NESACAINE - chloroprocaine hydrochloride injection, solutionNESACAINE MPF - chloroprocaine hydrochloride injection, solutionAPP Pharmaceuticals, LLCFor Infiltration and Nerve BlockDESCRIPTIONNesacaine and Nesacaine-MPF Injections are sterile non pyrogenic local anesthetics. The active ingredient in Nesacaine andNesacaine-MPF Injections is chloroprocaine HCl (benzoic acid, 4-amino-2-chloro-2-(diethylamino) ethyl ester, monohydrochloride),which is represented by the following structural formula:

Table 1: Composition of Available Injections

The solutions are adjusted to pH 2.7-4.0 by means of sodium hydroxide and/or hydrochloric acid. Filled under nitrogen.

Nesacaine and Nesacaine-MPF Injections should not be resterilized by autoclaving.

CLINICAL PHARMACOLOGY

Chloroprocaine, like other local anesthetics, blocks the generation and the conduction of nerve impulses, presumably by increasing thethreshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse and by reducing the rate of rise of theaction potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affectednerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and(5) skeletal muscle tone.Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrationsachieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheralvascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead toatrioventricular block and ultimately to cardiac arrest. In addition, with toxic blood concentrations myocardial contractility may bedepressed and peripheral vasodilation may occur, leading to decreased cardiac output and arterial blood pressure.Following systemic absorption, toxic blood concentrations of local anesthetics can produce central nervous system stimulation,depression, or both. Apparent central stimulation may be manifested as restlessness, tremors and shivering, which may progress toconvulsions. Depression and coma may occur, possibly progressing ultimately to respiratory arrest.However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occurwithout a prior stage of central nervous system stimulation.

PHARMACOKINETICS

The rate of systemic absorption of local anesthetic drugs is dependent upon the total dose and concentration of drug administered,the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anestheticinjection. Epinephrine usually reduces the rate of absorption and plasma concentration of local anesthetics and is sometimes added tolocal anesthetic injections in order to prolong the duration of action.

The onset of action with chloroprocaine is rapid (usually within 6 to 12 minutes), and the duration of anesthesia, depending upon the

amount used and the route of administration, may be up to 60 minutes.

Local anesthetics appear to cross the placenta by passive diffusion. However, the rate and degree of diffusion varies considerably

among the different drugs as governed by: (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of

lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, since

only the free, unbound drug is available for placental transfer. Thus, drugs with the highest protein binding capacity may have the

lowest fetal/maternal ratios. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the

drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.

Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high

concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease,

addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of administration, and the age of the patient. The in

vitro plasma half-life of chloroprocaine in adults is 21 +- 2 seconds for males and 25 +- 1 seconds for females. The in vitro plasma halflife

in neonates is 43 +- 2 seconds.

Chloroprocaine is rapidly metabolized in plasma by hydrolysis of the ester linkage by pseudocholinesterase. The hydrolysis of

chloroprocaine results in the production of ss-diethylaminoethanol and 2-chloro-4-aminobenzoic acid, which inhibits the action of the

sulfonamides (see PRECAUTIONS).

The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary

perfusion and factors affecting urinary pH.

CONTRAINDICATIONS

Nesacaine and Nesacaine-MPF Injections are contraindicated in patients hypersensitive (allergic) to drugs of the PABA ester group.Lumbar and caudal epidural anesthesia should be used with extreme caution in persons with the following conditions: existingneurological disease, spinal deformities, septicemia, and severe hypertension.

WARNINGS

LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS ANDMANAGEMENT OF DOSE RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROMTHE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER ENSURING THE IMMEDIATE AVAILABILITY OF OXYGEN,OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNELRESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES (see alsoADVERSE REACTIONS and PRECAUTIONS). DELAY IN PROPER MANAGEMENT OF DOSE RELATED TOXICITY,UNDERVENTILATION FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENTOF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH. NESACAINE (chloroprocaine HCl Injection, USP) containsmethylparaben and should not be used for lumbar or caudal epidural anesthesia because safety of this antimicrobial preservative hasnot been established with regard to intrathecal injection, either intentional or unintentional. NESACAINE-MPF Injection contains nopreservative; discard unused injection remaining in vial after initial use.Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there havebeen post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis haveinvolved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intraarticularinfusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information todetermine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain,stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effectivetreatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures andsome required arthroplasty or shoulder replacement.Vasopressors should not be used in the presence of ergot-type oxytocic drugs, since a severe persistent hypertension may occur.To avoid intravascular injection, aspiration should be performed before the anesthetic solution is injected. The needle must berepositioned until no blood return can be elicited. However, the absence of blood in the syringe does not guarantee that intravascularinjection has been avoided.Mixtures of local anesthetics are sometimes employed to compensate for the slower onset of one drug and the shorter duration ofaction of the second drug. Experiments in primates suggest that toxicity is probably additive when mixtures of local anestheticsare employed, but some experiments in rodents suggest synergism. Caution regarding toxic equivalence should be exercised whenmixtures of local anesthetics are employed.

