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Based on findings that the cardiotoxicity infrequently observed with racemic bupivacaine shows enantioselectivity, i.e. it is more pronounced with the R(+)-enantiomer, the S(−)-enantiomer (levobupivacaine) has been developed for clinical use as a long acting local anaesthetic.
The majority of in vitro, in vivo and human pharmacodynamic studies of nerve block indicate that levobupivacaine has similar potency to bupivacaine. However, levobupivacaine had a lower risk of cardiovascular and CNS toxicity than bupivacaine in animal studies. In human volunteers, levobupivacaine had less of a negative inotropic effect and, at intravenous doses >75mg, produced less prolongation of the QTc interval than bupivacaine. Fewer changes indicative of CNS depression on EEG were evident with levobupivacaine.
Levobupivacaine is long acting with a dose-dependent duration of anaesthesia. The onset of action is ≤15 minutes with various anaesthetic techniques. In studies of surgical anaesthesia in adults, levobupivacaine provided sensory block for up to 9 hours after epidural administration of ≤202.5mg, 6.5 hours after intrathecal 15mg, and 17 hours after brachial plexus block with 2 mg/kg. Randomised, double-blind clinical studies established that the anaesthetic and/or analgesic effects of levobupivacaine were largely similar to those of bupivacaine at the same dose. Sensory block tended to be longer with levobupivacaine than bupivacaine, amounting to a difference of 23 to 45 minutes with epidural administration and approximately 2 hours with peripheral nerve block. With epidural administration, levobupivacaine produced less prolonged motor block than sensory block. This differential was not seen with peripheral nerve block. Conditions satisfactory for surgery and good pain management were achieved by use of local infiltration or peribulbar administration of levobupivacaine. Levobupivacaine was generally as effective as bupivacaine for pain management during labour, and was effective for the management of postoperative pain, especially when combined with clonidine, morphine or fentanyl.
The tolerability profiles of levobupivacaine and bupivacaine were very similar in clinical trials. No clinically significant ECG abnormalities or serious CNS events occurred with the doses used. The most common adverse event associated with levobupivacaine treatment was hypotension (31%).
Conclusions: Levobupivacaine is a long acting local anaesthetic with a clinical profile closely resembling that of bupivacaine. However, current preclinical safety and toxicity data show an advantage for levobupivacaine over bupivacaine. Clinical data comparing levobupivacaine with ropivacaine are needed before the role of the drug can be fully established. Excluding pharmacoeconomic considerations, levobupivacaine is an appropriate choice for use in place of bupivacaine.
Levobupivacaine is a long acting, amide-type local anaesthetic that is the S(−) \3- isomer of the racemate bupivacaine. In general, in vitro, in vivo and human volunteer studies of nerve block indicate that levobupivacaine is as potent as bupivacaine and produces similar sensory and motor block. A trend towards a longer sensory block with levobupivacaine was seen in some studies, and may be related to the greater vasoconstrictive activity of levobupivacaine than that of the R(+)-enantiomer (dexbupivacaine) at lower doses. The minimum local analgesic concentration was 0.083% for epidural levobupivacaine 20ml and 0.081% for bupivacaine 20ml in women in the first stage of labour.
Levobupivacaine has been consistently less toxic than bupivacaine in animal models. The lethal dose of levobupivacaine was 1.3- to 1.6-fold higher than that of bupivacaine in most animal studies, providing supportive evidence for a safety advantage over bupivacaine. In vitro findings indicating a lower risk of cardiotoxicity with levobupivacaine compared with dexbupivacaine and/or bupivacaine have included lesser effects or lower potency in: blocking cardiac sodium channels in the inactivated state; blocking cardiac potassium channels; reducing the maximal rate of depolarisation; prolonging atrioventricular conduction; and prolonging QRS interval duration. Differences between the agents with regards to effects on contractility seem to be less consistent, but levobupivacaine also appears to be less detrimental in this regard. In animal studies, levobupivacaine was associated with fewer and less severe cardiac disturbances, especially ventricular arrhythmias. In human volunteers, intravenous levobupivacaine (mean dose 56mg) produced less of a negative inotropic effect than bupivacaine (48mg). In another study of intravenous administration, the mean maximum increase in QTc interval was significantly less with levobupivacaine than with bupivacaine (3 vs 24 msec) in volunteers receiving >75mg.
