

9(4)

26(7)

31(8)

5 min(n=8)

12(3)

8(3)

32(13)

38(18)

70mcg/kg

2 min (n=9)

12(2)

12(5)b

35(8)

41(10)

5 min(n=9)

12(2)

8(3)

28(9)

36(12)

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

b=(p=NS)

Hemodynamics

After the administration of RAPLONTM (rapacuronium bromide) for Injection, dose-related increase in heart rate were observed, peaking within the first few minutes after RAPLON (rapacuronium) 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 (rapacuronium) TM administration. After the administration of RAPLON (rapacuronium) TM, dose-related decreases in mean arterial pressure (MAP) were observed. Decreases in MAP occurred after all doses of RAPLON (rapacuronium) TM. These changes were observed to peak within 5 minutes after the administration of RAPLON (rapacuronium) 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 (rapacuronium) 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 (rapacuronium) TM is given in a high bolus dose or following prolonged infusion.

Electrocardiogram parameters (QT, QTC, and RR intervals) were assessed in patients during a 15 minute observation period after receiving 1.5 mg/kg RAPLON (rapacuronium) 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 (rapacuronium) TM group while small increases of up to 0.082 second were observed in the placebo group. Mean changes in the QTC 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 (rapacuronium) 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 (rapacuronium) 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 RAPLONTM (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 (rapacuronium) 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 (rapacuronium) 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 RAPLONTM (rapacuronium bromide) for Injection (n=8) decreased by a maximum of 15% at 3 minutes.

Pharmacokinetics

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.

Following intravenous administration of RAPLONTM (rapacuronium bromide) for Injection, plasma concentration data were best described by a three-compartment model. The pharmacokinetic model was parameterized in clearances and volumes. Estimates of these parameters were used subsequently to calculate volume of distribution at steady state and half-lives. Table 8 presents the results of a population pharmacokinetic analysis from 206 adult patients (18 to 83 years), including patients with end-stage renal disease (n=7) and cirrhosis (n=8). The variability for these parameters is not available from this analysis. See Tables 11 and 12 for variability estimates for these parameters.

TABLE 8: Population Pharmacokinetic Parameter Estimates for RAPLON (rapacuronium) TM a

PK Parameter

Estimate

CVb

Plasma Clearance (mL/kg/min)

6.56

2.5%

Volume of Distribution at steady State (mL/kg)

292

NDc

a= Based on basic three compartment model without covariates

b= Coefficient of variation (%)

c= Not determined for derived parameters

Distribution

The mean volume of distribution of RAPLON (rapacuronium) TM at steady state was 292 mL/kg in adult patients. The mean rapid distribution half-life was 4.56 minutes and the mean slow distribution half-life was 27.8 minutes.

Metabolism

Rapacuronium bromide undergoes hydrolysis of the acetyloxy-ester bond at the 3-position to form the 3-hydroxy metabolite, the major and active metabolite of rapacuronium. Relative to its parent, the 3-hydroxy metabolite has greater potency and a slower onset of action. This hydrolysis is non-specific and can occur at physiological temperature and PH. This hydrolysis may also be catalyzed by esterases of unknown identify and at unknown sites. The cytochrome P450 enzyme system does not appear to be involved in the hydrolsis of rapacuronium bromide. A mass balance study suggests that there may be seven additional minor metabolites of unknown identify in addition to the 3-hydroxy metabolite.

Elimination

A mass balance study using 1.5 mg/kg of [14C] rapacuronium bromide demonstrated that urine and feces are the main routes of elimination of [14C] rapacuronium bromide (Table 9). The mean combined excretion in urine and feces at the end of the continuous 13.5-day collection period was approximately 56% (range; 50%-64%), with approximately 28% excreted in urine samples and 28% in feces. Measurable concentrations of radiocarbon were also detected in urine samples collected once a week over four weeks after the end of the continuous 13.5-day collection period.

The estimated radioactivity excreted in expired CO2 over 24 hours was approximately 0.6% of the administered dose. The apparent elimination half-life of radioactivity was estimated to be approximately 22 days, suggesting that complete excretion can take several weeks.

