Levobupivacaine 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.
Levobupivacaine can be expected to share the pharmacodynamic properties of other local anesthetics. Systemic absorption of local anesthetics can produce effects on the central nervous system 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 levobupivacaine and bupivacaine in animal species, both the central nervous system (CNS) and the cardiac toxicity of levobupivacaine were less than that of bupivacaine. Arrhythmogenic effects were seen in animal at higher doses of levobupivacaine than bupivacaine. 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 mcg/mL and 1.6 mcg/mL. In a second study following a three-minute intravenous infusion, the mean convulsant dose (95% CI) for levobupivacaine was 101 mg (87 to 116 mg) and for bupivacaine 79 mg (72 to 87 mg).
A study in human volunteers was designed to assess the effects of levobupivacaine and bupivacaine on the electroencephalogram (EEG) following an intravenous dose (40 mg) that was predicted to be below the threshold to cause central nervous system (CNS) symptoms. In this study, levobupivacaine decreased high alpha power in 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 levobupivacaine 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 to 150 mg) for levobupivacaine and 48 mg (range 22.5 to 110 mg) for bupivacaine. The primary endpoints of the study were cardiac contractility and standard electrocardiographic parameters. Both drugs produced transient increases in heart rate and systolic and diastolic pressure, but the change in diastolic pressure was significantly less with levobupivacaine than with bupivacaine. Cardiac function measured by transthoracic electrical bioimpedance showed significant differences in that levobupivacaine produced a lesser reduction in stroke index, the acceleration index, and the ejection fraction.
A double-blind, randomized, parallel group trial was conducted on 22 healthy male volunteers to compare the effects of levobupivacaine and bupivacaine on QT dispersion and signal averaged ECG. The objective of the trial was to determine the effect of levobupivacaine and bupivacaine on myocardial depolarization and repolarization as measured by the QRS duration of signal-averaged ECGs, QT dispersion, and other ECG variables. During double-blind dosing, subjects received either levobupivacaine or bupivacaine in tolerated doses ranging from 30 mg to 120 mg. The results showed that ten of eleven bupivacaine subjects experienced CNS systems compared with six of eleven levobupivacaine subjects. In those subjects who received more than 75 mg of randomized drug, the maximum changes from baseline QTc interval was statistically significantly lower for levobupivacaine (3 ± 11 msec) than bupivacaine (24 ± 17 msec, p=0.022). No other statistically significant changes were seen in cardiac parameters.
The clinical trial program included 1220 patients and subjects who received levobupivacaine in 31 clinical trials. Levobupivacaine 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. Clinical trials have demonstrated that levobupivacaine and bupivacaine exhibit similar anesthetic effects (see previous text).
Central Administration: Epidural Administration in Cesarean Section: In one study, levobupivacaine 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 (±SD) time to sensory block measured at T4 to T6 was 10 ± 8 minutes for levobupivacaine and 6 ± 4 minutes for bupivacaine. The mean duration of sensory block and motor block was 8 ± 1 and 4 ± 1 hour for levobupivacaine and 7 ± 1 and 4 ± 1 hour for bupivacaine, respectively. Ninety-four percent of patients receiving levobupivacaine 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 levobupivacaine and bupivacaine was 10 ± 7 minutes and 9 ± 7 minutes, respectively, with 94% of levobupivacaine 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: Levobupivacaine 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% levobupivacaine 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 levobupivacaine and 90% of patients receiving bupivacaine achieved pain relief.
Epidural Administration for Surgery: Levobupivacaine 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 (±SD) time to onset of sensory block was 14 ± 6 minutes for levobupivacaine and 14 ± 10 minutes for bupivacaine. With respect to the duration of block, the time to complete regression was 551 ± 88 minutes for levobupivacaine and 506 ± 71 minutes for bupivacaine.
Postoperative Pain Management: Post-operative pain control was evaluated in 324 patients in four studies including one dose-ranging study and three studies assessing levobupivacaine in combination with epidural fentanyl, morphine or clonidine. The dose-ranging study evaluated levobupivacaine in concentrations of 0.0625%, 0.125%, and 0.25% in patients undergoing orthopedic surgery; the highest concentration was significantly more effective than were the other two concentrations. The levobupivacaine combination studies in post-operative pain management tested 0.125% levobupivacaine in combination with 4 mcg/mL fentanyl, 0.125% levobupivacaine in combination with clonidine 50 mcg/hour in orthopedic surgery, and 0.25% levobupivacaine and 0.005% morphine in abdominal surgery. In these studies, the efficacy variable was time to first request for rescue analgesia during the 24-hour epidural infusion period. In the studies, the combination treatment provided better pain control than clonidine, opioid or local anesthetic alone.
