Description: Levobupivacaine is an amino amide type of local anesthetic. Levobupivacaine is the S (-)-enantiomer of bupivacaine. Levobupivacaine produces sensory and motor blockade that is similar to bupivacaine. In a randomized, double blind study, there was no significant difference in onset time, maximum spread of sensory block, or intensity of motor block in patients receiving lumbar epidural anesthesia with either levobupivacaine or bupivacaine. The duration of sensory block was significantly longer in the levobupivacaine 0.75% group than in the levobupivacaine 0.5% or bupivacaine 0.5% groups. Levobupivacaine exhibits less cardiotoxicity than bupivacaine. In studies of levobupivacaine in healthy volunteers, levobupivacaine had less effect of myocardial contractility, stroke volume, and a weaker effect on the corrected QT interval than the same doses of bupivacaine. The threshold for CNS effects of levobupivacaine is higher than that of bupivacaine, and levobupivacaine is associated with fewer central or peripheral nervous system effects. The FDA approved levobupivacaine in August 1999 for the production of local or regional surgical or obstetric anesthesia, and for post-operative pain management. Mechanism of Action: As with other local anesthetics, levobupivacaine blocks the generation and conduction of nerve impulses at the level of the cell membrane. Local anesthetics block conduction by preventing the transient increase in permeability of excitable membranes. Local anesthetics bind directly within the intracellular portion of voltage-gated sodium channels. The degree of block produced by local anesthetics is dependent upon how the nerve has been stimulated and on its resting membrane potential. Local anesthetics are only able to bind to sodium channels in their charged form and when the sodium channels are open. In this situation, the local anesthetic is able to bind more tightly to and stabilize the sodium channel. Differences in pKa, lipid solubility, and molecular size affect the ability of different local anesthetics to bind to the sodium channels. In general, small nerve fibers are more sensitive to local anesthetics than large nerve fibers. However, myelinated fibers are blocked before non-myelinated fibers of the same diameter. Autonomic fibers, small unmyelinated C fibers (mediating pain) and small myelinated Adelta fibers (mediating pain and temperature sensation) are blocked before larger myelinated A-gamma, Abeta, or Aalpha fibers (mediating touch, pressure, muscle and postural inputs). Small, sensory fibers are preferentially blocked since nerve conduction is more easily blocked over shorter distances and these fibers have longer action potentials allowing more of the local anesthetic to bind. Clinically, the loss of nerve function proceeds as loss of pain, temperature, touch, proprioception, and then skeletal muscle tone. Pharmacokinetics: Levobupivacaine is given parenterally either as an epidural infusion or a regional nerve block. Systemic absorption of levobupivacaine is dependent upon the site of administration, the dose, and the vascularity of the tissue. The slower rate of dissociation of levobupivacaine from proteins and adipose tissue at the injection site differentiates levobupivacaine from other local anesthetics. Peak plasma levels of levobupivacaine are reached approximately 30 minutes after epidural administration. Epidural doses of levobupivacaine 150 mg result in Cmax levels of up to 1.2 µg/ml. Levobupivacaine is highly protein bound (>97%). When local anesthetics are absorbed into the circulation, they are initially taken up in the lungs, which may limit the amount of drug reaching the systemic circulation. Levobupivacaine is extensively metabolized by hepatic cytochrome P450 (CYP) isoenzymes 3A4 and 1A2 to desbutly- and 3-hydroxy-levobupivacaine, respectively. The 3-hydroxy metabolite undergoes further transformation to glucuronide and sulfate conjugates. Concurrent administration of drugs that may inhibit or induce these enzymes may affect the metabolism of levobupivacaine (see Drug Interactions). Metabolic inversion of levobupivacaine to R (+)-bupivacaine was not seen in vitro or in vivo. Approximately 95% of the dose is recovered in the urine (71%) or feces (24%) within 48 hours following intravenous administration. The terminal half-life of levobupivacaine following intravenous administration is 1.3 hours. No specific studies have been performed in patients with hepatic or renal disease. There is no evidence that levobupivacaine accumulates in patients with renal failure; however, some metabolites may accumulate since they are excreted by the kidney. Changes in hepatic function may adversely effect the metabolism of levobupivacaine and necessitate lower doses or an increased interval between repeated doses. Limited data indicate there are some differences in pharmacokinetics with regard to age (i.e., patients <65, 65—75, and > 75 years); however, these differences are small and vary depending upon the site of administration.
