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CLINICAL PHARMACOLOGY Mechanism of Action Etidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. Onset and Duration of Action In vivo animal studies have shown that etidocaine has a rapid onset (3-5 minutes) and a prolonged duration of action (5-10 hours). Based on comparative clinical studies of lidocaine and etidocaine, the anesthetic properties of etidocaine in man may be characterized as follows: Initial onset of sensory analgesia and motor blockade is rapid (usually 3-5 minutes) and similar to that produced by lidocaine. Duration of sensory analgesia is 1.5 to 2 times longer than that of lidocaine by the peridural route. The difference in analgesic duration between etidocaine and lidocaine may be even greater following peripheral nerve blockade than following central neural block. Duration of analgesia in excess of 9 hours is not infrequent when etidocaine is used for peripheral nerve blocks such as brachial plexus blockade. Etidocaine produces a profound degree of motor blockade and abdominal muscle relaxation when used for peridural analgesia. 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 etidocaine is completely absorbed following parenteral administration, its rate of absorption depending, for example, upon such factors as the site of administration and the presence or absence of a vasoconstrictor agent. Except for intravenous administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration. The plasma binding of etidocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At 0.5-1.0 µg/mL, 95% is bound to plasma protein. Etidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion. Etidocaine is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidney. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. To date, approximately 20 metabolites of etidocaine have been found in the urine. The percent of dose excreted as unchanged drug is less than 10%. The mean elimination half-life of etidocaine following a bolus intravenous injection is about 2.5 hours. Because of the rapid rate at which etidocaine is metabolized, any condition that affects liver function may alter etidocaine kinetics. Renal dysfunction may not affect etidocaine kinetics but may increase the accumulation of metabolites. Factors such as acidosis and the concomitant use of CNS stimulants and depressants affect the CNS levels of etidocaine required to produce overt systemic effects. In the rhesus monkey, arterial blood levels of 4.5 mg/mL have been shown to be threshold for convulsive activity.

Duranest (etidocaine hcl) Injections DURANEST (etidocaine hcl) INJECTIONS FOR INFILTRATION AND NERVE BLOCK SHOULD BE EMPLOYED ONLY BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES THAT MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED AND THEN ONLY AFTER ENSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY EQUIPMENT, AND THE PERSONNEL NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES (see also ADVERSE REACTIONS and PRECAUTIONS). DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST, AND POSSIBLY DEATH. DESCRIPTION Duranest (Etidocaine HCl) Injections are sterile aqueous solutions that contain a local anesthetic agent and are administered parenterally by injection. See INDICATIONS AND USAGE for specific uses. The specific quantitative composition of each available solution is shown in Table 1. Duranest Injections contain Etidocaine HCl, which is chemically designated as butanamide, N-(2,6-dimethylphenyl)-2-(ethylpropylamine)-, monohydrochloride and Epinephrine which is (-)-3, 4-Dihydroxy-a-[(methylamino) methyl] benzyl alcohol. Chemical structure is as follows: The PKa of etidocaine (7.74) is similar to that of lidocaine (7.86). However, etidocaine possesses a greater degree of lipid solubility and protein binding capacity than does lidocaine. Duranest (etidocaine hcl) Injections are sterile and, except for the 1.5% concentration, are available with or without epinephrine 1:200,000. Single dose containers of Duranest (etidocaine hcl) Injection without epinephrine may be reautoclaved it necessary. See Table 1 for composition of available injections. Table1. Composition of Available Injections Product Identification Formula Duranest (etidocaine HCl) Concentration % (mg/mL) Epinephrine Dilution (as the bitartrate) (mg/mL) pH Sodium chloride (mg/mL) Single Dose Vials/Dental Cartridge Sodium metabisulfite (mg/mL) Citric acid (mg/mL) 1.0 (10) None 4.0- 5.0 7.1 None 1.0 (1.0) 1 :200,000 (0.005 mg/mL) 3.0- 4.5 7.1 0.5 0.2 1.5 (1.5) 1 :200,000 (0.005 mg/mL) 3.0- 4.5 6.2 0.5 0.2 NOTE: pH of all solutions adjusted with sodium hydroxide and/ or hydrochloric acid. Duranest (etidocaine hcl) dental cartridges are only available as 1.5% solution with epinephrine 1:200,000. Filled under nitrogen.

