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DESCRIPTION: Mepivacaine hydrochloride is 2-Piperidinecarboxamide, N-(2, 6-dimethylphenyl)-1-methyl-, monohydrochloride and has the following structural formula: C 15 H 22 N 2 O • HCl It is a white, crystalline, odorless powder, soluble in water, but very resistant to both acid and alkaline hydrolysis. Mepivacaine hydrochloride is a local anesthetic available as sterile isotonic solutions (clear, colorless) in concentrations of 1%, 1.5% and 2% for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. Mepivacaine hydrochloride is related chemically and pharmacologically to the amide-type local anesthetics. It contains an amide linkage between the aromatic nucleus and the amino group. Composition of Available Solutions* 1% Single Dose 30 mL Vial mg/mL 1% Multiple Dose 50 mL Vial mg/mL 1.5% Single Dose 30 mL Vial mg/mL 2% Single Dose 20 mL Vial mg/mL 2% Multiple Dose 50 mL Vial mg/mL Mepivacaine hydrochloride 10 10 15 20 20 Sodium chloride 6.6 7 5.6 4.6 5 Potassium chloride 0.3 0.3 0.3 Calcium chloride 0.33 0.33 0.33 Methylparaben 1 1 *In Water For Injection The pH of the solution is adjusted between 4.5 and 6.8 with sodium hydroxide or hydrochloric acid. structure

<table cellspacing="0" cellpadding="0" border="0" width="100%"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> </td><td styleCode="Rrule" valign="top"> 1% Single Dose 30 mL Vial mg/mL </td><td styleCode="Rrule" valign="top"> 1% Multiple Dose 50 mL Vial mg/mL </td><td styleCode="Rrule" valign="top"> 1.5% Single Dose 30 mL Vial mg/mL </td><td styleCode="Rrule" valign="top"> 2% Single Dose 20 mL Vial mg/mL </td><td styleCode="Rrule" valign="top"> 2% Multiple Dose 50 mL Vial mg/mL </td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule" valign="top">Mepivacaine hydrochloride </td><td styleCode="Rrule" valign="top"> 10</td><td styleCode="Rrule" valign="top">10 </td><td styleCode="Rrule" valign="top">15</td><td styleCode="Rrule" valign="top">20 </td><td styleCode="Rrule" valign="top">20 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Sodium chloride</td><td styleCode="Rrule" valign="top"> 6.6</td><td styleCode="Rrule" valign="top">7 </td><td styleCode="Rrule" valign="top">5.6 </td><td styleCode="Rrule" valign="top">4.6 </td><td styleCode="Rrule" valign="top">5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Potassium chloride</td><td styleCode="Rrule" valign="top"> 0.3</td><td styleCode="Rrule" valign="top"> </td><td styleCode="Rrule" valign="top"> 0.3</td><td styleCode="Rrule" valign="top"> 0.3</td><td styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule" valign="top">Calcium chloride </td><td styleCode="Rrule" valign="top"> 0.33</td><td styleCode="Rrule" valign="top"> </td><td styleCode="Rrule" valign="top"> 0.33</td><td styleCode="Rrule" valign="top"> 0.33</td><td styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule" valign="top">Methylparaben </td><td styleCode="Rrule" valign="top"> </td><td styleCode="Rrule" valign="top"> 1</td><td styleCode="Rrule" valign="top"> </td><td styleCode="Rrule" valign="top"> </td><td styleCode="Rrule" valign="top"> 1</td></tr><tr><td colspan="6" styleCode="Lrule Rrule" valign="top">*In Water For Injection</td></tr></tbody></table>

CLINICAL PHARMACOLOGY: Local anesthetics block 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: pain, temperature, touch, proprioception, and skeletal muscle tone. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by depression and coma 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 occur without a prior excited stage. A clinical study using 15 mL of 2% epidural mepivacaine at the T 9-10 interspace in 62 patients, 20 to 79 years of age, demonstrated a 40% decrease in the amount of mepivacaine required to block a given number of dermatomes in the elderly (60 to 79 years, N=13) as compared to young adults 20 to 39 years. Another study using 10 mL of 2% lumbar epidural mepivacaine in 161 patients, 19 to 75 years of age, demonstrated a strong inverse relationship between patient age and the number of dermatomes blocked per cc of mepivacaine injected. Pharmacokinetics The rate of systemic absorption of local anesthetics 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 anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and plasma concentration of mepivacaine, however, it has been reported that vasoconstrictors do not significantly prolong anesthesia with mepivacaine. Onset of anesthesia with mepivacaine is rapid, the time of onset for sensory block ranging from about 3 to 20 minutes depending upon such factors as the anesthetic technique, the type of block, the concentration of the solution, and the individual patient. The degree of motor blockade produced is dependent on the concentration of the solution. A 0.5% solution will be effective in small superficial nerve blocks while the 1% concentration will block sensory and sympathetic conduction without loss of motor function. The 1.5% solution will provide extensive and often complete motor block and the 2% concentration of mepivacaine hydrochloride will produce complete sensory and motor block of any nerve group.