TABLE 9: Recovery of Radioactivity a From Volunteers (n=6) Given [14C] Rapacuronium

Source

Percentage Recovery mean (SD)

Duration of Sampling

Urine

28.4(4.3)

13.5 days

Stool

27.7(4.2)

13.5 days

Exhaled Gas b

0.6(0.07)

24 hours

Total c

58 (5) (range 50-64%)

13.5 days

a= Radioactivity recovery does not distinguish between rapacuronium and the 3-hydroxy metabolite

b= Sampling started 2 hours after anesthesia recovery and a total of 7 samples were collected

c= Excluding exhaled gas

Rapacuronium bromide, in addition to undergoing hydrolysis to its 3-hydroxy metabolite, is also excreted unchanged in urine and feces. The 3-hydroxy metabolite is excreted unchanged in urine and feces without further biotransformation. Approximately 8% of the administered rapacuronium bromide does was recovered from urine up to 48 hours after dosing as unchanged rapacuronium bromide and approximately 5% as the 3-hydroxy metabolite (Table 10).

TABLE 10: Recovery of Rapacuronium Bromide and the 3-hydroxy metabolite From a 48-Hour Urine Collection of Volunteers (n=10) Given Unlabelled Rapacuronium Bromide

Compound Excreted in Urine mean (SD)

Time After RAPLONTM 1.5mg/kg Bolus

0-24 hours

0-48 hours

Rapacuronium Bromide (% excreted)

7.96 (2)

8.12(2)

3-hydroxy metabolite (% excreted)

3.43 (1)

4.96(1.2)

The mean plasma clearance of rapacuronium bromide in adult patients was 6.56 mL/kg/min and the mean plasma elimination half-life (T½ ß) was 141 minutes. However, this half-life may not represent the terminal elimination of rapacuronium bromide from the body as characterized in the mass balance study.

Protein Binding

Plasma protein binding of rapacuronium was studied in vitro for human plasma by equilibrium dialysis. The protein binding was variable and ranged between 50% and 88%, which was at least partly due to hydrolysis of rapacuronium bromide to its 3-hydroxy metabolite. The specific plasma protein to which rapacuronium binds is unknown. Plasma protein binding of the 3-hydroxy metabolite was not determined.

Special Populations

Geriatrics

In the pooled population pharmacokinetic analysis based on 206 adult patients ages 18 to 63 years, the analysis of covariates showed that total plasma clearance of rapacuronium bromide decreases with increasing age. However, as these changes were not clinically significant, no dosage adjustment is recommended for geriatric patients.

Pediatrics

Pharmacokinetic parameters in pediatric patients (n=49) ranging in age from 1 month to 12 years (median 3 years) were estimated using population pharmacokinetic (PK) analyses. The plasma concentration data were best described by a three-compartment model in which all PK parameters were proportional to body weight. The mean plasma clearance was 10.6 mL/kg/min. The mean volume of distribution at steady state was 495 mL/kg and the mean elimination half-life was 262 min (see PRECAUTIONS, Pediatric Use).

Gender

In general, studies in normal adult subjects did not reveal any differences in the pharmacokinetics of RAPLON (rapacuronium) TM due to gender.

Race

Race was not examined as a covariate in the pooled population pharmacokinetic analysis of RAPLON (rapacuronium) TM.

Renal Insufficiency

Table 11 summarizes the results of conventional PK analyses from a US study of normal volunteers and patients with end-stage renal disease (ESRD) receiving a single bolus dose of 1.5 mg/kg of RAPLON (rapacuronium) TM. Patients with renal insufficiency had a mean 30% reduction in clearance compared with normal adult patients. The volume of distribution was more variable in patients with renal insufficiency compared to normal volunteers.

Comparison of the concentration of the 3-hydroxy metabolite relative to that of rapacuronium bromide up to eight hours after rapacuronium bromide administration and the plasma concentration versus time profiles between the normal volunteer group and patients with ESRD showed that the pharmacokinetics of the 3-hydroxy metabolite were altered in patients with ESRD. In normal volunteers, the ration of the 3-hydroxy metabolite to rapacuronium increased steadily through the 6-hour period but decreased by the 8-hour time point (from 0.03 at 3 minutes to 4.5 at 8 hours). In patients with ESRD, this ration showed an increasing trend even at the 8-hour time point (from 0.02 at 3 minutes to 7.5 at 8 hours). The decrease in the plasma concentration of the 3-hydroxy metabolite in patents with ESRD was only 35% from peak levels (265 to 171 ng/mL) compared an 87% decrease in the normal volunteer group (381 to 49 ng.mL). No clear elimination phase was observed at the end of 8 hours. Despite the persistence of the 3-hydroxy metabolite, neuromuscular function recovered completely with a mean time course to 70% T4/T1 only slightly longer in patients with ESRD, compared to that in healthy volunteers with normal renal function after a single 1.5 mg/kg bolus. However, it is likely that recovery from supplemental doses of RAPLON (rapacuronium) TM will be prolonged in patients with renal failure.

