Drug Criteria & Outcomes: Levobupivacaine (Chirocaine) Formulary Evaluation

By Elizabeth Butler, PharmD Written as a PharmD candidate at McWhorter School of Pharmacy, Samford University, Birmingham, AL

Local anesthetics

Bupivacaine — various manufacturers

Levobupicaine (Chirocaine) — Purdue Pharma L.P.

Mechanism of action

Local anesthetic agents such as levobupivacaine and bupivacaine are amide anesthetics, and they exert their action by affecting voltage-sensitive ion channels on excitable membranes. They potentiate this action by blocking impulse transmission through sodium channels, which occurs in sensory and motor nerves involved in perception and coordination. Hindrance of nerve impulse transmission in these nerves produces decreased muscle control and local anesthesia. Because sodium channels are so abundant in the body, these agents also exert some effects on the central nervous system and on smooth muscle and cardiac muscle. It is this action that contributes to the side effects seen with these agents.

Indications

Levobupivacaine is indicated for the production of local or regional anesthesia for surgery and obstetrics, and for postoperative pain management. In surgical anesthesia, levobupivacaine can be used in an epidural, as a peripheral neural blockade, and for local infiltration. In pain management, levobupivacaine can be used for continuous epidural infusion, intermittent epidural neural blockade, continuous or intermittent peripheral neural blockade, or local infiltration. For continuous epidural analgesia, levobupivacaine can be used in combination with epidural fentanyl or clonidine. Dosage of levobupivacaine should begin with a small test dose and be followed by small increments to produce effective analgesia with the smallest dose possible.

Pharmacokinetics

The pharmacokinetic profiles of levobupivacaine and bupivaine are summarized in Table 1.1

Clinical studies

Management of labor pain. A multicenter, randomized, double-blind, parallel group study of 137 patients comparing levobupivacaine 0.25% and bupivacaine 0.25% for epidural analgesia for labor pain found that levobupivacaine produced similar analgesia rates as bupivacaine.2,3 In another randomized, double-blind, parallel group study comparing levobupivacaine 0.125% and bupivacaine 0.125%, levobupivacaine was found to exhibit similar efficacy for labor analgesia as bupivacaine.4 The major limitation of these studies was small sample size; only 80 patients were evaluated in the Kopacz study.4 The recommended dose of levobupivacaine 0.25%, administered as an intermittent epidural bolus, is 10-20 mL (25-50 mg). In both of these studies, no major adverse effects were noted, and incidence of mild-to-moderate adverse events was the same between the two medications.

Epidural anesthesia for surgery. A randomized, double-blind, three-arm parallel group study compared the efficacy of two concentrations of levobupivacaine (0.5% and 0.75%) with bupivacaine 0.5%.5 Levobupivacaine 0.75% produced significantly longer duration of sensory block than did 0.5% levobupivacaine or bupivacaine. Similar efficacy was noted between levobupivacaine 0.5% and bupivacaine 0.5%. The number of patients (n = 57) limited this trial, and the sponsor was the manufacturer of levobupivacaine. Another randomized, double-blind, parallel group study compared levobupivacaine 0.75% to bupivacaine 0.75%. This study found similar efficacy between the two groups.3

Management of postoperative pain. A multicenter, randomized, double-blind, three parallel group study compared three concentrations of levobupivacaine for the treatment of postoperative pain.6 Patients in the levobupivacaine 0.0625% treatment group experienced more postoperative pain than did the patients in the levobupivacaine 0.125% and 0.25% groups. The 0.0625% concentration and the 0.125% concentration are not recommended for use as adjuncts in managing postoperative pain. Another study found levobupivacaine 0.125% to be efficacious as an adjunct when combined with fentanyl or clonidine for the management of postoperative pain.7,8

In general, the clinical studies shown here found similar efficacy between levobupivacaine and bupivacaine. The side effect profiles of both medications are similar; however, side effects develop at slightly lower doses of bupivacaine than levobupivacaine. In some cases, this difference was not statistically significant. The adverse effects occurring in these studies were similar between groups, with no major adverse effects occurring in either group.

Levobupivacaine’s manufacturer is promoting this difference as the reason to use levobupivacaine instead of bupivacaine. Also, the European manufacturer of levobupivacaine sponsored all the clinical trials mentioned above, and the numbers of patients studied were relatively small.

Adverse effects

The most dangerous side effects of this class of drugs occur with inadvertent intravascular injection. The result may be ventricular tachycardia or ventricular fibrillation. Clinical manifestations of central nervous system (CNS) and cardiac effects include lightheadedness, tinnitus, and numbness of tongue. More serious effects may present as convulsions, decreased cardiac function, potential arrhythmias, and cardiovascular collapse and death. These side effects can occur with both levobupivacaine and bupivacaine. One study tested the effects of levobupivacaine and bupivacaine when injected intravenously in sheep.9 This study found the mean dose at which seizures occurred was 85 mg for bupivacaine and 103 mg for levobupivacaine. Several sheep died with doses of 125, 150, and 200 mg of bupivacaine; however, no animals died at the same doses of levobupivacaine. It should be noted that these doses are larger than usual doses in epidural anesthesia. Large doses (greater than 100 mg) of both medications caused left ventricular myocardial fiber shortening.9

Bupivacaine doses of greater than 75 mg and levobupivacaine doses of greater than 100 mg caused increased heart rate. This increase occurred at lower doses with bupivacaine than with levobupivacaine. Large doses of both medications produced QRS prolongation; however, there was no significant difference between the two medications in this respect. In general, bupivacaine produced more significant arrhythmias than levobupivacaine. The arrhythmias caused by levobupivacaine were transient and caused no permanent sequale.9 This study had some major limitations including extremely small sample size (only 14 sheep were studied), possible introduction of bias in support of the article, direct intravenous administration, and the fact that the study was performed in sheep. The company that manufactures levobupivacaine in Europe sponsored this article.