There is limited safety experience with levobupivacaine therapy for periods exceeding 24 hours. Therefore, use of levobupivacaine is not recommended for more than 24 hours.
Peripheral Nerve Administration: Levobupivacaine has been evaluated for its anesthetic efficacy when used as a peripheral nerve block. These clinical trials include brachial plexus (by supraclavicular approach) block study, infiltration anesthesia studies (for inguinal hernia repair), and peribulbar block studies.
Brachial Plexus Block: Levobupivacaine 0.25% and 0.50% were compared with 0.5% bupivacaine in 74 patients receiving brachial plexus (supraclavicular) block for elective surgery. In the levobupivacaine 0.25% treated group, 68% of patients achieved satisfactory block and in the levobupivacaine 0.50% 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: Levobupivacaine 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 treatments were seen.
Peribulbar Block Anesthesia: Two clinical trials were conducted to evaluate 0.75% levobupivacaine 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 ten mL (10 mL) injection of 0.75% levobupivacaine or bupivacaine produced a block adequate for surgery at a median time of ten minutes. In the second study, a five mL (5 mL) dose of 0.75% levobupivacaine or bupivacaine injected in a technique more closely resembling a retrobulbar block resulted in a median time to adequate block of two minutes for both treatments. Postoperative pain was reported in fewer than ten percent of patients overall.
See Table 1.
Click on icon to see table/diagram/image
After IV infusion of equivalent doses of levobupivacaine and bupivacaine, the mean clearance, volume of distribution, and terminal half-life values of levobupivacaine were similar. No detectable levels of R(+)-bupivacaine were found after the administration of levobupivacaine.
A comparison of the estimates for plasma AUC and Cmax
between levobupivacaine and bupivacaine in two Phase III clinical trials involving short duration administration of either agent found that neither total plasma exposure nor Cmax
differed between the two drugs when compared within studies. Between study values differed somewhat, likely due to differences in injection sites, volume, and total dose administered in each of the studies. These data suggest that levobupivacaine and bupivacaine have a similar pharmacokinetic profile. Pharmacokinetic data from the two Phase III studies are presented in Table 2. (See Table 2.)
Click on icon to see table/diagram/image
Between 0.5% and 0.75% levobupivacaine given epidurally at doses of 75 mg and 112.5 mg respectively, the mean Cmax
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 Cmax
of levobupivacaine were approximately dose-proportional.
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 Cmax
levels of up to 1.2 mcg/mL.
Plasma protein binding of levobupivacaine evaluated in vitro was found to be >97% at concentrations between 0.1 and 1 mcg/mL. The association of levobupivacaine with human blood cells was very low (0 to 2%) over the concentration range 0.01 to 1 mcg/mL and increased to 32% at 10 mcg/mL. The volume of distribution of levobupivacaine after intravenous administration was 67 liters.
Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine and 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 in both in vitro and in vivo
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.
The limited data available indicate that while there are some differences in Tmax
, and AUC with regards to age (between age groups of <65, 65 to 75, and >75 years), these differences are small and vary depending on the site of administration.
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.
No pharmacokinetic data of levobupivacaine are available in the pediatric population.
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.
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).
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.
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.
Toxicology: Pre-Clinical Safety Data:
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term studies in animals of most local anesthetics, including levobupivacaine, to evaluate the carcinogenic potential have not been conducted. Mutagenicity was not observed in bacterial mutation assay, mouse lymphoma cells mutation assay, chromosome aberrations in human blood lymphocytes, and micronuclei in the bone marrow of treated mice. Studies performed with levobupivacaine in rats at 30 mg/kg/day (180 mg/m2
/day) did not demonstrate an effect on fertility or general reproductive performance over two generations. This dose is approximately one-half the maximum recommended human dose (570 mg/person) based on body surface area (352 mg/m2