PRECAUTIONS

GeneralThe safety and effective use of chloroprocaine depend on proper dosage, correct technique, adequate precautions and readiness foremergencies. Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use (see WARNINGSand ADVERSE REACTIONS). The lowest dosage that results in effective anesthesia should be used to avoid high plasma levelsand serious adverse effects. Injections should be made slowly, with frequent aspirations before and during the injection to avoidintravascular injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous(intermittent) catheter techniques. During the administration of epidural anesthesia, it is recommended that a test dose be administered(3 mL of 3% or 5 mL of 2% Nesacaine-MPF Injection) initially and that the patient be monitored for central nervous systemtoxicity and cardiovascular toxicity, as well as for signs of unintended intrathecal administration, before proceeding. When clinicalconditions permit, consideration should be given to employing a chloroprocaine solution that contains epinephrine for the test dosebecause circulatory changes characteristic of epinephrine may also serve as a warning sign of unintended intravascular injection. Anintravascular injection is still possible even if aspirations for blood are negative. With the use of continuous catheter techniques,it is recommended that a fraction of each supplemental dose be administered as a test dose in order to verify proper location of thecatheter.Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slowaccumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the physical condition of the patient.Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physicalstatus. Local anesthetics should also be used with caution in patients with hypotension or heart block.Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state ofconsciousness should be accomplished after each local anesthetic injection. It should be kept in mind at such times that restlessness,anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs of central nervous systemtoxicity.Local anesthetic injections containing a vasoconstrictor should be used cautiously and in carefully circumscribed quantities in areas ofthe body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease and thosewith hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result.Since ester-type local anesthetics are hydrolyzed by plasma cholinesterase produced by the liver, chloroprocaine should be usedcautiously in patients with hepatic disease.Local anesthetics should also be used with caution in patients with impaired cardiovascular function since they may be less able tocompensate for functional changes associated with the prolongation of A-V conduction produced by these drugs.Use in Ophthalmic Surgery: When local anesthetic injections are employed for retrobulbar block, lack of corneal sensation shouldnot be relied upon to determine whether or not the patient is ready for surgery. This is because complete lack of corneal sensationusually precedes clinically acceptable external ocular muscle akinesia.Information for PatientsWhen appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity,usually in the lower half of the body, following proper administration of epidural anesthesia.Clinically Significant Drug InteractionsThe administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidaseinhibitors, tricyclic antidepressants or phenothiazines may produce severe, prolonged hypotension or hypertension. Concurrent use ofthese agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.Concurrent administration of vasopressor drugs (for the treatment of hypotension related to obstetric blocks) and ergot-type oxytocicdrugs may cause severe, persistent hypertension or cerebrovascular accidents.The para-aminobenzoic acid metabolite of chloroprocaine inhibits the action of sulfonamides. Therefore, chloroprocaine should not beused in any condition in which a sulfonamide drug is being employed.Carcinogenesis, Mutagenesis, and Impairment of FertilityLong-term studies in animals to evaluate carcinogenic potential and reproduction studies to evaluate mutagenesis or impairment offertility have not been conducted with chloroprocaine.Pregnancy: Category CAnimal reproduction studies have not been conducted with chloroprocaine. It is also not known whether chloroprocaine can causefetal harm when administered to a pregnant woman or can affect reproduction capacity. Chloroprocaine should be given to a pregnantwoman only if clearly needed. This does not preclude the use of chloroprocaine at term for the production of obstetrical anesthesia.Labor and DeliveryLocal anesthetics rapidly cross the placenta, and when used for epidural, paracervical, pudendal or caudal block anesthesia, can causevarying degrees of maternal, fetal and neonatal toxicity (see CLINICAL PHARMACOLOGY and PHARMACOKINETICS).

