A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Chirocaine Pharmacology, Pharmacokinetics, Studies, Metabolism - Levobupivacaine
Chirocaine Pharmacology, Pharmacokinetics, Studies, Metabolism - Levobupivacaine
CLINICAL PHARMACOLOGY
Mechanism of Action
Chirocaine® is a member of the amino amide class of local anesthetics. Local
anesthetics block the generation and the conduction of nerve impulses by increasing
the threshold for electrical excitation in the nerve, by slowing propagation
of the nerve impulse, and by reducing the rate of rise of the action potential.
In general, the progression of anesthesia is related to the diameter, myelination,
and conduction velocity of affected nerve fibers. Clinically, the order of loss
of nerve function is as follows: 1) pain, 2) temperature, 3) touch, 4) proprioception,
and 5) skeletal muscle tone.
Pharmacokinetics
Table 1. Pharmacokinetic parameter values of levobupivacaine
after the administration of 40 mg levobupivacaine, and those of racemic bupivacaine,
R(+)- and S(-)- enantiomers after the administration of 40 mg of bupivacaine
intravenously in healthy volunteers (mean ± SD).
|
Parameter
|
Levobupivacaine |
Bupivacaine
Racemate |
R(+)-
bupivacaine |
S(-)-
bupivacaine |
|
C max , µg/mL
|
1.445 ± 0.237 |
1.421 ± 0.224 |
0.629 ± 0.100 |
0.794 ± 0.131 |
|
AUC 0-(infinity) , µg hour/mL
|
1.153 ± 0.447 |
1.166 ± 0.400 |
0.478 ± 0.166 |
0.715 ± 0.261 |
|
t 1/2 , hour
|
1.27 ± 0.37 |
1.15 ± 0.41 |
1.08 ± 0.17 |
1.34 ± 0.44 |
|
V d , Liter
|
66.91 ± 18.23 |
59.97 ± 17.65 |
68.58 ± 21.02 |
56.73 ± 15.14 |
|
CI, Liter/hour
|
39.06 ± 13.29 |
38.12 ± 12.64 |
46.72 ± 16.07 |
46.72 ± 16.07 |
After IV infusion of equivalent doses of levobupivacaine and bupivacaine, the
mean clearance, volume of distribution, and terminal half-life values of levobupivacaine
and bupivacaine were similar. No detectable levels of R (+)-bupivacaine were
found after the administration of levobupivacaine.
A comparison of the estimates for plasma AUC and C max between Chirocaine
and bupivacaine in two Phase III clinical trials involving short duration administration
of either agent found that neither total plasma exposure or C max differed
between the two drugs when compared within studies. Between study values differed
somewhat, likely due to differences in the injection sites, volume, and total
dose administered in each of the studies. These data suggest that Chirocaine
and bupivacaine have a similar pharmacokinetic profile. Pharmacokinetic data
from two Phase III studies are presented below:
Table 2. Pharmacokinetic parameter values of levobupivacaine
and bupivacaine in patients administered the respective drugs epidurally and
for brachial plexus block.
|
Route
|
Epidural |
Brachial Plexus Block |
|
|
Levobupivacaine |
Bupivacaine |
Levobupivacaine |
Bupivacaine |
|
Concentration (%)
|
0.50 |
0.75 |
0.50 |
0.25 |
0.50 |
0.50 |
|
Dose received
|
75mg |
112.5mg |
75mg |
1 mg/kg |
2 mg/kg |
2 mg/kg |
|
n
|
9 |
9 |
8 |
10 |
10 |
9 |
|
C max (µ/mL)
|
0.582 |
0.811 |
0.414 |
0.474 |
0.961 |
1.029 |
|
T max (h)
|
0.52 |
0.44 |
0.36 |
0.50 |
0.71 |
0.68 |
|
AUC (0-t) (µg.h/mL)
|
3.561 |
4.930 |
2.044 |
2.999 |
5.311 |
6.832 |
Between 0.5% and 0.75% levobupivacaine given epidurally at doses of 75 mg and
112.5 mg respectively, the mean C max and AUC 0-24 of
levobupivacaine were approximately dose-proportional. Similarly, between 0.25%
and 0.5% levobupivacaine used for brachial plexus block at doses of 1 mg/kg
and 2 mg/kg respectively, the mean C max and AUC 0-24 of
levobupivacaine were approximately dose-proportional.