A lower risk of CNS toxicity with levobupivacaine compared with dexbupivacaine and/or bupivacaine has also been reported, including less propensity to cause apnoea and higher convulsive doses (levobupivacaine 103mg vs bupivacaine 85mg) in animal studies. In human volunteers, 64% of intravenous bupivacaine recipients (mean dose 65.5mg) compared with 36% of levobupivacaine (67.7mg) recipients experienced central or peripheral nervous system disorders. Intravenous levobupivacaine 40mg produced fewer changes indicative of CNS depression on EEG than bupivacaine 40mg in volunteers.
When compared with ropivacaine in animals, levobupivacaine had similar or more pronounced nerve blocking effects, depending on the concentration and model. Levobupivacaine and ropivacaine had generally similar cardiovascular effects in in vitro and animal studies, although some studies reported greater QRS interval prolongation and/or arrhythmogenic risk with levobupivacaine at some concentrations, but no difference in mortality rates. However, cardiotoxicity has not been compared at established equipotent anaesthetic doses.
Only limited pharmacokinetic data are available for levobupivacaine. The plasma concentrations of levobupivacaine are dependent on dose and route of administration. Maximum plasma concentrations were 0.58 to 1.02 mg/L after epidural administration of 75 to 150mg, and 0.47 and 0.96 mg/L after brachial plexus block with 1 and 2 mg/kg, respectively, in patients. The elimination half-life after intravenous administration of 40mg in volunteers was 1.3 hours and the volume of distribution was 67L. Levobupivacaine is highly protein bound (>97%). The drug is extensively metabolised by the cytochrome P450 (CYP) system, primarily CYP1A2 and CYP3A4 isoforms, and then excreted in the urine (71% within 48 hours) and faeces (24%).
Levobupivacaine crosses the placenta, with an umbilical vein/maternal vein drug concentration ratio of 0.3 after epidural levobupivacaine 0.5% (150mg) in women undergoing Caesarean section.
After administration of racemic bupivacaine, it appears that systemic disposition is enantioselective, particularly with regards to plasma protein binding, which is higher with levobupivacaine than dexbupivacaine. Levobupivacaine does not undergo racaemisation in vivo.
Most trials of levobupivacaine have been randomised and double-blind and have involved 20 to 137 patients. All but 1 trial were in adults.
Surgical Anaesthesia: Levobupivacaine is long acting with an onset of action ≤15 minutes. The duration of action is dose-dependent and varies according to the anaesthetic technique. Adequate sensory and motor block for surgery was achieved in ≥90% of adult patients receiving adequate doses of levobupivacaine with satisfactory anaesthetic technique in most of the 10 available clinical trials. The anaesthetic and/or analgesic effects of levobupivacaine were largely similar to those with bupivacaine at the same dose in all comparative studies, including those of epidural, peripheral nerve block (supraclavicular or axillary brachial plexus nerve block), local infiltration and peribulbar administration. The duration of sensory block tended to be longer with levobupivacaine, although the difference was not statistically significant compared with bupivacaine in most cases. After epidural administration, the duration of sensory block with levobupivacaine was 8 to 9 hours with 0.75% (112.5 to 202.5mg), 7.5 hours with 0.5% (150mg) and 6 hours with 0.5% (75mg), and was 23 to 45 minutes longer than with bupivacaine at the same dose. The duration of sensory block after intrathecal levobupivacaine 15mg was 6.5 hours. With peripheral nerve block, the duration of sensory block was 17 hours with levobupivacaine 0.5% (2 mg/kg) versus 15 hours with bupivacaine 0.5% (2 mg/kg) or levobupivacaine 0.25% (1 mg/kg). With epidural administration, levobupivacaine produced less prolonged motor block than sensory block. This differential was not seen with peripheral nerve block.
Pain Management: Analgesia attained with epidural levobupivacaine was generally similar to that with bupivacaine in women in labour in the 2 available studies. The median time to onset of pain relief was 12 minutes and the duration of pain relief was approximately 50 minutes with levobupivacaine or bupivacaine 0.25% (25mg). With another regimen (mean dose of levobupivacaine 28 mg/h, bupivacaine 27 mg/h), 43% of the first stage of labour was pain free in both groups.