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 has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves.

Elevating the patient's legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also

should be monitored continuously, and electronic fetal monitoring is highly advisable.

Epidural, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal

expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage

labor and facilitation of cervical dilation. However, epidural anesthesia has also been reported to prolong the second stage of labor

by removing the parturient's reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may

increase the need for forceps assistance.

The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for

the first day or two of life. The long-term significance of these observations is unknown.

Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate

analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with

unintended fetal intracranial injection of local anesthetic injection have been reported following intended paracervical or pudendal

block or both. Babies so affected present with unexplained neonatal depression at birth which correlates with high local anesthetic

serum levels and usually manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary

excretion of the local anesthetic has been used successfully to manage this complication.

Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in

early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The

recommended maximum dose of each drug should not be exceeded. Injection should be made slowly and with frequent aspiration.

Allow a 5-minute interval between sides.

There are no data concerning use of chloroprocaine for obstetrical paracervical block when toxemia of pregnancy is present or when

fetal distress or prematurity is anticipated in advance of the block; such use is, therefore, not recommended.

The following information should be considered by clinicians who select chloroprocaine for obstetrical paracervical block anesthesia:

1. Fetal bradycardia (generally a heart rate of less than 120 per minute for more than 2 minutes) has been noted by electronic

monitoring in about 5 to 10 percent of the cases (various studies) where initial total doses of 120 mg to 400 mg of chloroprocaine

were employed. The incidence of bradycardia, within this dose range, might not be dose related.

2. Fetal acidosis has not been demonstrated by blood gas monitoring around the time of bradycardia or afterwards. These data are

limited and generally restricted to non-toxemic cases where fetal distress or prematurity was not anticipated in advance of the

block.

3. No intact chloroprocaine and only trace quantities of a hydrolysis product, 2-chloro-4-aminobenzoic acid, have been demonstrated

in umbilical cord arterial or venous plasma following properly administered paracervical block with chloroprocaine.

4. The role of drug factors and non-drug factors associated with fetal bradycardia following paracervical block are unexplained at this

time.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be

exercised when chloroprocaine is administered to a nursing woman.

Pediatric Use

Guidelines for the administration of Nesacaine and Nesacaine-MPF Injections to children are presented in DOSAGE AND

ADMINISTRATION.

Geriatric Use

Clinical studies of Nesacaine and Nesacaine-MPF did not include sufficient numbers of subjects 65 and over to determine whether

they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between

the elderly and younger patients. In general, dose selection for an elderly patient should be cautious usually starting at the low end of

the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other

drug therapy.

This drug and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be

greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should

be taken in dose selection and it may be useful to monitor renal function.

OVERDOSAGE

Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of localanesthetics or to unintended subarachnoid injection of local anesthetic solution (see ADVERSE REACTIONS, WARNINGS andPRECAUTIONS).In mice, the intravenous LD50 of chloroprocaine HCl is 97 mg/kg and the subcutaneous LD50 of chloroprocaine HCl is 950 mg/kg.Management of Local Anesthetic Emergencies: The first consideration is prevention, best accomplished by careful and constantmonitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness after each local anesthetic injection.At the first sign of change, oxygen should be administered.The first step in the management of convulsions, as well as underventilation or apnea due to unintentional subarachnoid injectionof drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation withoxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution ofthese ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsionssometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support,and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or abenzodiazepine (such as diazepam) may be administered intravenously; the clinician should be familiar, prior to the use of anesthetics,with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and,when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force).If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmiasand cardiac arrest. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may producethese same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standardcardiopulmonary resuscitative measures should be instituted. Recovery has been reported after prolonged resuscitative efforts.Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration ofoxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted orcontrolled) is indicated.