Indications...Dosage For use as local anesthesia or regional anesthesia: NOTE: Doses listed below are those considered necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration may occur. •for epidural anesthesia during surgery: Epidural dosage: Adults: 10—20 ml (50—150 mg) of 0.5%—0.75% levobupivacaine as an epidural infusion. This dose results in moderate to complete motor blockade. •for caesarean section anesthesia: Epidural dosage: Adults: 20—30 ml (100—150 mg) of 0.5% levobupivacaine administered as an epidural infusion. This dose results in moderate to complete motor blockade. The maximum dose of levobupivacaine in obstetric patients is 150 mg epidurally. Levobupivacaine 0.75% is not indicated in obstetric patients. •for ophthalmic anesthesia: Regional dosage: Adults: 5—15 ml (37.5—112.5 mg) of 0.75% levobupivacaine. •for peripheral nerve block anesthesia including brachial plexus nerve block: Regional dosage: Adults: 30 ml (75—150 mg) or 0.4 ml/kg (1—2 mg/kg) of 0.25—0.5% levobupivacaine results in moderate to complete motor blockade. •for infiltration anesthesia for intraabdominal anesthesia: Regional dosage: Adults: 60 ml (150 mg) of 0.25% levobupivacaine as infiltration administration. For the management of severe pain: •for post-operative pain (either alone or in combination with fentanyl or clonidine): Epidural dosage: Adults: 4—10 ml/hour (5—25 mg/hour) of 0.125—0.25% levobupivacaine as an epidural infusion. •for obstetric anesthesia during labor and delivery: Epidural dosage: Adults: 10—20 ml (25—50 mg) of 0.25% levobupivacaine injection as an epidural bolus. This dose results in minimal to moderate motor blockade. The total maximum dose of levobupivacaine in obstetric patients is 150 mg epidurally. Levobupivacaine 0.75% concentration is not indicated in obstetric patients. (Also see caesarean section anesthesia for epidural dosage.) Maximum Dosage Limits: NOTE: The dose of local anesthetics differs with the anesthetic procedure; the area to be anesthetized; the vascularity of the tissues; the number of neuronal segments to be blocked; the intensity of the block; the degree of muscle relaxation required; the duration of anesthesia desired; individual tolerance; and the physical condition of the patient. •Adults: Epidural doses up to 375 mg have been administered incrementally to patients during surgical procedures. The maximum dose for intraoperative block and post-operative analgesia has been 695 mg/24 hours. The maximum dose administered as a post-operative epidural infusion has been 570 mg/24 hours. The maximum dose administered as a single fractionated injection has been 300 mg for a brachial plexus block. The maximum dose of levobupivacaine in obstetric patients is 150 mg epidurally. •Children: Maximum dosage information is not available. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Patients with hepatic impairment: Levobupivacaine is extensively metabolized by the liver. Lower doses of levobupivacaine may be required in patients with hepatic dysfunction due to prolonged effects and systemic accumulation. Specific dosage guidelines are not available.
