IN PERFORMING CHIROCAINE ^® BLOCKS, UNINTENDED INTRAVENOUS INJECTION IS POSSIBLE AND MAY RESULT IN CARDIAC ARREST. DESPITE RAPID DETECTION AND APPROPRIATE TREATMENT, PROLONGED RESUSCITATION MAY BE REQUIRED. THE RESUSCITABILITY RELATIVE TO BUPIVACAINE IS UNKNOWN AT THIS POINT IN TIME AS IT HAS NOT BEEN STUDIED. AS WITH ALL LOCAL ANESTHETICS OF THE AMIDE TYPE, CHIROCAINE SHOULD BE ADMINISTERED IN INCREMENTAL DOSES. SINCE CHIROCAINE SHOULD NOT BE INJECTED RAPIDLY IN LARGE DOSES, IT IS NOT RECOMMENDED FOR EMERGENCY SITUATIONS, WHERE A FAST ONSET OF SURGICAL ANESTHESIA IS NECESSARY.

HISTORICALLY, PREGNANT PATIENTS WERE REPORTED TO HAVE A HIGH RISK FOR CARDIAC ARRHYTHMIAS, CARDIAC/CIRCULATORY ARREST AND DEATH WHEN BUPIVACAINE WAS INADVERTENTLY RAPIDLY INJECTED INTRAVENOUSLY. AVOID 0.75% CHIROCAINE IN OBSTETRICAL PATIENTS. THIS CONCENTRATION IS INDICATED ONLY FOR NON-OBSTETRICAL SURGERY REQUIRING PROFOUND MUSCLE RELAXATION AND LONG DURATION. FOR CESAREAN SECTION, THE 5 MG/ML (0.5%) CHIROCAINE SOLUTION IN DOSES UP TO 150 MG IS RECOMMENDED.

LOCAL ANESTHETICS SHOULD ONLY BE ADMINISTERED BY CLINICIANS WHO ARE WELL VERSED IN THE DIAGNOSIS AND MANAGEMENT OF DRUG-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK BEING ADMINISTERED. THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES MUST BE ENSURED. (see also ADVERSE REACTIONSand

PRECAUTIONS

). DELAY IN PROPER MANAGEMENT OF DRUG-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST, AND POSSIBLY DEATH.

SOLUTIONS OF CHIROCAINE SHOULD NOT BE USED FOR THE PRODUCTION OF OBSTETRICAL PARACERVICAL BLOCK ANESTHESIA. THERE ARE NO DATA TO SUPPORT SUCH USE AND THERE IS THE ADDITIONAL RISK OF FETAL BRADYCARDIA AND DEATH.

INTRAVENOUS REGIONAL ANESTHESIA (BIER BLOCK) SHOULD NOT BE PERFORMED USING CHIROCAINE BECAUSE OF THE LACK OF CLINICAL EXPERIENCE AND THE RISK OF ATTAINING TOXIC BLOOD LEVELS OF LEVOBUPIVACAINE.

It is essential that aspiration for blood or cerebrospinal fluid (where applicable), be done prior to injecting ay local anesthetic, both before the original dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration does not ensure against intravascular or intrathecal injection. Chirocaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive.

When contemplating a peripheral nerve block, where large volumes of local anesthetic are needed, caution should be exercised when using the higher mg/mL concentrations of Chirocaine. Animal studies demonstrate CNS and cardiac toxicity that is dose related, thus equal volumes of higher concentration will be more likely to produce cardiac toxicity.

General

The safe and effective use of local anesthetics depends on proper dosage, correct technique, adequate precautions, and readiness for emergencies.

Resuscitative equipment, oxygen, and resuscitative drugs should be available for immediate use (see

WARNINGS

and ADVERSE REACTIONS). The lowest dosage that results in effective anesthesia should be used to avoid high plasma or dermatomal levels and serious adverse effects. Injections should be made slowly and incrementally, with frequent aspirations before and during the injection to avoid intravascular injection. When a continuous catheter technique is used, syringe aspirations should also be performed before and during each supplemental injection. During the administration of epidural anesthesia, it is recommended that a test dose of a local anesthetic with a fast onset be administered initially and that the patint be monitored for central nervous system and cardiovascular toxicity, as well as for signs of unintended intrathecal administration before proceeding. When clinical conditions permit, consideration should be given to employing local anesthetic solutions that contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative.

Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites or to slow metabolic degradation. Tolerance to elevated blood levels varies with the physical condition of the patient. Local anesthetics should also be used with caution in patients with hypotension, hypovolemia, or impaired cardiovascular function, especially heart block.

