SENSORCAINE

1 INDICATIONS AND USAGE SENSORCAINE / SENSORCAINE WITH EPINEPHRINE is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations of SENSORCAINE / SENSORCAINE WITH EPINEPHRINE are recommended for each type of block indicated to produce local or regional anesthesia or analgesia [see Dosage and Administration ( 2.2 )]. SENSORCAINE contains bupivacaine, an amide local anesthetic, and SENSORCAINE WITH EPINEPHRINE is a combination of bupivacaine, an amide local anesthetic, and epinephrine, an alpha and beta-adrenergic agonist. SENSORCAINE/ SENSORCAINE WITH EPINEPHRINE is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. For each type of block indicated to produce local or regional anesthesia or analgesia, specific concentrations and presentations are recommended. ( 1 , 2.2 ) Limitations of Use Not all blocks are indicated for use with SENSORCAINE/ SENSORCAINE WITH EPINEPHRINE given clinically significant risks associated with use. ( 1 , 2.2 , 4 , 5.1 , 5.4 , 5.5 , 5.7 , 5.9 ) Limitations of Use Not all blocks are indicated for use with SENSORCAINE / SENSORCAINE WITH EPINEPHRINE given clinically significant risks associated with use [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 , 5.4 , 5.5 , 5.7 , 5.9 )] .

2 Dosage and Administration 2.1 Important Dosage and Administration Information SENSORCAINE / SENSORCAINE WITH EPINEPHRINE is not for intrathecal use. Avoid use of SENSORCAINE / SENSORCAINE WITH EPINEPHRINE solutions containing antimicrobial preservatives (i.e., multiple dose vials) for epidural or caudal anesthesia [see Warnings and Precautions (5.4)]. Discard unused portions of solution not containing preservatives, i.e., those supplied in single dose vials, following initial use. Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit. SENSORCAINE are clear, colorless solutions. Do not administer solutions which are discolored or contain particulate matter. SENSORCAINE WITH EPINEPHRINE are clear, colorless to slightly yellow solutions. Do not administer solutions which are pinkish or darker than slightly yellow or contain particulate matter. Mixing or the prior or intercurrent use of any other local anesthetic with SENSORCAINE / SENSORCAINE WITH EPINEPHRINE is not recommended because of insufficient data on the clinical use of such mixtures. Administration Precautions SENSORCAINE / SENSORCAINE WITH EPINEPHRINE are to be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed. Use SENSORCAINE / SENSORCAINE WITH EPINEPHRINE only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies [see Warnings and Precautions (5.2), Adverse Reactions (6), Overdosage (10)]. The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with SENSORCAINE / SENSORCAINE WITH EPINEPHRINE [see Warnings and Precautions (5.2), Drug Interactions (7.1), Overdosage (10)]. Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting SENSORCAINE / SENSORCAINE WITH EPINEPHRINE, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection [see Warnings and Precautions (5.9)]. Avoid rapid injection of a large volume of SENSORCAINE / SENSORCAINE WITH EPINEPHRINE and use fractional (incremental) doses when feasible. During major regional nerve blocks, such as those of the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access. The lowest dosage of SENSORCAINE / SENSORCAINE WITH EPINEPHRINE that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions. Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient's level of consciousness after each local anesthetic injection. Use SENSORCAINE WITH EPINEPHRINE in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis [see Warnings and Precautions (5.12)]. 2.2 Recommended Concentrations and Dosages of SENSORCAINE/ SENSORCAINE WITH EPINEPHRINE The dosage of SENSORCAINE / SENSORCAINE WITH EPINEPHRINE administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. Administer the smallest dosage and concentration req …