TABLE 11: Estimates of PK Parameters of RAPLON (rapacuronium) TM in Normal Volunteers and Patients With ESRD

PK Parameter

Normal Volunteers a

Patients with ESRDa

Elimination Half-Life C (t1/2b ,min)

240(97)

198(141)b

Volume of Distribution at Steady State (mL/kg)

431.7(78)

440.3(347)

Plasma Clearance (mL/kg/min)

9.4(2.2)

6.1(1.7)b

a= Normal volunteers n=10 patients with ESRD n=9, values are mean (SD)

b= p<0.05 for comparison with normal volunteers

c= May not represent the slow elimination kinetics of rapacuronium bromide

Hepatic Insufficiency

The pharmacokinetics (PK) parameters for patients with mild to moderate hepatic insufficiency and patients with normal liver function are presented in Table 12. These estimates are based on conventional PK analyses. Plasma clearance and volume of distribution at steady-state are greater in patients with cirrhosis compared to patients with normal liver function. Pharmacokinetics of rapacuronium bromide in patients with severe hepatic impairment have not been evaluated.

TABLE 12: Estimates of PK Parameters of RAPLON (rapacuronium) TM in Patients With Normal Liver Function and Patients With Hepatic Insufficiency

PK Parameter

Normal Liver Function a

Hepatic Insufficiency (cirrhotic)a

Elimination Half-Life c (t1/2b , min

84(4)

88(6)

Volume of Distribution at Steady State (mL/kg)

252(77)

465(82)b

Plasma Clearance (mL/kg/min)

6.6(1.7)

9.0(1.4)b

a= Normal liver function n=7, hepatic insufficiency n=6, values are mean (SD)

b= P<0.01 for comparison with normal patients

c= may not represent the slow elimination kinetics if rapacuronium bromide. Values are harmonic mean and standard error of harmonic mean, Harmonic mean is calculated of 0.693/t¹ bela.

Drug-Drug Interactions

There were no specific pharmacokinetic studies conducted to examine the drup-drug interactions of RAPLONTM (see PRECAUTIONS).

Clinical Studies

In Us studies, 929 patients received RAPLONTM (rapacuronium bromide) for Injection including 219 pediatric, 146 geriatric, and 20 obstetric patients. In European studies, 964 patients received RAPLON (rapacuronium) TM including 165 pediatric and 63 geriatric patients. The majority of patients, 91% were ASA (American Society of Anesthesiologists) Class I or II, approximately 8% were ASA Class III, and approximately 1% were ASA Class IV.

Neuromuscular function parameters following administration of RAPLON (rapacuronium) TM succinylcholine, and mivacurium were compared in one clinical study. In direct comparison with succinylcholine and mivacurium, RAPLON (rapacuronium) TM at the recommended 1.5 mg/kg dose had a mean (SD) onset of action of 98(46) seconds compared with 67(27) seconds for succinycholine and 127 (50) seconds for mivacurium. RAPLON (rapacuronium) TM had a mean (SD) clinical duration of 15(6) minutes compared with 9(3) minutes for succinyholine and 21(5) minutes for mivacunium. Table 13 presents these neuromuscular function parameters in patients 8 years of age and older.

TABLE 13: Neuromuscular Function Parameters Following an Initial Dose of RAPLON (rapacuronium) . Succinylcholine, or Mivacurium in Adults (>18 years)

Drug/Dosage

Time to Maximum Blocka (seconds)

Maximum Block b(%)

Clinical Duration c (minutes)

25-75% T1 Recovery Index (minutes)

Time to 70% T4/T1 recovery d (minutes)

Raplon (rapacuronium) 1.5 mg/kg

n

28

28

25

22

16

Mean (SD)

98(46)

99(2)

15(6)

8(5)

38(21)

Range

35-219

94-100

7-30

2-21

21-101

Succinylcholine 1mg/kg

n

30

30

29

29

N/A

Mean (SD)

67(27)

99(2)

9(3)

2(1)

Range

31-138

90-100

5-15

1-4

Mivacurium 0.25mg/kge

n

25

25

21

24

16

Mean (SD)

127(50)

100(0.4)

21(5)

9(4)

32(7)

Range

64-261

99-100

14-29

4-20

22-45

a= time fro injection to maximum block (peak effect)

b=100-% T1 control at peak effect

c=time from injection to return to 25% of control T1

d= time from injection to recovery of 70% T4/T1

e= administered as a divided dose (0.15mg/kg followed in 30 sec by 0.10 mg/kg), parameter measured from second dose