uperficial nerve blocks while the 1% concentration will block sensory and sympathetic conduction without loss of motor function. The 1.5% solution will provide extensive and often complete motor block and the 2% concentration of mepivacaine hydrochloride will produce complete sensory and motor block of any nerve group. The duration of anesthesia also varies depending upon the technique and type of block, the concentration, and the individual. Mepivacaine will normally provide anesthesia which is adequate for 2 to 2½ hours of surgery. Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma. Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by the degree of plasma protein binding, the degree of ionization, and the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Mepivacaine is approximately 75% bound to plasma proteins. 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 drug administration, and the age of the patient. The half-life of mepivacaine in adults is 1.9 to 3.2 hours and in neonates 8.7 to 9 hours. Mepivacaine, because of its amide structure, is not detoxified by the circulating plasma esterases. It is rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of mepivacaine have been identified from human adults: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2’, 6’-pipecoloxylidide).

Pharmacokinetics The rate of systemic absorption of local anesthetics 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 anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and plasma concentration of mepivacaine, however, it has been reported that vasoconstrictors do not significantly prolong anesthesia with mepivacaine. Onset of anesthesia with mepivacaine is rapid, the time of onset for sensory block ranging from about 3 to 20 minutes depending upon such factors as the anesthetic technique, the type of block, the concentration of the solution, and the individual patient. The degree of motor blockade produced is dependent on the concentration of the solution. A 0.5% solution will be effective in small superficial nerve blocks while the 1% concentration will block sensory and sympathetic conduction without loss of motor function. The 1.5% solution will provide extensive and often complete motor block and the 2% concentration of mepivacaine hydrochloride will produce complete sensory and motor block of any nerve group. The duration of anesthesia also varies depending upon the technique and type of block, the concentration, and the individual. Mepivacaine will normally provide anesthesia which is adequate for 2 to 2½ hours of surgery. Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma. Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by the degree of plasma protein binding, the degree of ionization, and the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Mepivacaine is approximately 75% bound to plasma proteins. 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 drug administration, and the age of the patient. The half-life of mepivacaine in adults is 1.9 to 3.2 hours and in neonates 8.7 to 9 hours. Mepivacaine, because of its amide structure, is not detoxified by the circulating plasma esterases. It is rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. The principal route of excretion is via the kidney.

ipal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of mepivacaine have been identified from human adults: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2’, 6’-pipecoloxylidide).

INDICATIONS AND USAGE: POLOCAINE (Mepivacaine HCl Injection, USP), is indicated for production of local or regional analgesia and anesthesia by local infiltration, peripheral nerve block techniques, and central neural techniques including epidural and caudal blocks. The routes of administration and indicated concentrations for mepivacaine are: local infiltration 0.5% (via dilution) or 1 % peripheral nerve blocks 1% and 2% epidural block 1%, 1.5%, 2% caudal block 1%, 1.5%, 2% See DOSAGE AND ADMINISTRATION for additional information. Standard textbooks should be consulted to determine the accepted procedures and techniques for the administration of mepivacaine.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> local infiltration</td><td styleCode="Rrule" valign="top"> 0.5% (via dilution) or 1 %</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">peripheral nerve blocks </td><td styleCode="Rrule" valign="top"> 1% and 2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">epidural block </td><td styleCode="Rrule" valign="top"> 1%, 1.5%, 2% </td></tr><tr><td styleCode="Lrule Rrule" valign="top">caudal block </td><td styleCode="Rrule" valign="top"> 1%, 1.5%, 2% <content styleCode="italics"> </content> </td></tr></tbody></table>

CONTRAINDICATIONS: Mepivacaine is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide-type or to other components of solutions of mepivacaine.