3 DOSAGE FORMS AND STRENGTHS SENSORCAINE ® -MPF (bupivacaine hydrochloride) injection is a clear, colorless, methyl paraben free solution available as: 0.25% (25 mg per 10 mL) (2.5 mg/mL), in 10 mL Single Dose Vial 0.25% (75 mg per 30 mL) (2.5 mg/mL), in 30 mL Single Dose Vial 0.5% (50 mg per 10 mL) (5 mg/mL), in 10 mL Single Dose Vial 0.5% (150 mg per 30 mL) (5 mg/mL), in 30 mL Single Dose Vial 0.75% (75 mg per 10 mL) (7.5 mg/mL), in 10 mL Single Dose Vial 0.75% (225 mg per 30 mL) (7.5 mg/mL), in 30 mL Single Dose Vial SENSORCAINE ® -MPF WITH EPINEPHRINE 1:200,000 (bupivacaine hydrochloride and epinephrine injection, USP) is a clear, colorless to slightly yellow, methyl paraben free solution available as: 0.25% (75 mg per 30 mL) (2.5 mg/mL), in 30 mL Single Dose Vial 0.25% (25 mg per 10 mL) (2.5 mg/mL), in 10 mL Single Dose Vial 0.5% (50 mg per 10 mL) (5 mg/mL), in 10 mL Single Dose Vial 0.5% (150 mg per 30 mL) (5 mg/mL), in 30 mL Single Dose Vial 0.75% (225 mg per 30 mL) (7.5 mg/mL), in 30 mL Single Dose Vial SENSORCAINE ® (bupivacaine hydrochloride), injection is a clear, colorless solution available as: 0.25% (125 mg per 50 mL) (2.5 mg/mL), in 50 mL Multiple Dose Vial 0.5% (250 mg per 50 mL) (5 mg/mL), in 50 mL Multiple Dose Vial SENSORCAINE ® WITH EPINEPHRINE 1:200,000 (bupivacaine hydrochloride and epinephrine, USP) injection is a clear, colorless to slightly yellow solution available as: 0.25% (125 mg per 50 mL) (2.5 mg/mL), 50 mL Multiple Dose Vial 0.5% (250 mg per 50 mL) (5 mg/mL), 50 mL Multiple Dose Vial SENSORCAINE-MPF/SENSORCAINE-MPF WITH EPINEPHRINE and SENSORCAINE/ SENSORCAINE WITH EPINEPHRINE injections are available in multiple concentrations. See full prescribing information for detailed description of each formulation. ( 3 )

4 CONTRAINDICATIONS SENSORCAINE / SENSORCAINE WITH EPINEPHRINE is contraindicated in: obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. intravenous regional anesthesia (Bier Block) [see Warnings and Precautions ( 5.7 )] . patients with a known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of SENSORCAINE / SENSORCAINE WITH EPINEPHRINE. Obstetrical paracervical block anesthesia. ( 4 ) Intravenous regional anesthesia (Bier Block). ( 4 ) Known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of SENSORCAINE/ SENSORCAINE WITH EPINEPHRINE. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions section of the labeling: Cardiac Arrest in Obstetrical Anesthesia [see Warnings and Precautions ( 5.1 )] Dose-Related Toxicity [see Warnings and Precautions ( 5.2 )] Methemoglobinemia [see Warnings and Precautions ( 5.3 )] Chondrolysis with Intra-Articular Infusion [see Warnings and Precautions ( 5.5 )] Severe, Persistent Hypertension, Cerebrovascular Accidents, and Bradycardia Due to Drug Interactions [see Warnings and Precautions ( 5.6 )] Cardiac Arrest with Intravenous Regional Anesthesia Use [see Contraindications ( 4 ), Warnings and Precautions ( 5.7 )] Allergic-Type Reactions [see Warnings and Precautions ( 5.8 )] Systemic Toxicities with Unintended Intravascular or Intrathecal Injection [see Warnings and Precautions ( 5.9 )] Respiratory Arrest Following Retrobulbar Block [see Warnings and Precautions ( 5.15 )] The following adverse reactions from voluntary reports or clinical studies have been reported with bupivacaine or bupivacaine and epinephrine. Because many of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions to SENSORCAINE/ SENSORCAINE WITH EPINEPHRINE are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation. The most commonly encountered acute adverse reactions that demand immediate counter-measures were related to the CNS and the cardiovascular system. These adverse reactions were generally dose-related and due to high plasma levels which may have resulted from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional intrathecal injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) has resulted in underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia have occurred. This has led to secondary cardiac arrest when untreated. Nervous System Disorders : Adverse reactions were characterized by excitation and/or depression of the central nervous system and included restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness, unconsciousness, respiratory arrest, nausea, vomiting, chills, pupillary constriction. In the practice of caudal or lumbar epidural block, unintentional penetration of the subarachnoid space by the catheter or needle has occurred. Subsequent adverse effects may have depended partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. Neurologic effects following epidural or caudal anesthesia have included spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control, all of which had slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal …

7 DRUG INTERACTIONS Local Anesthetics : The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects when additional local anesthetics are administered. ( 7.1 ) Monoamine Oxidase Inhibitors and Tricyclic Antidepressants : Administration of SENSORCAINE WITH EPINEPHRINE to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. ( 5.6 , 7.2 ) Ergot-Type Oxytocic Drugs : Concurrent administration of SENSORCAINE WITH EPINEPHRINE and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. ( 5.6 , 7.3 ) Nonselective Beta-Adrenergic Antagonists : Administration of SENSORCAINE WITH EPINEPHRINE (containing a vasoconstrictor) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. ( 5.6 , 7.4 ) Drugs Associated with Methemoglobinemia : Patients are at increased risk of developing methemoglobinemia when concurrently exposed to nitrates, nitrites, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, and other drugs. ( 7.5 ) Potent Inhalation Anesthetics : Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics. ( 5.13 , 7.6 ) 7.1 Local Anesthetics The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with SENSORCAINE/ SENSORCAINE WITH EPINEPHRINE cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.2 )] . 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants The administration of SENSORCAINE WITH EPINEPHRINE to patients receiving monoamine oxidase inhibitors, or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's hemodynamic status is essential [see Warnings and Precautions ( 5.6 )] . 7.3 Ergot-Type Oxytocic Drugs Concurrent administration of SENSORCAINE WITH EPINEPHRINE and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of SENSORCAINE WITH EPINEPHRINE concomitantly with ergot-type oxytocic drugs [see Warnings and Precautions ( 5.6 )]. 7.4 Nonselective Beta-Adrenergic Antagonists Administration of SENSORCAINE WITH EPINEPHRINE (containing a vasoconstrictor) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's blood pressure and heart rate is essential [see Warnings and Precautions ( 5.6 )]. 7.5 Drugs Associated with Methemoglobinemia Patients who are administered SENSORCAINE/ SENSORCAINE WITH EPINEPHRINE are at increased risk of developing methemoglobinemia when concurrently exposed to following drugs, which could include other local anesthetics [see Warnings and Precautions ( 5.3 )]. Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminop …

8 Use in Specific Populations 8.1 Pregnancy Risk Summary SENSORCAINE/ SENSORCAINE WITH EPINEPHRINE is contraindicated for obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death [see Contraindications (4), Warnings and Precautions (5.1)]. There are no available data on use of SENSORCAINE/ SENSORCAINE WITH EPINEPHRINE in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at clinically relevant doses. Decreased pup survival was observed in a rat pre- and post-natal developmental study (dosing from implantation through weaning) at a dose level comparable to the daily maximum recommended human dose (MRHD) on a body surface area (BSA) basis. Based on animal data, advise pregnant women of the potential risks to a fetus (see Data). Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity [see Clinical Pharmacology (12.3)]. 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 CNS, peripheral vascular tone, and cardiac function. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Maternal Adverse Reactions Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient's legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. Labor or Delivery Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Epidural anesthesia has 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. This has not been reported with bupivacaine. It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left. Data Animal Data Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses. Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closur …

12.1 Mechanism of Action Bupivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve 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. Epinephrine is a vasoconstrictor added to bupivacaine to slow absorption into the general circulation and thus prolong maintenance of an active tissue concentration.