Administration Parenteral Administration •Specialized references should be consulted for specific procedures and administration techniques. •Resuscitative equipment and drugs used in the management of adverse reactions should be immediately available while administering local anesthetics. •Levobupivacaine is administered by infiltration or peripheral block techniques. Avoid intravascular administration. •Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Peripheral block: •Inject slowly and with frequent aspirations to prevent intravascular injection. Epidural Administration •This route of administration should only be used by specially trained healthcare professionals. Specialized references should be consulted for specific procedures and administration techniques. •Resuscitative equipment and drugs used in the management of adverse reactions should be immediately available while administering local anesthetics. •May be given as intermittent bolus, continuous infusion or as patient controlled epidural analgesia. •Placement of the epidural catheter and administration should be at a site near the dermatomes covering the field of pain to decrease dose requirements and increase specificity. •A test dose of 3 ml of a short acting amide anesthetic (e.g., lidocaine with epinephrine) is recommended to detect unintentional intrathecal administration. This will be manifested within a few minutes by signs of subarachnoid block (e.g., decreased sensation of the buttocks, paresis of the legs or absence of knee jerk reflex). •Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Unopened solutions should be discarded if a precipitate is present that does not disappear with shaking. Epidural injection: •Injections containing preservatives should not be used for epidural injections. Discard any partially used injections that do not contain preservatives. •After ensuring proper placement of the needle or catheter, inject appropriate dose in 3—5 ml increments into the epidural. Inject doses slowly with frequent aspirations. Time should be taken in between doses to evaluate for toxic manifestations of inadvertent intravascular or intrathecal injection. Epidural infusion: •A controlled-infusion device must be used. For highly concentrated injections, an implantable controlled-microinfusion device is used. Patients should be monitored for several days following implantation of the device. •Injections containing preservatives should not be used for epidural infusion. Discard any partially used injections that do not contain preservatives. •Preservative-free NS injection is recommended for dilution. •Implantable controlled epidural infusion device: Filling of the infusion device reservoir should only be done by fully trained and qualified healthcare professionals. Strict aseptic technique must be used. Withdraw dose from the ampule through a 5-µm (or smaller pore diameter) microfilter to avoid contamination with glass or other particles. Remove filter needle and replace with a clean needle prior to injecting dosage into the reservoir. Ensure proper placement of the needle when filling the reservoir to avoid accidental overdosage. •To avoid exacerbation of severe pain and/or reflux of CSF into the reservoir, depletion of the reservoir should be avoided.
Contraindications Local anesthetics should only be administered by a clinician trained in the diagnosis and management of drug-related toxicity and other acute emergencies that might arise from the administration of a regional anesthetic block. The immediate availability of oxygen, cardiopulmonary resuscitative equipment and drugs and the appropriate support personnel for the management of toxic reactions or emergencies must be ensured. Any delay in appropriate management may lead to the development of acidosis, cardiac arrest and possibly death. While performing levobupivacaine blocks, intravenous administration, intraarterial administration, or intrathecal administration should be avoided. Unintended intravenous or intraarterial administration may result in cardiac arrest and may require prolonged resuscitation. During epidural administration, a test dose of a local anesthetic with a fast onset (i.e., lidocaine) should be administered initially and the patient should be monitored for CNS and cardiovascular toxicity, as well as signs of inadvertent intrathecal administration (see Adverse Effects). Syringe aspiration should also be performed before and during each supplemental injection in continuous catheter techniques. Levobupivacaine should be administered in incremental doses with close monitoring between doses for signs of intravascular or intrathecal administration. Since levobupivacaine should not be injected rapidly in large doses, it is not recommended in emergency situations, where fast onset of surgical anesthesia is necessary. Intravenous regional anesthesia (Bier Block) should not be performed using levobupivacaine due to the lack of clinical experience and the risk of attaining toxic blood levels of levobupivacaine. During head and neck anesthesia, including dental and ophthalmic anesthesia, small doses of local anesthetics may produce adverse reactions similar to the systemic toxicity seen with unintentional intravascular injections of larger doses. Patients receiving local head and neck anesthesia are at increased risk of CNS toxicity due to potential intraarterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their ventilatory and circulatory systems monitored closely. Recommended doses should not be exceeded in these patients. When local anesthetics are used for retrobulbar block during ocular surgery, lack of corneal sensation should not be relied upon to determine whether or not the patient is ready for surgery. Lack of corneal sensation usually precedes clinically acceptable