WARNINGS: LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER INSURING 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 (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. Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious CNS and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Polocaine and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Local anesthetic solutions containing antimicrobial preservatives (ie, those supplied in multiple-dose vials) should not be used for epidural or caudal anesthesia because safety has not been established with regard to intrathecal injection, either intentionally or inadvertently, of such preservatives. Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine 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 effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection. Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics. Mepivacaine with epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of mepivacaine containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection. Mixing or the prior or intercurrent use of any local anesthetic with mepivacaine cannot be recommended because of insufficient data on the clinical use of such mixtures.

PRECAUTIONS: General The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use (see WARNINGS and ADVERSE REACTIONS ). During major regional nerve blocks, the patient should have IV fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Current opinion favors fractional administration with constant attention to the patient, rather than rapid bolus injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) 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 be administered initially and the effects monitored before the full dose is given. When using a “continuous” catheter technique, test doses should be given prior to both the original and all reinforcing doses, because plastic tubing in the epidural space can migrate into a blood vessel or through the dura. When the clinical conditions permit, an effective test dose should contain epinephrine (10 mcg to 15 mcg have been suggested) to serve as a warning of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce an “epinephrine response” within 45 seconds, consisting of an increase of pulse and 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. Therefore, following the test dose, the heart rate should be monitored for a heart rate increase. The test dose should also contain 45 mg to 50 mg of mepivacaine hydrochloride to detect an unintended intrathecal administration. This will be evidenced within a few minutes by signs of spinal block (eg, decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). 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 status of the patient. Debilitated, elderly patients, and acutely ill patients should be given reduced doses commensurate with their age and physical status. Local anesthetics should also be used with caution in patients with severe disturbances of cardiac rhythm, shock, heart block, or hypotension. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs, and the patient’s state of consciousness should be performed after each local anesthetic injection.

so be used with caution in patients with severe disturbances of cardiac rhythm, shock, heart block, or hypotension. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs, and the patient’s state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times 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. Local anesthetic solutions containing a vasoconstrictor should be used cautiously and 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, penis. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Mepivacaine should be used with caution in patients with known allergies and sensitivities. Because amide-type local anesthetics such as mepivacaine are metabolized by the liver and excreted by the kidneys, these drugs, especially repeat doses, should be used cautiously in patients with hepatic and renal disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs. Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients during or following the administration of potent inhalation anesthetics. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s), and institution of treatment, including oxygen therapy, indicated supportive measures, and dantrolene. (Consult dantrolene sodium intravenous package insert before using.) 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 intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available.

to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded. Information for Patients 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 caudal or epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions listed in this package insert. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue. Clinically Significant Drug Interactions The administration of local anesthetic solutions containing epinephrine or norepinephrine 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 patient monitoring is essential. Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitroglycerin, nitroprusside, nitric oxide, 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 acetaminophen, metoclopramide, quinine, sulfasalazine Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals of most local anesthetics including mepivacaine to evaluate the carcinogenic potential have not been conducted. Mutagenic potential or the effect on fertility have not been determined. There is no evidence from human data that mepivacaine may be carcinogenic or mutagenic or that it impairs fertility. Pregnancy Animal reproduction studies have not been conducted with mepivacaine. There are no adequate and well-controlled studies in pregnant women of the effect of mepivacaine on the developing fetus. Mepivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. This does not preclude the use of mepivacaine at term for obstetrical anesthesia or analgesia (see Labor and Delivery ). Mepivacaine has been used for obstetrical analgesia by the epidural, caudal, and paracervical routes without evidence of adverse effects on the fetus when no more than the maximum safe dosages are used and strict adherence to technique is followed.

term for obstetrical anesthesia or analgesia (see Labor and Delivery ). Mepivacaine has been used for obstetrical analgesia by the epidural, caudal, and paracervical routes without evidence of adverse effects on the fetus when no more than the maximum safe dosages are used and strict adherence to technique is followed. Labor and Delivery Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity (see CLINICAL PHARMACOLOGY , 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, caudal, 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. 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. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving para-cervical block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. Added risk appears to be present in prematurity, postmaturity, toxemia of pregnancy, and fetal distress. The physician should weigh the possible advantages against dangers when considering paracervical block in these conditions. 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 solution 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 the local anesthetic should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a five-minute interval between sides.

l block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of the local anesthetic should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a five-minute interval between sides. 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 the gravid uterus displaced to the left. Nursing Mothers It is not known whether local anesthetic drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when local anesthetics are administered to a nursing woman. Pediatric Use Guidelines for the administration of mepivacaine to pediatric patients are presented in DOSAGE AND ADMINISTRATION . Geriatric Use Clinical studies and other reported clinical experience indicates that use of the drug in elderly patients requires a decreased dosage (see CLINICAL PHARMACOLOGY , PRECAUTIONS , General , and DOSAGE AND ADMINISTRATION ). Mepivacaine and mepivacaine 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.