INDICATIONS Duranest (Etidocaine HCl) Injections are indicated for infiltration anesthesia, peripheral nerve blocks (e.g., brachial plexus, intercostal, retrobulbar, ulnar, inferior alveolar), and central neural block (i.e., lumbar or caudal epidural blocks). DOSAGE AND ADMINISTRATION As with all local anesthetic agents, the dose of Duranest (Etidocaine HCl) Injection to be employed will depend upon the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the type of regional anesthetic technique, and the physical condition and tolerance of the individual patient. The maximum dose to be employed as a single injection should be determined on the basis of the status of the patient and the type of regional anesthetic technique to be performed. Although single injections of 450 mg have been employed for regional anesthesia without adverse effects, at present it is strongly recommended that the maximal dose as a single injection should not exceed 400 mg (approximately 8.0 mg/kg or 3.6 mg/lb based on a 50 kg person) with epinephrine 1:200,000 and 300 mg (approximately 6 mg/kg or 2.7 mg/lb based on a 50 kg person) without epinephrine. Because etidocaine has been shown to disappear quite rapidly from blood, toxicity is influenced by rapidity of administration, and therefore, injection in vascular areas is highly recommended. Incremental doses of Duranest (etidocaine hcl) Injection may be repeated at 2 - 3 hour intervals. Caudal and Lumbar Epidural Block As a precaution against the adverse experiences sometimes observed following unintentional penetration of the subarachnoid space, a test dose of 2 - 5 mL should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block. The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter. Epinephrine, if contained in the test dose (10 - 15 mg have been suggested), may serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient "epinephrine response" within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure. Adequate time should be allowed for onset of anesthesia after administration of each test dose. The rapid injection of a large volume of Duranest (etidocaine hcl) Injection through the catheter should be avoided, and when feasible, fractional doses should be administered. In the event of the known injection of a large volume of local anesthetic solution 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. Use in Dentistry When used for local anesthesia in dental procedures the dosage of Duranest (Etidocaine HCl) Injection depends on the physical status of the patient, the area of the oral cavity to be anesthetized, the vascularity of the oral tissues, and the technique of anesthesia. The least volume of solution that results in effective local anesthesia should be administered. For specific techniques and procedures of local anesthesia in the oral cavity, refer to standard textbooks. Dosage requirements should be determined on an individual basis. In maxillary infiftration and/or inferior alveolar nerve block, initial dosages of 1.0 - 5.0 mL (½ - 2 ½ cartridges) of Duranest (etidocaine hcl) Injection 1.5% with epinephrine 1:200,000 are usually effective. Aspiration is recommended since it reduces the possibility of intravascular injection, thereby keeping the incidence of side effects and anesthetic failures to a minimum. The following dosage recommendations are intended as guides for the use of Duranest (etidocaine hcl) Injection in the average adult patient. As indicated previously, the dosage should be reduced for elderly or debilitated patients or patients with severe renal disease. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The Injection is not to be used if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Table 2. Dosage Recommendations PROCEDURE Duranest (etidocaine hcl) HCl with epinephrine 1:200,000 Conc. (%) Vol. (mL) Total Dose (mg) Peripheral Nerve Block Central Neural Block Lumbar Peridural 1.0 5-40 50-400 Intra-abdominal or Pelvic Surgery Lower Limb Surgery Caesarean Section 1.0 or 1.5 10-30 10-20 100-300 150-300 Caudal 1.0 10-30 100-300 Retrobulbar 1.0 or 1.5 2-4 20-60 Maxillary Infiltration and/or Inferior Alveolar Nerve Block 1.5 1-5 15-75 HOW SUPPLIED Dosage Form and Volume Duranest Injection Concentration Epinephrine Dilution. (as the bitartrate) pH NDC Number Single DoseVials* 30 mL 1.0 % None 4.0-5.0 0186-0820-01 1.0 % 1: 200,000 3.0-4.5 0186-0825-01 20 mL 1.5 % 1: 200,000 3.0-4.5 0186-0836-03 DentalCartridge** 1.8 mL 1.5 % 1: 200,000 3.0-4.5 0186-0840-14 Solutions containing epinephrine should be protected from light. * Store at controlled room temperature 15°- 30° C (59°- 86° F). ** Store at room temperature, approx. 25° C (77° F).

PATIENT INFORMATION When 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.

OVERDOSE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution (see ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS). Management of Local Anesthetic Emergencies The first consideration is prevention, best accomplished by careful and constant monitoring 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 under ventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes 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 a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a Vasopressor as directed by the clinical situation (e.g., ephedrine). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Under ventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. Dialysis is of negligible value in the treatment of acute overdosage with etidocaine. The intravenous LD 50 of etidocaine HCl in female mice is 7.6 (6.6-8.5) mg/kg and the subcutaneous LD50 is 112 (96-166) mg/kg. CONTRAINDICATIONS Etidocaine is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type.

SIDE EFFECTS Systemic Adverse experiences following the administration of etidocaine are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption or unintended intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the party of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported: Central Nervous System CNS manifestations are excitatory and/or depressant and may be characterized by light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of etidocaine is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption. Cardiovascular System Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest. Allergic Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to the methylparaben used as a preservative in multiple dose vials. The detection of sensitivity by skin testing is of doubtful value. Neurologic The incidences of adverse reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration and the physical status of the patient. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter may occur. Subsequent adverse effects may depend partially on the amount of drug administered subdurally. These may include spinal block of varying magnitude (including total spinal block), hypotension secondary to spinal block, loss of bladder and bowel control, and loss of perineal sensation and sexual function. Persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with recovery (several months) or incomplete recovery have been reported in rare instances when caudal or lumbar epidural block has been attempted. Backache and headache have also been noted following use of these anesthetic procedures. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration. Other There have been rare reports of TRISMUS in patients who have received Duranest (etidocaine HCl) for dental anesthesia. Onset of symptoms occurs within hours or days upon resolution of blockade. No correlation has been demonstrated with dosage, administration technique or dental procedure. In most patients, symptoms resolved within days to weeks, although some reports have suggested that symptoms were present for many months. Symptomatic treatment with analgesics, moist heat and physiotherapy was helpful in some cases. DRUG INTERACTIONS The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors, tricyclic antidepressants or phenothiazines may produce severe, prolonged hypotension or hypertension. Concurrent use of these 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 epidural blocks) and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.