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Pharmacotherapeutic group: Local anaesthetics, amide. ATC Code: N01B B10.
Pharmacology: Pharmacodynamics: Levobupivacaine is a long acting local anaesthetic and analgesic. It blocks nerve conduction in sensory and motor nerves largely by interacting with voltage sensitive sodium channels on the cell membrane, but also potassium and calcium channels are blocked. In addition, levobupivacaine interferes with impulse transmission and conduction in other tissues where effects on the cardiovascular and central nervous systems are most important for the occurrence of clinical adverse reactions.
The dose of levobupivacaine is expressed as base, whereas, in the racemate bupivacaine the dose is expressed as hydrochloride salt. This gives rise to approximately 13% more active substance in levobupivacaine solutions compared to bupivacaine. In clinical studies at the same nominal concentrations levobupivacaine showed similar clinical effect to bupivacaine.
In a clinical pharmacology study using the ulnar nerve block model, levobupivacaine was equipotent with bupivacaine.
There is limited safety experience with levobupivacaine therapy for periods exceeding 24 hours.
Pharmacokinetics: Absorption: In human studies, the distribution kinetics of levobupivacaine following i.v. administration are essentially the same as bupivacaine.
The plasma concentration of levobupivacaine following therapeutic administration depends on dose and, as absorption from the site of administration is affected by the vascularity of the tissue, on route of administration. Experience from clinical studies shows onset of sensory block adequate for surgery in 10-15 minutes following epidural administration, with a time to regression in the range of 6-9 hours.
In a clinical pharmacology study where 40 mg levobupivacaine was given by intravenous administration, the mean half-life was approximately 80 ± 22 minutes, Cmax 1.4 ± 0.2 μg/ml and AUC 70 ± 27 μg·min/ml.
The mean Cmax and AUC(0-24h) of levobupivacaine were approximately dose-proportional following epidural administration of 75 mg (0.5%) and 112.5 mg (0.75%) and following doses of 1 mg/kg (0.25%) and 2 mg/kg (0.5%) used for brachial plexus block. Following epidural administration of 112.5 mg (0.75%) the mean Cmax and AUC values were 0.58 μg/ml and 3.56 μg·h/ml respectively.
Distribution: Plasma protein binding of levobupivacaine in man was evaluated in vitro and was found to be >97% at concentrations between 0.1 and 1.0 μg/ml.
The volume of distribution after intravenous administration was 67 litres.
Biotransformation: There are no relevant data in patients with hepatic impairment (see Precautions).
Levobupivacaine is extensively metabolised with no unchanged levobupivacaine detected in urine or faeces. 3-hydroxylevobupivacaine, a major metabolite of levobupivacaine, is excreted in the urine as glucuronic acid and sulphate ester conjugates. In vitro studies showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl-levobupivacaine and 3-hydroxylevobupivacaine respectively. These studies indicate that the metabolism of levobupivacaine and bupivacaine are similar.
There is no evidence of in vivo racemisation of levobupivacaine.
Elimination: There are no data in patients with renal impairment. Levobupivacaine is extensively metabolised and unchanged levobupivacaine is not excreted in urine.
The mean total plasma clearance and terminal half-life of levobupivacaine after intravenous infusion were 39 litres/hour and 1.3 hours, respectively.
Following intravenous administration, recovery of levobupivacaine was quantitative with a mean total of about 95% being recovered in urine (71%) and faeces (24%) in 48 hours.
Toxicology: Preclinical safety data: In an embryo-foetal toxicity study in rats, an increased incidence of dilated renal pelvis, dilated ureters, olfactory ventricle dilatation and extra thoraco-lumbar ribs was observed at systemic exposure levels in the same range as those obtained at clinical use. There were no treatment-related malformations.
Levobupivacaine was not genotoxic in a standard battery of assays for mutagenicity and clastogenicity. No carcinogenicity testing has been conducted.