<table ID="t300" width="100%"><col width="30.100%" align="left"/><col width="69.900%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Class</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Examples</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Nitrates/Nitrites </td><td align="left" styleCode="Botrule Rrule" valign="top">nitroglycerin, nitroprusside, nitric oxide, nitrous oxide </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Local anesthetics </td><td align="left" styleCode="Botrule Rrule" valign="top">articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Antineoplastic agents </td><td align="left" styleCode="Botrule Rrule" valign="top">cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Antibiotics </td><td align="left" styleCode="Botrule Rrule" valign="top">dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Antimalarials </td><td align="left" styleCode="Botrule Rrule" valign="top">chloroquine, primaquine </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Anticonvulsants </td><td align="left" styleCode="Botrule Rrule" valign="top">phenobarbital, phenytoin, sodium valproate </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Other drugs </td><td align="left" styleCode="Botrule Rrule" valign="top">acetaminophen, metoclopramide, quinine, sulfasalazine </td></tr></tbody></table>

General The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use (see WARNINGS and ADVERSE REACTIONS ). During major regional nerve blocks, the patient should have IV fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Current opinion favors fractional administration with constant attention to the patient, rather than rapid bolus injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) 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 be administered initially and the effects monitored before the full dose is given. When using a “continuous” catheter technique, test doses should be given prior to both the original and all reinforcing doses, because plastic tubing in the epidural space can migrate into a blood vessel or through the dura. When the clinical conditions permit, an effective test dose should contain epinephrine (10 mcg to 15 mcg have been suggested) to serve as a warning of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce an “epinephrine response” within 45 seconds, consisting of an increase of pulse and 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. Therefore, following the test dose, the heart rate should be monitored for a heart rate increase. The test dose should also contain 45 mg to 50 mg of mepivacaine hydrochloride to detect an unintended intrathecal administration. This will be evidenced within a few minutes by signs of spinal block (eg, decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). 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 status of the patient. Debilitated, elderly patients, and acutely ill patients should be given reduced doses commensurate with their age and physical status. Local anesthetics should also be used with caution in patients with severe disturbances of cardiac rhythm, shock, heart block, or hypotension. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs, and the patient’s state of consciousness should be performed after each local anesthetic injection.

so be used with caution in patients with severe disturbances of cardiac rhythm, shock, heart block, or hypotension. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs, and the patient’s state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times 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. Local anesthetic solutions containing a vasoconstrictor should be used cautiously and 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, penis. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Mepivacaine should be used with caution in patients with known allergies and sensitivities. Because amide-type local anesthetics such as mepivacaine are metabolized by the liver and excreted by the kidneys, these drugs, especially repeat doses, should be used cautiously in patients with hepatic and renal disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs. Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients during or following the administration of potent inhalation anesthetics. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s), and institution of treatment, including oxygen therapy, indicated supportive measures, and dantrolene. (Consult dantrolene sodium intravenous package insert before using.)

Information for Patients 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 caudal or epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions listed in this package insert. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

Clinically Significant Drug Interactions The administration of local anesthetic solutions containing epinephrine or norepinephrine 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 patient monitoring is essential. Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitroglycerin, nitroprusside, nitric oxide, 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 acetaminophen, metoclopramide, quinine, sulfasalazine

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals of most local anesthetics including mepivacaine to evaluate the carcinogenic potential have not been conducted. Mutagenic potential or the effect on fertility have not been determined. There is no evidence from human data that mepivacaine may be carcinogenic or mutagenic or that it impairs fertility.

Pregnancy Animal reproduction studies have not been conducted with mepivacaine. There are no adequate and well-controlled studies in pregnant women of the effect of mepivacaine on the developing fetus. Mepivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. This does not preclude the use of mepivacaine at term for obstetrical anesthesia or analgesia (see Labor and Delivery ). Mepivacaine has been used for obstetrical analgesia by the epidural, caudal, and paracervical routes without evidence of adverse effects on the fetus when no more than the maximum safe dosages are used and strict adherence to technique is followed.