Intubating conditions following administration of RAPLON (rapacuronium) TM and succinylcholine were compared in three randomized, multicenter trials conducted in the U.S., France, and Germany. A blinded rater assessed intubating conditions on the Viby-Mogensen scale (see Table 14) 50 seconds after administration of the neuromuscular blocking agent. Several different anesthetic techniques were used. In the U.S. study, fentanyl was given about 5 minutes before intubation followed by propofol one to two minutes before intubation. The French study was similar except that thiopental was used instead of propofol. The German study tested a rapid sequence, with initiation of administration of the neuromuscular blocking agent within a few seconds after the end of the injection of the hypnotic, either fentanyl and thiopental or alfentanil and propofol were used at random. Tables 15 and 16 show the intubation scores in adults (18 to 64 years) and in geriatric patients (>65 years).

TABLE 14: Viby-Mogensen Scale

 

CLINICALLY ACCEPTABLE

 
 

Excellent

Good=

Poor=

Vocal Cord Position

Abducted

Intermediate

Closed

Vocal Cord Movement

None

Moving

Closing

Easiness of Laryngoscopy·

Easy

Fair

Difficult

Airway Reaction

None

Diaphragm

Sustained > 10 sec

Movement of Limbs

None

Slight

Vigorous

· Easy : Jaw relaxed; no resistance

Fair : Jaw relaxed; slight resistance

= Excellent ; All items excellent

Good: All items excellent or good

Poor: Any item poor

Intubating dosages of 1.5 and 2.5 mg/kg of RAPLON (rapacuronium) TM were evaluated in 784 patients. A population of patients undergoing Cesarean section was also studied (see below).

TABLE 15: Intubation Scores in Adults (16 to 64 years) With Laryngoscopy Initiated at 50 Seconds following Administration of RAPLON (rapacuronium) TM or succinylcholine

Study

U.S.

France

Germany

 

Drug/Dosage

RAPLONTM

Succinylch-oline

RAPLONTM

Succinylch-oline

RAPLONTM

Succinylch-oline

1.5mg/kg

1.0mg/kg

1.5mg/kg

1.0mg/kg

1.5mg/kg

1.0mg/kg

n=124

n=112

n=128

n=128

n=160

n=156

Excellent

43%

67%

30%

48%

51%

73%

Good

44%

29%

55%

41%

39%

24%

Poor

13%

4%

9%

9%

11%

3%

Impossible

0%

2%

5%

2%

0%

0%

TABLE 16: Intubation Scores in Geriatric Patients (>65 years) With Laryngoscopy Initiated at 50 Seconds after Administration of RAPLON (rapacuronium) TM or succinylcholine

Study

U.S.

France

Drug/Dosage

RAPLONTM

Succinylcholine

RAPLONTM

Succinylcholine

 

1.5 mg/kg

1.0 mg/kg

1.5 mg/kg

1.0 mg/kg

 

n=26

n=28

n=25

n=36

Excellent

50%

79%

32%

62%

Good

46%

21%

48%

35%

Poor

4%

0%

4%

0%

Impossible

0%

0%

16%

4%

Intubating conditions were also studied in pediatric patients (>1 month to < 12 years)in one non-comparative European study. Patients were premedicated with midazolam and induced with thiopental. Results are presented in Tasble 17.

TABLE 17: Intubation Scores in Pediatric Patients With Laryngoscopy Initiated at 50 Seconds after Administration of RAPLON (rapacuronium) TM

 

Infants (1mo to 1 yr) 2.0 mg/kg n=9

Children (1 to 12 yr) 2.0 mg/kg n=17

Excellent

100%

58%

Good

0%

41%

Poor

0%

0%

Impossible

0%

0%

Cesarean Section

In a controlled clinical trial, patients undergoing rapid sequence induction of anesthesia for Cesarean section received thiopental 4-6 mg/kg followed by 2.5 mg/kg of RAPLON (rapacuronium) TM or1.5

Mg/kg of succinylcholine. Laryngoscopy was initiated 50 seconds after the muscle relaxant was administered and intubation completed by 60 seconds in all patients. Acceptable (excellent or good) intubating conditions were achieved in 14/15 (93%) patients receiving RAPLON (rapacuronium) TM and in 17/19 (89%) patients receiving succinylcholine. Excellent scores were recorded in 10/15 (67%) RAPLON (rapacuronium) TM patients and 13/19 (68%) succinylcholine patients.