Another study evaluated the safety of levo-bupivacaine and bupivacaine in 14 healthy volunteers.10 The doses used in this study were between 100 and 200 mg. This study found mild-to-moderate CNS symptoms occurred after intravenous administration in all participants with both medications. Both drugs produced slight increases in the PR and QTc intervals, but the differences between the two drugs were not statistically significant.

Bupivacaine caused a greater decrease in stroke index, acceleration index, and ejection fraction than did levobupivacaine.10 This indicates that levobupivacaine may be used as an alternative drug in patients needing high doses of local anesthetics. This study also has several limitations including small sample size and inclusion of healthy subjects. The manufacturer of levobupivacaine sponsored the trial.

It is important to remember that all the studies regarding safety of these medications were conducted with intravenous administration. These medications are approved only for epidural or local use.

Bupivacaine is classified as pregnancy category C, and levobupivacaine is classified as category B. These two drugs will be administered most frequently near delivery time in pregnancy situations.

Drug interactions

Levobupivacaine should be used with caution in patients who are receiving other local anesthetics or agents structurally related to amide-type local anesthetics. The metabolism of levobupivacaine could be affected by known CYP3A4 inducers such as phenytoin, phenobarbital, and rifampin, and by CYP3A4 inhibitors such as ketoconazole, protease inhibitors, erythromycin, and verapamil. No drug interactions have been reported; however, these mentioned medications have the potential to interact with levobupivacaine.

Cost

If levobupivacaine replaced bupivacaine on the formulary, and usage in the next year is comparable to the past 12 months usage, the additional cost to the hospital for levobupivacaine would be about $45,000/yr. For more pricing information, see Table 2.11

Summary and recommendations

According to the data presently available, including clinical trials, both levobupivacaine and bupivacaine demonstrate approximately the same efficacy and safety. Bupivacaine is available as generic and levobupivacaine is not. This would present a large cost difference. Because of the similarity between the two drugs, it is difficult to select one over the other in terms of efficacy. Safety is a concern with patients who require high doses of local anesthetics, and in patients with high cardiac risk. The differences in safety between levobupivacaine and bupivacaine are not significant enough to warrant the use of levobupivacaine exclusively.

An important factor to explore is the cost to the hospital of a complete change to levobupivacaine. If levobupivacaine must be added to the formulary, then criteria for use should be established and each patient should meet these criteria before levobupivacaine is dispensed. Some examples of possible inclusion criteria for levobupivacaine use include the use of high doses of anesthetics, increased cardiovascular risk of developing arrhythmias, and pregnant women at increased risk of developing cardiac complications.

References

1. Levobupivacaine Package Insert. Stamford, CT: Purdue Pharma, L.P.; 2000.

2. Burke D, Henderson DJ, Simpson AM, et al. Comparison of 0.25% S(-)-bupivacaine with 0.25% RS-bupivacaine for epidural analgesia in labour. Br J Anasth 1999;83:750-755.

3. Kopacz DJ, Allen HW, Thompson GE. A comparison of epidural levobupivacaine 0.75% with racemic bupivacaine for lower abdominal surgery. Anasth Analg 2000; 90:642-648.

4. Convery P, Burke D, Donaldson L, et al. Comparison of 0.125% levobupivacaine and 0.125% bupivacaine epidural infusions for labour analgesia. Br J Anasth 1999;82(Suppl 1):163.

5. Bader AM, Tsen LC, Camann WR, et al. Clinical effects and maternal and fetal concentrations of 0.5% epidural levobupivacaine versus bupivacaine for cesarean delivery. Anesthesiology 1999;90:1596-1601.

6. Dickson U, Murdoch J, Wilson P, et al. The efficacy and safety of levobupivacaine administered as a continuous epidural infusion for postoperative analgesia in patients undergoing elective orthopaedic surgery. Reg Anesth Pain Med 1999;24(suppl):18.

• Kopacz DJ, Sharrock NE, Allen HW. A comparison of levobupivacaine 0.125%, fentanyl 4 mcg/mL, or their combination for patient controlled epidural analgesia after major orthopedic surgery. Anasth Analg 1999;89:1497-1503.

• Milligan KR, Convery PN, Weir P, et al. The efficacy and safety of epidural infusions of levobupivacaine with and without clonidine for postoperative pain relief in patients undergoing total hip replacement. Anasth Analg 2000;91:393-397.

• Huang YF, Pryor ME, Mather LE, et al. Cardiovas-cular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep. Anasth Analg 1998;86:797-804.

• Bardsley H, Gristwood R, Baker H, et al. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol 1998;46:245-249.

• Hall, Cindy. Pharmacy buyer. Huntsville Hospital System Pharmacy. January 2002.