Labor and Delivery Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity (see CLINICAL PHARMACOLOGY , 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, caudal, 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. 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. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving para-cervical block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. Added risk appears to be present in prematurity, postmaturity, toxemia of pregnancy, and fetal distress. The physician should weigh the possible advantages against dangers when considering paracervical block in these conditions. 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 solution 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 the local anesthetic should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a five-minute interval between sides.

l block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of the local anesthetic should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a five-minute interval between sides. 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 the gravid uterus displaced to the left.

Geriatric Use Clinical studies and other reported clinical experience indicates that use of the drug in elderly patients requires a decreased dosage (see CLINICAL PHARMACOLOGY , PRECAUTIONS , General , and DOSAGE AND ADMINISTRATION ). Mepivacaine and mepivacaine 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.

ADVERSE REACTIONS: To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Reactions to mepivacaine 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, inadvertent intravascular injection, or slow metabolic degradation. Systemic The most commonly encountered acute adverse experiences which demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result 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 subarachnoid 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) may result 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 may occur. This may lead to secondary cardiac arrest if untreated. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. Central Nervous System Reactions These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. Cardiovascular Reactions High doses or, inadvertent intravascular injection, may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension (or sometimes hypertension), bradycardia, ventricular arrhythmias, and possibly cardiac arrest (see WARNINGS , PRECAUTIONS , and OVERDOSAGE ). Allergic Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben, contained in multiple-dose vials. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported.

ioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established. Neurologic The incidences of adverse neurologic 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. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. Neurologic effects following epidural or caudal anesthesia may include 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 may have slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete or no recovery.

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 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 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, standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged period if necessary.

nintentional 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 and maintained for a prolonged period if necessary. Recovery has been reported after 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 mepivacaine in rhesus monkeys was found to be 18.8 mg/kg with mean arterial plasma concentration of 24.4 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 23 mg/kg to 35 mg/kg and 280 mg/kg respectively.

DOSAGE AND ADMINISTRATION: The dose of any local anesthetic 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. The smallest dose and concentration required to produce the desired result should be administered. Dosages of mepivacaine hydrochloride should be reduced for elderly and debilitated patients and patients with cardiac and/or liver disease. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional doses should be used when feasible. 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. Polocaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION ). The recommended single adult dose (or the total of a series of doses given in one procedure) of mepivacaine hydrochloride for unsedated, healthy, normal-sized individuals should not usually exceed 400 mg. The recommended dosage is based on requirements for the average adult and should be reduced for elderly or debilitated patients. While maximum doses of 7 mg/kg (550 mg) have been administered without adverse effect, these are not recommended, except in exceptional circumstances and under no circumstances should the administration be repeated at intervals of less than 1½ hours. The total dose for any 24-hour period should not exceed 1,000 mg because of a slow accumulation of the anesthetic or its derivatives or slower than normal metabolic degradation or detoxification with repeat administration (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). Pediatric patients tolerate the local anesthetic as well as adults. However, the pediatric dose should be carefully measured as a percentage of the total adult dose based on weight , and should not exceed 5 mg/kg to 6 mg/kg (2.5 mg/lb to 3 mg/lb) in pediatric patients, especially those weighing less than 30 lbs. In pediatric patients under 3 years of age or weighing less than 30 lbs concentrations less than 2% (eg, 0.5% to 1.5%) should be employed. Unused portions of solutions not containing preservatives, ie, those supplied in single-dose vials, should be discarded following initial use. This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered. Recommended Concentrations and Doses of Mepivacaine Hydrochloride Procedure Concentration Total Dose Comments mL mg Cervical, brachial, intercostal, Pudendal nerve block 1% 5 to 40 50 to 400 Pudendal block: one half of total dose injected each side. 2% 5 to 20 100 to 400 Transvaginal block (paracervical plus pudendal) 1% up to 30 (both sides) up to 300 (both sides) One half of total dose injected each side. See PRECAUTIONS . Paracervical block 1% up to 20 (both sides) up to 200 (both sides) One half of total dose injected each side. This is maximum recommended dose per 90-minute period in obstetrical and non-obstetrical patients. Inject slowly, 5 minutes between sides. See PRECAUTIONS .

f of total dose injected each side. See PRECAUTIONS . Paracervical block 1% up to 20 (both sides) up to 200 (both sides) One half of total dose injected each side. This is maximum recommended dose per 90-minute period in obstetrical and non-obstetrical patients. Inject slowly, 5 minutes between sides. See PRECAUTIONS . Caudal and Epidural block 1% 15 to 30 150 to 300 *Use only single-dose vials which do not contain a preservative. 1.5% 10 to 25 150 to 375 2% 10 to 20 200 to 400 Infiltration 1% up to 40 up to 400 An equivalent amount of a 0.5% solution (prepared by diluting the 1% solution with Sodium Chloride Injection, USP) may be used for large areas. Therapeutic block (pain management) 1% 1 to 5 10 to 50 2% 1 to 5 20 to 100 Unused portions of solutions not containing preservatives should be discarded. * Dosage forms listed as POLOCAINE-MPF (Mepivacaine HCl Injection, USP) are single-dose solutions which do not contain a preservative.

