DESCRIPTION

Xylocaine (lidocaine HCl) Injections are sterile, nonpyrogenic,aqueous solutions that contain a local anesthetic agent with or withoutepinephrine and are administered parenterally by injection. See INDICATIONS for specificuses.

Xylocaine solutions contain lidocaine HCl, which is chemicallydesignated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-,monohydrochloride and has the molecular wt. 270.8. Lidocaine HCl(C14H22N2O • HCl) has thefollowing structural formula:

structure-1

Epinephrine is (-) -3, 4-Dihydroxy-α-[(methylamino) methyl]benzyl alcohol and has the molecular wt. 183.21. Epinephrine(C9H13NO3) has the followingstructural formula:

structure-2

Dosage forms listed as Xylocaine-MPF indicate single dose solutions that are Methyl Paraben Free (MPF).

Xylocaine-MPF is a sterile, nonpyrogenic,isotonic solution containing sodium chloride. Xylocaine in multiple dose vials, each mL also contains 1 mg methylparaben as antisepticpreservative. The pH of these solutions is adjusted toapproximately 6.5 (5.0 to 7.0) with sodium hydroxide and/or hydrochloricacid.

Xylocaine-MPF with Epinephrine is asterile, nonpyrogenic, isotonic solution containing sodiumchloride. Each mL contains lidocaine hydrochloride andepinephrine, with 0.5 mg sodium metabisulfite as an antioxidant and 0.2mg citric acid as a stabilizer. Xylocaine withEpinephrine in multiple dose vials, each mL also contains 1 mg methylparaben as antisepticpreservative. The pH of these solutions is adjusted toapproximately 4.5 (3.3 to 5.5) with sodium hydroxide and/or hydrochloricacid. Filled under nitrogen.

CLINICAL PHARMACOLOGY

Mechanism of Action

Lidocaine stabilizes the neuronal membrane byinhibiting the ionic fluxes required for the initiation andconduction of impulses thereby effecting local anestheticaction.

Hemodynamics

Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded.

Pharmacokinetics and Metabolism

Information derived from diverse formulations,concentrations and usages reveals that lidocaine iscompletely absorbed following parenteral administration, itsrate of absorption depending, for example, upon various factorssuch as the site of administration and the presence or absenceof a vasoconstrictor agent. Except for intravascularadministration, the highest blood levels are obtained followingintercostal nerve block and the lowest after subcutaneousadministration.

The plasma binding of lidocaine is dependent on drugconcentration, and the fraction bound decreases with increasingconcentration. At concentrations of 1 to 4 mcg of freebase per mL 60 to 80 percent of lidocaine is proteinbound. Binding is also dependent on the plasmaconcentration of the alpha-1-acid glycoprotein.

Lidocaine crosses the blood-brain and placentalbarriers, presumably by passive diffusion.

Lidocaine is metabolized rapidly by the liver, andmetabolites and unchanged drug are excreted by thekidneys. Biotransformation includes oxidativeN-dealkylation, ring hydroxylation, cleavage of the amidelinkage, and conjugation. N-dealkylation, a major pathwayof biotransformation, yields the metabolitesmonoethylglycinexylidide and glycinexylidide. Thepharmacological/toxicological actions of these metabolites aresimilar to, but less potent than, those of lidocaine.Approximately 90% of lidocaine administered is excretedin the form of various metabolites, and less than 10% isexcreted unchanged. The primary metabolite in urine is aconjugate of 4-hydroxy-2,6-dimethylaniline.

The elimination half-life of lidocaine following anintravenous bolus injection is typically 1.5 to 2 hours.Because of the rapid rate at which lidocaine is metabolized,any condition that affects liver function may alter lidocaine kinetics. The half-life may be prolonged two-fold ormore in patients with liver dysfunction. Renal dysfunctiondoes not affect lidocaine kinetics but may increase theaccumulation of metabolites.

Factors such as acidosis and the use of CNS stimulantsand depressants affect the CNS levels of lidocaine requiredto produce overt systemic effects. Objective adversemanifestations become increasingly apparent with increasingvenous plasma levels above 6 mcg free base per mL. In therhesus monkey arterial blood levels of 18 to 21 mcg/mL have beenshown to be threshold for convulsive activity.

INDICATIONS AND USAGE

Xylocaine (lidocaine HCl) Injections are indicated for production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks, when the accepted procedures for these techniques as described in standard textbooks are observed.

CONTRAINDICATIONS

Lidocaine is contraindicated in patients with a known historyof hypersensitivity to local anesthetics of the amide type.

WARNINGS

XYLOCAINE INJECTIONS FOR INFILTRATION AND NERVE BLOCK SHOULD BEEMPLOYED ONLY BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS ANDMANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES THATMIGHT ARISE FROM THE BLOCK TO BE EMPLOYED AND THEN ONLY AFTER ENSURINGTHE IMMEDIATE AVAILABILITY OF OXYGEN, OTHERRESUSCITATIVE DRUGS, CARDIOPULMONARY EQUIPMENT AND THE PERSONNEL NEEDEDFOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (Seealso ADVERSEREACTIONS and PRECAUTIONS.) DELAY INPROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANYCAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OFACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH.