Absorption
The plasma concentration of levobupivacaine following therapeutic administration
depends on dose and also on route of administration, because absorption from
the site of administration is affected by the vascularity of the tissue. Peak
levels in blood were reached approximately 30 minutes after epidural administration,
and doses up to 150 mg resulted in mean C max levels of up to 1.2
µg/mL.
Distribution
Plasma protein binding of levobupivacaine evaluated in vitro was found
to be >97% at concentrations between 0.1 and 1 µg/mL. The association of
levobupivacaine with human blood cells was very low (0-2%) over the concentration
range 0.01-1 µg/mL and increased to 32% at 10 µg/mL. The volume of distribution
of levobupivacaine after intravenous administration was 67 liters.
Metabolism
Levobupivacaine is extensively metabolized with no unchanged levobupivacaine
detected in urine or feces. In vitro studies using [ 14 C]levobupivacaine
showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine
to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In
vivo , the 3-hydroxy levobupivacaine appears to undergo further transformation
to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine
to R(+)-bupivacaine was not evident both in vitro and in vivo .
Elimination
Following intravenous administration, recovery of the radiolabelled dose of
levobupivacaine was essentially quantitative with a mean total of about 95%
being recovered in urine and feces in 48 hours. Of this 95%, about 71% was in
urine while 24% was in feces. The mean elimination half-life of total radioactivity
in plasma was 3.3 hours. The mean clearance and terminal half-life of levobupivacaine
after intravenous infusion were 39 liters/hour and 1.3 hours, respectively.
Special Populations
Elderly: The limited data available indicate that while
there are some differences in T max , C max and AUC with
regards to age (between age groups of <65, 65-75, and >75 years), these
differences are small and vary depending on the site of administration.
Gender: The small number of subjects in either of the male
and female groups and the different routes of administration (data could not
be pooled) in the different studies did not permit the assessment of gender
differences in the pharmacokinetics of levobupivacaine.
Pediatrics: No pharmacokinetic data of levobupivacaine are
available in the pediatric population.
Maternal/Fetal Ratio: The ratio of umbilical venous and
maternal concentration of levobupivacaine ranged from 0.252-0.303 after the
epidural administration of levobupivacaine for cesarean section. These are within
the range normally seen for bupivacaine.
Nursing Mothers: It is known that some local anesthetic
drugs are excreted in human milk and caution should be exercised when they are
administered to a nursing woman. The excretion of levobupivacaine or its metabolites
in human milk has not been studied (see PRECAUTIONS).
Renal Failure: No special studies were conducted in renal
failure patients. Unchanged levobupivacaine is not excreted in the urine. Although
there is no evidence that levobupivacaine accumulates in patients with renal
failure, some of its metabolites may accumulate because they are primarily excreted
by the kidney.
Hepatic Failure: No special studies were conducted in hepatic
failure patients. Levobupivacaine is eliminated primarily by hepatic metabolism
and changes in hepatic function may have significant consequences. Levobupivacaine
should be used with caution in patients with severe hepatic disease, and repeated
doses may need to be reduced due to delayed elimination.
Drug-Drug Interactions: In vitro studies showed
that morphine, fentanyl, clonidine, and sufentanil are not likely to have an
inhibitory effect on the oxidative metabolism of levobupivacaine. However, none
of these tested compounds was an inhibitor of the CYP3A4 or CYP1A2 isoforms.
Although no clinical studies have been conducted, it is likely that the metabolism
of levobupivacaine may be affected by the known CYP3A4 inducers (such as phenytoin,
phenobarbital, rifampin), CYP3A4 inhibitors (azole antimycotics e.g., ketoconazole;
certain protease inhibitors e.g., ritonavir; macrolide antibiotics e.g., erythromycin;
and calcium channel antagonists e.g., verapamil), CYP1A2 inducers (omeprazole)
and CYP1A2 inhibitors (furafylline and clarithromycin).
Relative Potency
The relative potency of Chirocaine compared to bupivacaine has not been established.