external ocular muscle akinesia. Local anesthetics should be used with caution in patients with hypotension, hypovolemia or dehydration, myasthenia gravis, shock, or cardiac disease. Patients with impaired cardiac function, particularly AV block, may be less able to compensate for functional changes associated with prolonged A-V conduction (i.e., PR or QT prolongation) caused by local anesthetics. Epidural and nerve block injections of levobupivacaine are contraindicated in patients with the following: infection or inflammation at the injection site, bacteremia, platelet abnormalities, thrombocytopenia < 100,000/mm3, increased bleeding time, uncontrolled coagulopathy, or anticoagulant therapy. Lumbar and caudal anesthesia should be used with extreme caution in patients with neurological disease, spinal deformities, sepsis, or severe hypertension. Elderly patients, especially those receiving treatment for hypertension, may be at increased risk for the hypotensive effects of levobupivacaine. Although, in clinical studies, no difference in efficacy and or safety was noted between elderly patients and younger patients. Greater sensitivity in some elderly patients cannot be ruled out. Levobupivacaine is contraindicated in patients with a known amide local anesthetic hypersensitivity. Due to extensive liver metabolism of levobupivacaine by cytochrome P450 (CYP) isoenzymes 3A4 and 1A2, dosage adjustments may be needed in patients with hepatic disease. In addition, any condition that affects liver blood flow, such as congestive heart failure, may result in increased toxicity due to decreased clearance of levobupivacaine. Repeated doses of levobupivacaine may cause a significant increase in blood levels with each successive dose. A decreased dosage and/or increase in the interval between doses may be necessary. Due to the extensive liver metabolism of levobupivacaine by hepatic microsomal isoenzymes, drugs that affect these enzymes may interact with levobupivacaine (see Drug Interactions). Local anesthetics are known to cross the placenta. Levobupivacaine is classified in FDA pregnancy category B. Well-controlled studies have not been performed in pregnant women; however, no toxicity was seen in animal studies. The 0.75% solution of levobupivacaine is not indicated for obstetric anesthesia during labor; levobupivacaine 0.5% in total doses up to 150 mg may be utilized for caesarean section. Inadvertent intravascular injections of the concentrated solution of bupivacaine have been associated with maternal cardiac arrest and death. Fetal heart rate should be monitored continuously during labor and delivery because fetal distress has occurred during regional anesthesia with levobupivacaine. During obstetric delivery, appropriate patient positioning may decrease maternal hypotension that can result from regional anesthesia. Injection of the local anesthetic should be performed with the patient in the left lateral decubitus position to displace the gravid uterus, thereby minimizing aortocaval compression. Paracervical nerve block with levobupivacaine for obstetrical anesthesia is not recommended. Use with caution in mothers who are breast-feeding because it is not known whether levobupivacaine is excreted in milk. The safety and efficacy of levobupivacaine have not been established in children.
Interactions Levobupivacaine is metabolized by cytochrome P450 (CYP) isoenzymes 3A4 and 1A2. Other drugs that affect these isoenzymes and are given concurrently with levobupivacaine may affect the efficacy of levobupivacaine. Agents that are known inducers of CYP 3A4 or CYP 1A2 such as carbamazepine, phenytoin, phenobarbital, rifabutin, and rifampin may decrease the half-life of levobupivacaine. Levobupivacaine is metabolized by cytochrome P450 (CYP) isoenzymes 3A4 and 1A2. Known inhibitors of either CYP 3A4 or CYP 1A2 such as amiodarone, azole antifungals, cimetidine, ciprofloxacin, clarithromycin, diltiazem, erythromycin, indinavir, isoniazid, INH, nefazodone, omeprazole, quinine, ritonavir, saquinavir, some SSRIs (e.g., fluoxetine, fluvoxamine, sertraline), venlafaxine, and verapamil, may result in increased systemic levels of levobupivacaine when given concurrently, resulting in toxicity. Dosage adjustments of levobupivacaine may be necessary. Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Dosage adjustment of the cholinesterase inhibitor may be necessary to control the symptoms of myasthenia gravis. Patients receiving MAOIs (including linezolid) and local anesthetics may have an increased risk of hypotension. It is advisable to discontinue MAOIs 10 days before surgery requiring a subarachnoid block. High doses of local anesthetics can prolong and enhance the effects of neuromuscular blockers by an unknown mechanism. Patients receiving antihypertensive agents may experience additive hypotensive effects during epidural administration of local anesthestics due to loss of sympathetic tone in some cases. Use of local anesthetics with rapid-onset vasodilators, such as nitrates, can result in hypotension. Concomitant use of low-dose local anesthetics (0.125—0.25%) and epidural opiate agonists (e.g., alfentanil, fentanyl, morphine, and sufentanil), may increase analgesia and decrease opiate dosage requirements. The vagal effects and respiratory depression induced by opiate agonists can be increased by local anesthetics. Use of disinfectant solutions containing heavy metals are not recommended for chemical disinfection and preventative measures are required if heavy metal disinfectants are used for skin or mucous membrane disinfection prior to local anesthetic administration. Local anesthetics may cause the release of heavy metal ions from disinfectant solutions, which, if injected with the anesthetic, may cause severe local irritation, swelling and edema.