11 DESCRIPTION SENSORCAINE-MPF / SENSORCAINE-MPF WITH EPINEPHRINE injections contains bupivacaine hydrochloride, a local anesthetic agent with and without epinephrine (as bitartrate) 1:200,000. The route of administration for SENSORCAINE-MPF / SENSORCAINE-MPF WITH EPINEPHRINE is parenterally by injection, for infiltration, perineural, caudal, epidural, or retrobulbar use. SENSORCAINE-MPF / SENSORCAINE-MPF WITH EPINEPHRINE injections are Methyl Paraben Free (MPF). SENSORCAINE/SENSORCAINE WITH EPINEPHRINE injections contains bupivacaine hydrochloride, a local anesthetic agent with and without epinephrine (as bitartrate) 1:200,000. The route of administration for SENSORCAINE / SENSORCAINE WITH EPINEPHRINE is parenterally by injection, for infiltration and perineural use. Bupivacaine hydrochloride is a white or almost white, crystalline powder or colorless crystals, soluble in water, freely soluble in alcohol. Bupivacaine is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. Bupivacaine hydrochloride chemical name is 2-piperidinecarboxamide, 1-butyl- N -(2,6-dimethylphenyl)-, monohydrochloride, monohydrate. The molecular formula is C 18 H 28 N 2 O·HCl·H 2 O, with a molecular weight of 342.9 g/mol. Bupivacaine hydrochloride monohydrate has the following chemical structure: The pK a of bupivacaine (8.1) is similar to that of lidocaine (7.86). However, bupivacaine possesses a greater degree of lipid solubility and is protein bound to a greater extent than lidocaine. Epinephrine bitartrate is a white to greyish white or light brownish-grey, odorless, crystalline powder, freely soluble in water, slightly soluble in 96% ethanol and methanol, practically insoluble in chloroform, methylene chloride and ether. Epinephrine bitartrate chemical name is (-)-3,4-Dihydroxy- α [(methylamino)methyl] benzyl alcohol (+) tartrate (1:1) salt. The molecular formula is C 9 H 13 NO 3 ·C 4 H 6 O 6 , with a molecular weight of 333.29 g/mol. Epinephrine bitartrate has the following chemical structure: Bupivacaine Hydrochloride Monohydrate Chemical Structure Epinephrine Bitartrate Chemical Structure SENSORCAINE-MPF in single dose vials is a sterile, isotonic, clear, colorless, and preservative-free solution. Each mL contains 2.64 mg, 5.27 mg, or 7.92 mg of bupivacaine hydrochloride monohydrate (equivalent to 2.22 mg, 4.44 mg or 6.66 mg of bupivacaine, and also equivalent to 2.5 mg, 5.0 mg, or 7.5 mg of bupivacaine hydrochloride anhydrous; respectively), 8.0 mg sodium chloride for isotonicity, and sodium hydroxide and/or hydrochloric acid as pH adjusters. The pH of these solutions is adjusted to between 4.0 and 6.5. SENSORCAINE-MPF WITH EPINEPHRINE 1:200,000 (as bitartrate) in single dose vials is a sterile, isotonic, clear, colorless to slightly yellow and preservative-free solution. Each mL contains 2.64 mg, 5.27 mg, or 7.92 mg of bupivacaine hydrochloride monohydrate (equivalent to 2.22 mg, 4.44 mg or 6.66 mg of bupivacaine, and also equivalent to 2.5 mg, 5.0 mg or 7.5 mg bupivacaine hydrochloride anhydrous; respectively), 0.0091 mg or 9.09 mcg of epinephrine bitartrate (equivalent to 0.005 mg of epinephrine base), 0.5 mg sodium metabisulfite as an antioxidant, 0.2 mg citric acid (anhydrous) as a stabilizer, 8.0 mg sodium chloride for isotonicity, and sodium hydroxide and/or hydrochloric acid as pH adjusters. The pH of these solutions is adjusted to between 3.3 to 5.5. SENSORCAINE in multiple dose vials is a sterile, isotonic, clear, colorless solution. Each mL contains 2.64 mg, or 5.27 mg, of bupivacaine hydrochloride monohydrate (equivalent to 2.22 mg, or 4.44 mg of bupivacaine, and also equivalent to 2.5 mg and 5.0 mg of bupivacaine hydroch …

OVERDOSAGE: 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 systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred. If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory, and cardiac function, add to postictal depression and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). 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. Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation 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, successful outcome may require prolonged resuscitative efforts. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels should be accomplished. The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL …

16 HOW SUPPLIED/STORAGE AND HANDLING Solutions should be stored at 20° to 25°C (68° to 77°F); excursion permitted between 15 0 C to 30 0C (59 0 F to 86 0 F) [see USP Controlled Room Temperature]. These solutions are not for spinal anesthesia. SENSORCAINE ® -MPF (methylparaben free) does not contain epinephrine and is clear and colorless. Do not use the solution if it is discolored or if it contains a precipitate. SENSORCAINE ® -MPF is available in the following forms: Product Code Unit of Sale Strength Each 460417 NDC 63323-464-17 Trays of 25 0.25% 25 mg per 10 mL (2.5 mg per mL) NDC 63323-464-01 10 mL Single Dose Vial 460437 NDC 63323-464-37 Trays of 25 0.25% 75 mg per 30 mL (2.5 mg per mL) NDC 63323-464-02 30 mL Single Dose Vial 460617 NDC 63323-466-17 Trays of 25 0.5% 50 mg per 10 mL (5 mg per mL) NDC 63323-466-03 10 mL Single Dose Vial 460637 NDC 63323-466-37 Trays of 25 0.5% 150 mg per 30 mL (5 mg per mL) NDC 63323-466-01 30 mL Single Dose Vial 470217 NDC 63323-472-17 Trays of 25 0.75% 75 mg per 10 mL (7.5 mg per mL) NDC 63323-472-03 10 mL Single Dose Vial 470237 NDC 63323-472-37 Trays of 25 0.75% 225 mg per 30 mL (7.5 mg per mL) NDC 63323-472-01 30 mL Single Dose Vial SENSORCAINE ® - MPF WITH EPINEPHRINE (1:200,000) should be protected from light. This product is clear, colorless to slightly yellow. Do not use the solution if it is pinkish or darker than slightly yellow or if it contains a precipitate. SENSORCAINE ® -MPF WITH EPINEPHRINE is available in the following forms: Product Code Unit of Sale Strength Each 460837 NDC 63323-468-37 Trays of 25 0.25% 75 mg per 30 mL (2.5 mg per mL) NDC 63323-468-02 30 mL Single Dose Vial 460817 NDC 63323-468-17 Trays of 25 0.25% 25 mg per 10 mL (2.5 mg per mL) NDC 63323-468-01 10 mL Single Dose Vial 460217 NDC 63323-462-17 Trays of 25 0.5% 50 mg per 10 mL (5 mg per mL) NDC 63323-462-04 10 mL Single Dose Vial 460237 NDC 63323-462-37 Trays of 25 0.5% 150 mg per 30 mL (5 mg per mL) NDC 63323-462-01 30 mL Single Dose Vial 461037 NDC 63323-460-37 Trays of 25 0.75% 225 mg per 30 mL (7.5 mg per mL) NDC 63323-460-01 30 mL Single Dose Vial For Single Dose Vials: Discard unused portion. SENSORCAINE ® (preserved with methylparaben) does not contain epinephrine and is clear and colorless. Do not use the solution if it is discolored or if it contains a precipitate. SENSORCAINE ® is available in the following forms: Product Code Unit of Sale Strength Each 460557 NDC 63323-465-57 Trays of 25 0.25% 125 mg per 50 mL (2.5 mg per mL) NDC 63323-465-01 50 mL Multiple Dose Vial 460757 NDC 63323-467-57 Trays of 25 0.5% 250 mg per 50 mL (5 mg per mL) NDC 63323-467-01 50 mL Multiple Dose Vial SENSORCAINE ® WITH EPINEPHRINE (1:200,000) should be protected from light. This product is clear, colorless to slightly yellow. Do not use the solution if it is pinkish or darker than slightly yellow or if it contains a precipitate. SENSORCAINE® WITH EPINEPHRINE is available in the following forms: Product Code Unit of Sale Strength Each 460157 NDC 63323-461-57 Trays of 25 0.25% 125 mg per 50 mL (2.5 mg per mL) NDC 63323-461-01 50 mL Multiple Dose Vial 460357 NDC 63323-463-57 Trays of 25 0.5% 250 mg per 50 mL (5 mg per mL) NDC 63323-463-01 50 mL Multiple Dose Vial