HOW SUPPLIED: Single-dose vials and multiple-dose vials of POLOCAINE may be sterilized by autoclaving at 15 pound pressure, 121°C (250°F) for 15 minutes. Solutions of POLOCAINE may be reautoclaved when necessary. Do not administer solutions which are discolored or which contain particulate matter. THESE SOLUTIONS ARE NOT INTENDED FOR SPINAL ANESTHESIA OR DENTAL USE. POLOCAINE ® -MPF (Mepivacaine HCl Injection, USP) without preservatives is available as follows: Product Code Unit of Sale Strength Each 261037 NDC 63323-260-37 Unit of 25 1% 300 mg per 30 mL (10 mg per mL) NDC 63323-260-01 30 mL Single Dose Vial 293037 NDC 63323-293-37 Unit of 25 1.5% 450 mg per 30 mL (15 mg per mL) NDC 63323-293-01 30 mL Single Dose Vial 294027 NDC 63323-294-27 Unit of 25 2% 400 mg per 20 mL (20 mg per mL) NDC 63323-294-01 20 mL Single Dose Vial POLOCAINE ® (Mepivacaine HCl Injection, USP) with preservatives is available as follows: Product Code Unit of Sale Strength Each 283057 NDC 63323-283-57 Unit of 25 1% 500 mg per 50 mL (10 mg per mL) NDC 63323-283-01 50 mL Multiple Dose Vial 296057 NDC 63323-296-57 Unit of 25 2% 1,000 mg per 50 mL (20 mg per mL) NDC 63323-296-01 50 mL Multiple Dose Vial For single-dose vials: Discard unused portion. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]; brief exposure up to 40 ° C (104 ° F) does not adversely affect the product. All trademarks are the property of Fresenius Kabi USA, LLC. Manufactured for: www.fresenius-kabi.com/us 451105D/Revised: April 2019 Fresenius Kabi Logo

<table width="100%"><col width="14.496%" align="left"/><col width="28.093%" align="left"/><col width="32.917%" align="left"/><col width="24.494%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Product Code</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Unit of Sale</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Strength</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Each</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">261037 </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-260-37 Unit of 25 </td><td align="left" styleCode="Botrule Rrule" valign="top">1% 300 mg per 30 mL (10 mg per mL) </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-260-01 30 mL Single Dose Vial </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">293037 </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-293-37 Unit of 25 </td><td align="left" styleCode="Botrule Rrule" valign="top">1.5% 450 mg per 30 mL (15 mg per mL) </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-293-01 30 mL Single Dose Vial </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">294027 </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-294-27 Unit of 25 </td><td align="left" styleCode="Botrule Rrule" valign="top">2% 400 mg per 20 mL (20 mg per mL) </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-294-01 20 mL Single Dose Vial </td></tr></tbody></table>

>294027 </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-294-27 Unit of 25 </td><td align="left" styleCode="Botrule Rrule" valign="top">2% 400 mg per 20 mL (20 mg per mL) </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-294-01 20 mL Single Dose Vial </td></tr></tbody></table> <table width="100%"><col width="14.496%" align="left"/><col width="28.093%" align="left"/><col width="32.917%" align="left"/><col width="24.494%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Product Code</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Unit of Sale</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Strength</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Each</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">283057 </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-283-57 Unit of 25 </td><td align="left" styleCode="Botrule Rrule" valign="top">1% 500 mg per 50 mL (10 mg per mL) </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-283-01 50 mL Multiple Dose Vial </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">296057 </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-296-57 Unit of 25 </td><td align="left" styleCode="Botrule Rrule" valign="top">2% 1,000 mg per 50 mL (20 mg per mL) </td><td align="left" styleCode="Botrule Rrule" valign="top">NDC 63323-296-01 50 mL Multiple Dose Vial </td></tr></tbody></table>