Pharmacodynamics
Chirocaine ® can be expected to share the pharmacodynamic properties
of other local anesthetics. Systemic absorption of local anesthetics can produce
effects on the central nervous and cardiovascular systems. At blood concentrations
achieved with therapeutic doses, changes in cardiac conduction, excitability,
refractoriness, contractility, and peripheral vascular resistance have been
reported. Toxic blood concentrations depress cardiac conduction and excitability,
which may lead to atrioventricular block, ventricular arrhythmias, and cardiac
arrest, sometimes resulting in death. In addition, myocardial contractility
is depressed and peripheral vasodilation occurs, leading to decreased cardiac
output and arterial blood pressure.
Following systemic absorption, local anesthetics can produce central nervous
system stimulation, depression, or both. Apparent central nervous system stimulation
is usually manifested as restlessness, tremors, and shivering, progressing to
convulsions. Ultimately central nervous system depression may progress to coma
and cardio-respiratory arrest. However, the local anesthetics have a primary
depressant effect on the medulla and on higher centers. The depressed stage
may occur without a prior excited stage.
In nonclinical pharmacology studies comparing Chirocaine and bupivacaine in
animal species, both the CNS and the cardiac toxicity of Chirocaine were less
than that of bupivacaine. Arrhythmogenic effects were seen in animals at higher
doses of Chirocaine than bupivacaine. Animal data comparing the difficulty of
resuscitation from levobupivacaine- and bupivacaine-induced arrhythmia are not
available. Central nervous system toxicity occurred with both drugs at lower
doses and at lower plasma concentrations than those doses and plasma concentrations
associated with cardiotoxicity.
In two intravenous infusion studies in conscious sheep, the convulsive doses
of levobupivacaine were found to be significantly higher than for bupivacaine.
Following repeated intravenous bolus administration mean (± SD) convulsive doses
for levobupivacaine and bupivacaine were 9.7 (7.9) mg/kg and 6.1 (3.4) mg/kg
respectively. The associated median total serum concentrations were 3.2 µg/mL
and 1.6 µg/mL. In a second study following a 3 minute intravenous infusion the
mean convulsant dose (95% CI) for levobupivacaine was 101 mg (87-116 mg) and
for bupivacaine 79 mg (72-87 mg).
A study in human volunteers was designed to assess the effects of Chirocaine
and bupivacaine on the EEG following an intravenous dose (40 mg) that was predicted
to be below the threshold to cause CNS symptoms. In this study, levobupivacaine
decreased high alpha power in the parietal, temporal and occipital regions,
but to a lesser extent than bupivacaine. Levobupivacaine had no effect on high
alpha power in the frontal and central regions, nor did it produce the increase
in theta power observed at some electrodes following bupivacaine.
In another study, 14 subjects received Chirocaine or bupivacaine infusions
intravenously until significant CNS symptoms occurred (occurrence of numbness
of the tongue, light-headedness, tinnitus, dizziness, blurred vision, or muscle
(twitching). The mean dose at which CNS symptoms occurred was 56 mg (range 17.5-150
mg) for Chirocaine and 48 mg (range 22.5-110 mg) for bupivacaine; this difference
did not reach statistical significance. The primary endpoints of the study were
cardiac contractility and standard electrocardiograph parameters. Although some
differences were seen between treatments, the clinical relevance of these is
unknown.
CLINICAL TRIALS
The clinical trial program included 1220 patients and subjects who received
Chirocaine in 31 clinical trials. Chirocaine has been studied as a local anesthetic
in adults administered as an epidural block for surgical cases, including cesarean
section; in peripheral neural blockade; and for post-operative pain control.
Although relative potency has not been established, clinical trials have demonstrated
that Chirocaine and bupivacaine exhibit similar anesthetic effects (see CLINICAL
PHARMACOLOGY ; Relative Potency ).