DOSAGE & ADMINISTRATION

Chloroprocaine may be administered as a single injection or continuously through an indwelling catheter. As with all localanesthetics, the dose administered varies with the anesthetic procedure, the vascularity of the tissues, the depth of anesthesia anddegree of muscle relaxation required, the duration of anesthesia desired, and the physical condition of the patient. The smallestdose and concentration required to produce the desired result should be used. Dosage should be reduced for children, elderly and

debilitated patients and patients with cardiac and/or liver disease. The maximum single recommended doses of chloroprocaine in

adults are: without epinephrine, 11 mg/kg, not to exceed a maximum total dose of 800 mg; with epinephrine (1:200,000), 14 mg/kg,

not to exceed a maximum total dose of 1000 mg. For specific techniques and procedures, refer to standard textbooks.

There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following

arthroscopic and other surgical procedures. Nesacaine is not approved for this use (see WARNINGS and DOSAGE AND

ADMINISTRATION).

Caudal and Lumbar Epidural Block: In order to guard against adverse experiences sometimes noted following unintended

penetration of the subarachnoid space, the following procedure modifications are recommended:

1. Use an adequate test dose (3 mL of Nesacaine-MPF 3% Injection or 5 mL of Nesacaine-MPF 2% Injection) prior to induction

of complete block. This test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural

catheter. Allow adequate time for onset of anesthesia following administration of each test dose.

2. Avoid the rapid injection of a large volume of local anesthetic injection through the catheter. Consider fractional doses, when

feasible.

3. In the event of the known injection of a large volume of local anesthetic injection into the subarachnoid space, after suitable

resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of

cerebrospinal fluid (such as 10 mL) through the epidural catheter.

As a guide for some routine procedures, suggested doses are given below:

1. Infiltration and Peripheral Nerve Block: NESACAINE or NESACAINE-MPF (chloroprocaine HCl Injection, USP)

2. Caudal and Lumbar Epidural Block: NESACAINE-MPF INJECTION.

For caudal anesthesia, the initial dose is 15 to 25 mL of a 2% or 3% solution. Repeated doses may be given at 40 to 60 minute

intervals.

For lumbar epidural anesthesia, 2 to 2.5 mL per segment of a 2% or 3% solution can be used. The usual total volume of

Nesacaine-MPF Injection is from 15 to 25 mL. Repeated doses 2 to 6 mL less than the original dose may be given at 40 to 50 minute

intervals.

The above dosages are recommended as a guide for use in the average adult. Maximum dosages of all local anesthetics must be

individualized after evaluating the size and physical condition of the patient and the rate of systemic absorption from a particular

injection site.

Pediatric Dosage: It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and

weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is

determined by the child's age and weight and should not exceed 11 mg/kg (5 mg/lb). For example, in a child of 5 years weighing

50 lbs (23 kg), the dose of chloroprocaine HCl without epinephrine would be 250 mg. Concentrations of 0.5-1% are suggested for

infiltration and 1-1.5% for nerve block. In order to guard against systemic toxicity, the lowest effective concentration and lowest

effective dose should be used at all times. Some of the lower concentrations for use in infants and smaller children are not available

in prepackaged containers; it will be necessary to dilute available concentrations with the amount of 0.9% sodium chloride injection

necessary to obtain the required final concentration of chloroprocaine injection.

Preparation of Epinephrine Injections--To prepare a 1:200,000 epinephrine-chloroprocaine HCl injection, add 0.1 mL of a 1 to

1000 Epinephrine Injection USP to 20 mL of Nesacaine-MPF Injection.

Chloroprocaine is incompatible with caustic alkalis and their carbonates, soaps, silver salts, iodine and iodides.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever

injection and container permit. As with other anesthetics having a free aromatic amino group, Nesacaine and Nesacaine-MPF

Injections are slightly photosensitive and may become discolored after prolonged exposure to light. It is recommended that these vials

be stored in the original outer containers, protected from direct sunlight. Discolored injection should not be administered. If exposed

to low temperatures, Nesacaine and Nesacaine-MPF Injections may deposit crystals of chloroprocaine HCl which will redissolve with

shaking when returned to room temperature. The product should not be used if it contains undissolved (eg, particulate) material.

HOW SUPPLIED

HOW SUPPLIEDNESACAINE (chloroprocaine HCl Injection, USP) with preservatives is supplied as follows:

NESACAINE-MPF (chloroprocaine HCl Injection, USP) without preservatives and without EDTA is supplied as follows:

Keep from freezing. Protect from light. Store at 20deg to 25degC (68deg to 77degF) [see USP Controlled Room Temperature].

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451109D/Revised: July 2010

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