Rx only THESE SOLUTIONS ARE INTENDED FOR DENTAL USE ONLY. DISINFECTION OF CARTRIDGES As in the case of any cartridge, the diaphragm should be disinfected before needle puncture. The diaphragm should be thoroughly swabbed with either pure 91% isopropyl alcohol or 70% ethyl alcohol, USP, just prior to use. Many commercially available alcohol solutions contain ingredients which are injurious to container components, and therefore, should not be used. Cartridges should not be immersed in any solution. Manufactured by Novocol Pharmaceutical of Canada, Inc. Cambridge, Ontario, Canada N1R 6X3 Rev. 04/2020 (2222-2) Cook-Waite is a trademark of Septodont Holdings SAS.

DESCRIPTION CARBOCAINE (mepivacaine hydrochloride), a tertiary amine used as a local anesthetic, is 1-methyl-2', 6' - pipecoloxylidide monohydrochloride with the following structural formula: C 15 H 22 N 2 0.HCl M.W. 282.81 It is a white, crystalline, odorless powder soluble in water, but very resistant to both acid and alkaline hydrolysis. NEO-COBEFRIN, a sympathomimetic amine used as a vasoconstrictor in local anesthetic solution, is (-)- -(1-Aminoethyl)-3, 4-dihydroxybenzyl alcohol with the following structural formula: C 9 H 13 NO 3 M.W. 183.21 It is a white or buff-colored crystalline solid, freely soluble in aqueous solutions of mineral acids, but practically insoluble in water. DENTAL CARTRIDGES MAY NOT BE AUTOCLAVED. CARBOCAINE 3% (30 mg/mL) injection and CARBOCAINE 2% (20 mg/mL) with NEO-COBEFRIN 1:20,000 injection are sterile solutions for injection. COMPOSITION: CARTRIDGE Each mL contains: 2% 3% Mepivacaine hydrochloride 20 mg 30 mg Levonordefrin 0.05mg - Sodium chloride 4 mg 6 mg Potassium metabisulfite 1.2 mg - Edetate disodium 0.25mg - Sodium hydroxide q.s. ad pH Hydrochloric acid 0.5 mg - Water for injections qs. ad. 1 mL 1 mL The pH of the 2% cartridge solution is adjusted between 3.3 and 5.5 with NaOH. The pH of the 3% cartridge solution is adjusted between 4.5 and 6.8 with NaOH. Chemical Structure Chemical Structure Symbol

<table width="80%"><colgroup><col width="50%" align="center" valign="middle"/><col width="50%" align="left" valign="middle"/></colgroup><tbody><tr><td align="center"><renderMultiMedia referencedObject="MM1"/></td><td align="left">C₁₅H₂₂N₂ 0.HCl M.W. 282.81</td></tr></tbody></table> <table width="80%"><colgroup><col width="50%" align="center" valign="middle"/><col width="50%" align="left" valign="middle"/></colgroup><tbody><tr><td align="center"><renderMultiMedia referencedObject="MM2"/></td><td align="left">C₉H₁₃NO₃ M.W. 183.21</td></tr></tbody></table> <table width="100%"><colgroup><col width="80%" align="left" valign="bottom"/><col width="10%" align="center" valign="bottom"/><col width="10%" align="center" valign="bottom"/></colgroup><thead><tr styleCode="First Last"><th align="left">COMPOSITION:</th><th colspan="2" align="center">CARTRIDGE</th></tr></thead><tbody><tr><td align="left">Each mL contains:</td><td align="center">2%</td><td align="center">3%</td></tr><tr><td align="left"> Mepivacaine hydrochloride</td><td align="center">20 mg</td><td align="center">30 mg</td></tr><tr><td align="left"> Levonordefrin</td><td align="center">0.05mg</td><td align="center">-</td></tr><tr><td align="left"> Sodium chloride</td><td align="center">4 mg</td><td align="center">6 mg</td></tr><tr><td align="left"> Potassium metabisulfite</td><td align="center">1.2 mg</td><td align="center">-</td></tr><tr><td align="left"> Edetate disodium</td><td align="center">0.25mg</td><td align="center">-</td></tr><tr><td align="left"> Sodium hydroxide q.s. ad pH</td><td align="center"/><td align="center"/></tr><tr><td align="left"> Hydrochloric acid</td><td align="center">0.5 mg</td><td align="center">-</td></tr><tr><td align="left"> Water for injections qs. ad.</td><td align="center">1 mL</td><td align="center">1 mL</td></tr><tr><td align="left"> The pH of the 2% cartridge solution is adjusted between 3.3 and 5.5 with NaOH.</td><td align="center"/><td align="center"/></tr><tr><td align="left"> The pH of the 3% cartridge solution is adjusted between 4.5 and 6.8 with NaOH.</td><td align="center"/><td align="center"/></tr></tbody></table>