Central Administration
Epidural Administration in Cesarean Section
In one study, Chirocaine and bupivacaine, 0.50%, were evaluated as an epidural
block in 62 patients undergoing cesarean section in a randomized, double-blind
comparative trial. The mean (± S.D.) time to sensory block measured at T4 to
T6 was 10 ± 8 minutes for Chirocaine and 6 ± 4 minutes for bupivacaine. The
mean duration of sensory and motor block was 8 ± 1 and 4 ± 1 hours for Chirocaine
and 7 ±1 and 4 ± 1 hours for bupivacaine, respectively. Ninety-four percent
of patients receiving Chirocaine and 100% of patients receiving bupivacaine
achieved a block adequate for surgery. In a second bupivacaine-controlled cesarean
section study involving 62 patients, the mean time to onset of T4 to T6 sensory
block for Chirocaine and bupivacaine was 10 ± 7 minutes and 9 ± 7 minutes, respectively,
with 94% of Chirocaine patients and 91% of bupivacaine patients achieving a
bilateral block adequate for surgery. The mean time to complete regression of
sensory block was 8 ± 2 hours for both treatments.
Epidural Administration During Labor and Delivery
Chirocaine 0.25% was evaluated as intermittent injections via an epidural catheter
in 68 patients during labor in a randomized double-blind comparative trial to
bupivacaine 0.25%. The median duration of pain relief in the subset of patients
receiving 0.25% Chirocaine who had relief was 49 minutes; for bupivacaine patients
the median duration was 51 minutes. Following the first top-up injections, 91%
of patients receiving Chirocaine and 90% of patients receiving bupivacaine achieved
pain relief.
Epidural Administration for Surgery
Chirocaine ® concentrations of 0.50% and 0.75% administered by epidural
injection were evaluated in 85 patients undergoing lower limb or major abdominal
surgery in randomized, double-blind comparisons to bupivacaine. Anesthesia sufficient
for surgery was achieved in almost all patients on either treatment. In patients
having abdominal surgery, the mean (± S.D.) time to onset of sensory block was
14 ± 6 minutes for Chirocaine and 14 ± 10 minutes for bupivacaine. With respect
to the duration of block, the time to complete regression was 551 ± 88 minutes
for Chirocaine and 506 ± 71 minutes for bupivacaine.
Post-operative Pain Management
Post-operative pain control was evaluated in 258 patients in three studies
including one dose-ranging study and two studies assessing Chirocaine in combination
with epidural fentanyl or clonidine. The dose ranging study evaluated Chirocaine
in patients undergoing orthopedic surgery; the highest concentration, 0.25%,
was significantly more effective than lower concentrations. The Chirocaine combination
studies in post-operative pain management tested 0.125% Chirocaine in combination
with 4 µg/mL fentanyl and 0.125% Chirocaine in combination with clonidine 50
µg/hour in orthopedic surgery. In these studies, the efficacy variable was time
to first request for rescue analgesia during the 24 hour epidural infusion period.
In both studies, the combination treatment provided better pain control than
clonidine, opioid or local anesthetic alone.
Peripheral Nerve Administration
Chirocaine has been evaluated for its anesthetic efficacy when used as a peripheral
nerve block. These clinical trials included brachial plexus (by supraclavicular
approach) block study, infiltration anesthesia studies (for inguinal hernia
repair), peribulbar block studies.
Brachial Plexus Block
Chirocaine 0.25% and 0.5% were compared with 0.5% bupivacaine in 74 patients
receiving a brachial plexus (supraclavicular) block for elective surgery. In
the Chirocaine 0.25% treated group 68% of patients achieved satisfactory block
and in the Chirocaine 0.5% treated group, 81% of patients achieved satisfactory
block for surgery. In the bupivacaine 0.5% treated group, 74% of patients achieved
satisfactory block for surgery.
Infiltration Anesthesia
Chirocaine 0.25% was evaluated in 68 patients in two randomized, double-blind,
bupivacaine-controlled clinical trials for infiltration anesthesia during surgery
and for post-operative pain management in patients undergoing inguinal hernia
repair. No clear differences between the treatments were seen.
Peribulbar Block Anesthesia
Two clinical trials were conducted to evaluate 0.75% Chirocaine and bupivacaine
in 110 patients for peribulbar block for anterior segment ophthalmic surgery,
including cataract, glaucoma, and graft surgery, and for post-operative pain
management. In one study, a 10 mL injection of 0.75% Chirocaine or bupivacaine
produced a block adequate for surgery at a median time of 10 minutes. In the
second study, a 5 mL dose of 0.75% Chirocaine or bupivacaine injected in a technique
more closely resembling a retrobulbar block resulted in a median time to adequate
block of 2 minutes for both treatments. Post-operative pain was reported in
fewer than 10% of patients overall.
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