Effective postoperative pain relief was attained by combining epidural levobupivacaine 0.125% (7.5 mg/h) with clonidine, levobupivacaine 0.25% (10 mg/h) with morphine or levobupivacaine 0.125% (5 mg/h) with fentanyl or using higher doses of levobupivacaine 0.25% (15 mg/h). The time to first request for rescue analgesia was 10 to 17 hours. The combined regimens were more effective than any of the comparator agents alone, and the higher dose was more effective than lower doses of levobupivacaine. Ilioinguinal/iliohypogastric nerve block with levobupivacaine 0.5% (1.25 mg/kg per operated side) at the conclusion of surgery provided better pain relief than placebo in children.
When used at the lower doses needed for pain management, most patients did not have significant motor block.
The tolerability profiles of levobupivacaine and bupivacaine were very similar in clinical trials. The most common adverse events associated with levobupivacaine anaesthesia in 1141 patients in phase II/III trails (regardless of causality to the drug; route not stated) were: hypotension (31%), nausea (21%), postoperative pain (18%), fever (17%), vomiting (14%), anaemia (12%), pruritus (9%), pain (8%), headache (7%), constipation (7%), dizziness (6%) and fetal distress (5%).
Levobupivacaine and bupivacaine generally exerted similar effects on blood pressure and heart rate. No clinically significant ECG abnormalities occurred in clinical trials. No serious adverse CNS events were caused by levobupivacaine at the doses used; a small number of patients reported transient hypoaesthesia or paraesthesia, but these effects may have been operation-related. When levobupivacaine was used in obstetric indications, fetal outcome was not significantly different with levobupivacaine and bupivacaine. No significant CNS toxicity or cardiotoxicity was seen in a patient who received prompt treatment following an unintentional intravascular injection of levobupivacaine 142.5mg.
Dosage and Administration
Indications and recommended dosages for levobupivacaine differ markedly between Europe and the US.
The indications for levobupivacaine in Europe include epidural, intrathecal, peripheral nerve block, peribulbar administration and local infiltration for surgical anaesthesia in adults. Levobupivacaine is also indicated for epidural use for the management of pain, including labour and postoperative pain in adults. In children, levobupivacaine is indicated for ilioinguinal/iliohypogastric nerve block. The recommended maximum single dose for surgical anaesthesia in adults (other than for intrathecal administration) is generally 150mg. Additional doses may be required for a prolonged procedure. The recommended maximum single dose for intrathecal administration is 15mg. The recommended maximum epidural dose for labour analgesia is a 0.125% infusion of 12.5 mg/h or epidural injections of 0.25% up to 25mg at ≥15-minute intervals. For postoperative pain management in adults, the dose should not exceed 18.75 mg/h. The maximum dose for children undergoing ilioinguinal/iliohypogastric block is 1.25 mg/kg/ side.
In the US, levobupivacaine is indicated for epidural, peripheral nerve block, peribulbar administration and local infiltration for surgical anaesthesia in adults. Levobupivacaine is also indicated for epidural use for the management of pain, including labour and postoperative pain in adults. The drug is not currently indicated in the US for intrathecal administration or use in children. Surgical anaesthesia doses are similar to those in Europe, but doses of up to 50mg can be given for labour analgesia and up to 25 mg/h for postoperative pain management.
According to European prescribing information, the use of 0.75% (7.5 mg/ml) of levobupivacaine is contraindicated in obstetric patients; this is based on experience with bupivacaine and the 0.75% concentration of levobupivacaine has not been studied in obstetric patients. Concentrations up to 0.5% (150mg) can be used for Caesarean section. The drug is contraindicated for paracervical block in obstetrics and intravenous regional anaesthesia (Bier’s block) as well as in patients with severe hypotension or known hypersensitivity to local anaesthetics of the amide type.
US product labelling carries warnings against the use of levobupivacaine in obstetric patients at the 0.75% concentration, obstetrical paracervical block, and intravenous regional anaesthesia. Use of levobupivacaine in patients with known hypersensitivity to amide-type local anaesthetics is contraindicated.
Levobupivacaine should be used with caution in patients with impaired cardiovascular function or liver disease or reduced liver blood flow.
As with all local anaesthetics, epidural levobupivacaine can cause hypotension, bradycardia and possibly cardiac arrest. Appropriate treatments, equipment and personnel should be readily available in the event that a serious adverse event occurs. The toxic effects of other local anaesthetics, antiarrhythmic agents with local anaesthetic activity or class III antiarrhythmic agents may be additive to those of levobupivacaine.
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