Intra-articular infusions of local anesthetics followingarthroscopic and other surgical procedures is an unapproved use, andthere have been post-marketing reports of chondrolysis in patientsreceiving such infusions. The majority of reported cases ofchondrolysis have involved the shoulder joint; cases of gleno-humeralchondrolysis have been described in pediatric and adult patientsfollowing intra-articular infusions of local anesthetics with andwithout epinephrine for periods of 48 to 72 hours. There isinsufficient information to determine whether shorter infusion periodsare not associated with these findings. The time of onset ofsymptoms, such as joint pain, stiffness and loss of motion can bevariable, but may begin as early as the 2nd month after surgery.Currently, there is no effective treatment for chondrolysis; patientswho experienced chondrolysis have required additional diagnostic andtherapeutic procedures and some required arthroplasty or shoulderreplacement.

To avoid intravascular injection, aspiration should be performedbefore the local anesthetic solution is injected. The needle mustbe repositioned until no return of blood can be elicited byaspiration. Note, however, that the absence of blood in thesyringe does not guarantee that intravascular injection has beenavoided.

Local anesthetic solutions containing antimicrobial preservatives(e.g., methylparaben) should not be used for epidural or spinal anesthesiabecause the safety of these agents has not been established with regardto intrathecal injection, either intentional or accidental.

Xylocaine with epinephrine solutions contain sodiummetabisulfite, a sulfite that may cause allergic-type reactionsincluding anaphylactic symptoms and life-threatening or less severeasthmatic episodes in certain susceptible people. The overallpreva lence of sulfite sensitivity in the general population is unknownand probably low. Sulfite sensitivity is seen more frequently inasthmatic than in non-asthmatic people.

PRECAUTIONS

General

The safety and effectiveness of lidocaine depend onproper dosage, correct technique, adequate precautions, andreadiness for emergencies. Standard textbooks should beconsulted for specific techniques and precautions for variousregional anesthetic procedures.

Resuscitative equipment, oxygen, and other resuscitativedrugs should be available for immediate use (see WARNINGS and ADVERSEREACTIONS). Thelowest dosage that results in effective anesthesia should beused to avoid high plasma levels and serious adverseeffects. Syringe aspirations should also be performedbefore and during each supplemental injection when usingindwelling catheter techniques. During the administrationof epidural anesthesia, it is recommended that a test dose beadministered initially and that the patient be monitored forcentral nervous system toxicity and cardiovascular toxicity, aswell as for signs of unintended intrathecal administration,before proceeding. When clinical conditions permit,consideration should be given to employing local anestheticsolutions that contain epinephrine for the test dose becausecirculatory changes compatible with epinephrine may also serveas a warning sign of unintended intravascular injection.An intravascular injection is still possible even if aspirationsfor blood are negative. Repeated doses of lidocainemay cause significant increases in blood levels with eachrepeated dose because of slow accumulation of the drug or itsmetabolites. Tolerance to elevated blood levels varieswith the status of the patient. Debilitated, elderlypatients, acutely ill patients, and children should be givenreduced doses commensurate with their age and physicalcondition. Lidocaine should also be used with cautionin patients with severe shock or heart block.

Lumbar and caudal epidural anesthesia should be used withextreme caution in persons with the following conditions:existing neurological disease, spinal deformities, septicemia,and severe hypertension.

Local anesthetic solutions containing a vasoconstrictorshould be used cautiously and in carefully circumscribedquantities in areas of the body supplied by end arteries orhaving otherwise compromised blood supply. Patients withperipheral vascular disease and those with hypertensive vasculardisease may exhibit exaggerated vasoconstrictor response.Ischemic injury or necrosis may result. Preparationscontaining a vasoconstrictor should be used with caution inpatients during or following the administration of potentgeneral anesthetic agents, since cardiac arrhythmias may occurunder such conditions.

Careful and constant monitoring of cardiovascular andrespiratory (adequacy of ventilation) vital signs and thepatient’s state of consciousness should be accomplishedafter each local anesthetic injection. It should be keptin mind at such times that restlessness, anxiety, tinnitus,dizziness, blurred vision, tremors, depression or drowsiness maybe early warning signs of central nervous systemtoxicity.

Since amide-type local anesthetics are metabolized by theliver, Xylocaine Injection should be used with caution inpatients with hepatic disease. Patients with severehepatic disease, because of their inability to metabolize localanesthetics normally, are at greater risk of developing toxicplasma concentrations. Xylocaine Injection should also beused with caution in patients with impaired cardiovascularfunction since they may be less able to compensate forfunctional changes associated with the prolongation of A-Vconduction produced by these drugs.

Many drugs used during the conduct of anesthesia areconsidered potential triggering agents for familial malignanthyperthermia. Since it is not known whether amide-typ