Adverse Reactions The following adverse events occurred in > 5% of patients during clinical trials with levobupivacaine: hypotension (31%), nausea/vomiting (21%/14%), post-operative pain (18%), fever (17%), anemia (12%), pruritus (9%), headache (7%), constipation (7%), dizziness (6%), and fetal distress (5%). Like all local anesthetics, levobupivacaine can produce significant CNS toxicity when high serum concentrations are achieved. CNS toxicity occurs at lower doses and at lower plasma concentrations than those associated with cardiac toxicity. Early signs of CNS toxicity include anxiety, blurred vision, depression, dizziness, drowsiness, incoherent speech, lightheadedness, metallic taste, nausea/vomiting, numbness and tingling of the mouth and lips, restlessness, shivering, tinnitus, tremors, and twitching. Levobupivacaine-induced CNS toxicity may progress to unconsciousness, respiratory depression leading to respiratory arrest, and seizures. Unintentional intrathecal administration has been associated with apnea, severe hypotension, and loss of consciousness. In some patients, the symptoms of CNS toxicity may be minor and transient. Cardiac effects of local anesthetics are due to the interference of conduction within the myocardium. Cardiac effects are seen at very high doses and usually occur after the onset of CNS toxicity. Levobupivacaine causes less cardiac toxicity than bupivacaine at equal doses. Local anesthetic-induced cardiovascular adverse effects may include AV block, PR prolongation, QT prolongation, myocardial depression, sinus bradycardia, cardiac arrhythmias including atrial fibrillation, hypotension, cardiovascular collapse, metabolic acidosis, and cardiac arrest. These effects typically occur with high plasma drug concentrations. Cardiovascular side effects resulting from local anesthetic administration should be treated with general supportive physiologic measures such as oxygen therapy, assisted ventilation, and IV fluids. Transient burning can occur at the injection site of levobupivacaine. Preexisting inflammation or infection increases the risk of developing local dermatologic side effects. Patients should be monitored for an injection site reaction. During labor and obstetric delivery, local anesthetics can cause varying degrees of maternal, fetal, and neonatal toxicities. The potential for toxicity is related to the procedure performed, the type and amount of drug used, and the technique of administration. Fetal heart rate should be monitored continuously because fetal bradycardia may occur in patients receiving levobupivacaine anesthesia and may be associated with fetal acidosis. Maternal hypotension can result from regional anesthesia; patient position can alleviate this problem. The injection should be performed with the patient in the left lateral decubitus position to displace the gravid uterus, thereby minimizing aortocaval compression. Epidural levobupivacaine may cause decreased uterine contractility or maternal expulsion efforts and alter the forces of parturition. During caudal or lumbar epidural block, unintentional penetration of the subarachnoid space may occur. Adverse effects depend upon the amount of drug given subdurally and may include spinal block of varying magnitude, hypotension secondary to spinal block, loss of bowel and bladder control, and loss of perineal sensation and sexual function. Persistent motor, sensory, and/or autonomic (sphincter control) deficit of lower spinal segments with slow (several months) or incomplete recovery has been reported rarely. Back pain and headache have been reported following these procedures.
Levobupivacaine Chirocaine® | Chirocaine®
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