No neonates born of mothers who received RAPLON (rapacuronium) TM during Cesarean section had APGAR scores below 6 at 5 minutes post-delivery or NAC (Neurological and Adaptive Capacity) scores <30 at 24 hours post-delivery.

The venous umbilical/maternal concentrations of RAPLON (rapacuronium) TM (median 8.4%, range of 4.4. to 16.1%) and its 3-hydroxy medabolite (median 10.2, range of 4.6% to 19.9%) demonstrated that there is some placental transfer of the drug from the maternal blood to the fetal blood at delivery.

Individualization of Dosage

DOSES OF RAPLONTM (rapacuronium bromide) FOR INJECTION SHOULD BE INDIVIDUALIZED AND A PERIPHERAL NERVE STIMULATOR SHOULD BE USED TO

MEASURE NEUROMUSCULAR FUNCTION DURING RAPLON (rapacuronium) TM ADMINISTRATION IN ORDER TO MONITOR DRUG EFFECT, DETERMINE THE NEED FOR ADDITIONAL DOSES, AND CONFIRM RECOVERY FROM NEUROMUSCULAR BLOCK

Based on the known actions of rapacuronium bromide and other neuromuscular blocking agents, the following factors should be considered when administering RAPLON (rapacuronium) TM.

Renal or Hepatic Impairment

A slight delay in the onset of neuromuscular block and prolongation of duration of block were observed in patients with ESRD when compared to normal volunteers. A greater variability of onset and duration was also observed in patients with renal insufficiency. The mean time to 25%-75%T1 recovery was greater in patients with renal and hepatic impairment. Although dosage adjustments are not recommended in patients with renal or hepatic impairment. RAPLON (rapacuronium) TM should be used with caution in these patient populations.

The results of studies in patients with renal failure and hepatic dysfunction do not suggest any additional safety concerns in these patients when RAPLON (rapacuronium) TM is administered as a single dose.

Reduced Plasma Colinesterese Activity

RAPLON (rapacuronium) TM metabolism does not depend on plasma cholinesterase, therefore, no differences in clinical effect are expected in patients with reduced or normal plasma cholinesterase activity.

Drugs or Conditions Causing Potentiation of, or Resistance to, Neuromuscular Block

Use of inhalation anesthetics (enflurane, isoflurane, halothane, desflurane, sevoflurane) has been shown to enhance the activity of other neuromuscular blocking agents (see PRECAUTIONS, Drug Interactions, Inhalational Anesthetics).

Magnesium salts, lithium, local anesthetics, procainamide, quinidine, and certain antibiotics have been shown to increase the duration of neuromuscular block and decrease infusion requirements of other neuromuscular blocking agents. In patients in whom potentiation of neuromuscular block may be anticipated, a decrease from the recommended initial dose of Raplon should be considered (see PRECAUTIONS, Drug Interactions, Other).

Severe acid-base and/or electrolyte abnormalities may potentiate or cause resistance to the neuromuscular blocking action of RAPLON (rapacuronium) TM.

Resistance to non-depolarizing agents, consistent with up-regulation of skeletal muscle acetylcholine receptors, is associated with burns, disuse atrophy, deservation, and direct muscle trauma. Receptor up-regulation may also contribute to the resistance to nondepolarizing muscle relaxants that sometimes develops in patients with cerebral palsy and in patients with chronic exposure to anticonvulsant or nondepolarizing agents (see PRECAUTIONS, Drug Interactions).

Other nondepolarizing neuromuscular blicking agents have been found to exhibit profound 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, a decrease from the recommended initial dose of Raplon (rapacuronium) should be considered.

Obesity

In obese patients, the initial dose of RAPLON (rapacuronium) TM should be based upon the patients actual body weight (see CLINICAL PHARMACOLOGY, Obese Patients).

The neuromuscular blocking effect of 1.5 mg/kg RAPLON (rapacuronium) TM was determined in a group of obese patients (body mass index > 30 and a group of non-obese patients (body mass index 20-28). When dosed by actual body weight, the obese group had approximately the same percentage of patients with acceptable (excellent or good) intubating conditions as the non-obese group.

Although RAPLON (rapacuronium) TM has not been formally studied in morbidly obese patients (body mass index > 40). Clinical should consider dosing this patient population based on ideal body weight. As with other neuromuscular blocking drugs, RAPLON (rapacuronium) TM may exhibit prolonged duration and delayed spontaneous recovery when the morbidly obese are dosed based on actual body weight.

Burns

Patients with burns are known to develop resistance to nondepolaizing neuromuscular blocking agents, probably due to up-regulation of post-synaptic skeletal muscle cholinergic receptors.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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