Careful and constant monitoring of cardiovascular and respiratory vital signs (adequacy of ventilation) and the patient's state of consciousness should be performed after each local anesthetic injection. The clinician must be aware that restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity.

Amide-type local anesthetics such as Chirocaine are metabolized by the liver, therefore these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk for developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function as they may be less able to compensate for functional changes associated with prolonged A-V conduction caused by these drugs.

Many drugs used during the conduct of anesthesia are considered potential triggering agents for malignant hyperthermia. Amide-type local anesthetics are not known to trigger this reaction.

Epidural Anesthesia

During epidural administration, Chirocaine should be administered in incremental volumes of 3 to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose is administered initially and the effects monitored before the full dose is given. A test dose of a short-acting amide anesthetic, such as 3 mL of lidocaine, is recommended to detect unintentional intrathecal administration. This will be manifested within a few minutes by signs of a subarachnoid block (e.g., decreased sensation of the buttocks, paresis of the legs or, in the sedated patient, absent knee jerk). Unintentional intrathecal injection of local anesthetics can lead to very high spinal anesthesia, possibly apnea, severe hypotension and loss of consciousness. An intravascular or intrathecal injection is still possible even if the results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, extensive subarachnoid block, or cardiovascular effects.

Use in Head and Neck Area

Small doses of local anesthetics injected into the head and neck area may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest and cardiovascular stimulation or depression have been reported. These reactions may be due to intraarterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their respirations and circulation monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded (see DOSAGE AND ADMINISTRATION ).

Information for Patients

When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity in the anesthetized part of the body following correct administration of regional anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the Chirocaine package insert.

Clinically Significant Drug-Drug Interactions

Chirocaine ^® should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics since the toxic effects of these drugs could be additive. In vitro studies indicate CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. Thus agents likely to be concomitantly administered with Chirocaine that are metabolized by this isoenzyme family may potentially interact with Chirocaine. Although no clinical studies have been conducted, it is likely that the metabolism of levobupivacaine may be affected by the known CYP3A4 inducers (such as phenytoin, phenobarbital, rifampin), CYP3A4 inhibitors (azole antimycotics e.g., ketoconazole; certain protease inhibitors e.g., ritanovir; macrolide antibiotics e.g., erythromycin; and calcium channel antagonists e.g., verapamil), CYP1A2 inducers (omeprazole) and CYP1A2 inhibitors (furafylline and clarithromycin). Dosage adjustment may be warranted when levobupivacaine is concurrently administered with CYP3A4 inhibitors and CYP1A2 inhibitors as systemic levobupivacaine levels may rise resulting in toxicity.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals of most local anesthetics, including Chirocaine, 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 Chirocaine in rats at 30 mg/kg/day (180 mg/m ² /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/m ² ).

Pregnancy Category B

Teratogenicity studies in rats (180 mg/m ² /day) and rabbits (220 mg/m ² /day) did not show evidence of any adverse effects on organogenesis or early fetal development. The doses used were approximately one-half the maximum recommended human dose (570 mg/person or 352 mg/m ² ) based on body surface area. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring in a perinatal and postnatal study in rats at dose levels up to approximately one-half the maximum recommended human dose based on body surface area. There were no adequate and well-controlled studies in pregnant women of the effects of Chirocaine on the developing fetus. Chirocaine should only be used during pregnancy if the benefits outweigh the risks.

Labor and Delivery

Local anesthetics, including Chirocaine, rapidly cross the placenta, and, when used for epidural block, can cause varying degrees of maternal, fetal, and neonatal toxicity. The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension, fetal bradycardia and fetal decelerations have resulted from regional anesthesia with Chirocaine for obstetrical pain relief. Local anesthetics produce vasodilation by blocking sympathetic nerves. Administration of intravenous fluids, elevation of the patient's legs and left uterine displacement will help prevent decreases in blood pressure. The fetal heart rate should also be monitored continuously and electronic fetal monitoring is highly advisable.

Nursing Mothers

Some local anesthetic drugs are excreted in human milk and caution should be exercised when Chirocaine is administered to a nursing woman. The excretion of Chirocaine or its metabolites in human milk has not been studied. Studies in rats demonstrated that small amounts of Chirocaine can be detected in the pups after administration of Chirocaine to the nursing mothers.

Pediatric Use

The safety and effectiveness of Chirocaine in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of Chirocaine, 16% were 65 and over, while 8% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.