CLINICAL PHARMACOLOGY CARBOCAINE stabilizes the neuronal membrane and prevents the initiation and transmission of nerve impulses, thereby effecting local anesthesia. CARBOCAINE is rapidly metabolized, with only a small percentage of the anesthetic (5 to 10 percent) being excreted unchanged in the urine. CARBOCAINE because of its amide structure, is not detoxified by the circulating plasma esterases. The liver is the principal site of metabolism, with over 50 percent of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of mepivacaine have been identified from adult humans: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2', 6' - pipecoloxylidide). The onset of action is rapid (30 to 120 seconds in the upper jaw; 1 to 4 minutes in the lower jaw) and CARBOCAINE 3% (30 mg/mL) injection will ordinarily provide operating anesthesia of 20 minutes in the upper jaw and 40 minutes in the lower jaw . CARBOCAINE 2% (20 mg/mL) with Neo-Cobefrin 1:20,000 injection provides anesthesia of longer duration for more prolonged procedures, 1 hour to 2.5 hours in the upper jaw and 2.5 hours to 5.5 hours in the lower jaw. CARBOCAINE does not ordinarily produce irritation or tissue damage. Neo-Cobefrin is a sympathomimetic amine used as a vasoconstrictor in local anesthetic solutions. It has pharmacologic activity similar to that of Epinephrine but it is more stable than Epinephrine. In equal concentrations, Neo-Cobefrin is less potent than Epinephrine in raising blood pressure, and as a vasoconstrictor.

WARNINGS RESUSCITATIVE EQUIPMENT AND DRUGS SHOULD BE IMMEDIATELY AVAILABLE. (See ADVERSE REACTIONS ). Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics, even in the absence of a history of hypersensitivity. Fatalities may occur with use of local anesthetics in the head and neck region as the result of retrograde arterial flow to vital CNS areas even when maximum recommended doses are observed. The practitioner should be alert to early evidence of alteration in sensorium or vital signs. The solution which contains a vasoconstrictor (CARBOCAINE 2% (20 mg/mL)) should be used with extreme caution for patients whose medical history and physical evaluation suggest the existence of hypertension, arteriosclerotic heart disease, cerebral vascular insufficiency, heart block, thyrotoxicosis and diabetes, etc. The solution which contains a vasoconstrictor (CARBOCAINE 2% (20 mg/mL)) also contains potassium bisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. CARBOCAINE 3% (30 mg/mL) is SULFITE FREE. CARBOCAINE, along with other local anesthetics, is capable of producing methemoglobinemia. The clinical signs of methemoglobinemia are cyanosis of the nail beds and lips, fatigue and weakness. If methemoglobinemia does not respond to administration of oxygen, administration of methylene blue intravenously 1-2 mg/kg body weight over a 5 minute period is recommended. The American Heart Association has made the following recommendations regarding the use of local anesthetics with vasoconstrictors in patients with ischemic heart disease: "Vasoconstrictor agents should be used in local anesthesia solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection. The minimum possible amount of vasoconstrictor should be used." (Kaplan, EL. editor: Cardiovascular disease in dental practice, Dallas 1986, American Heart Association). Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use; CARBOCAINE, along with other local anesthetics, is capable of producing this condition. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by cyanosis of the skin, nail beds and lips, and/or abnormal coloration of the blood, fatigue and weakness. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death.

yanosis of the skin, nail beds and lips, and/or abnormal coloration of the blood, fatigue and weakness. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue CARBOCAINE and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. If methemoglobinemia does not respond to administration of oxygen, a more severe clinical presentation may require treatment with methylene blue exchange transfusion, or hyperbaric oxygen.

PRECAUTIONS The safety and effectiveness of mepivacaine depend upon proper dosage, correct technique, adequate precautions, and readiness for emergencies. The lowest dose that results in effective anesthesia should be used to avoid high plasma levels and possible adverse effects. Injection of repeated doses of Mepivacaine may cause significant increases in blood levels with each repeated dose due to slow accumulation of the drug or its metabolites, or due to slower metabolic degradation than normal. Tolerance varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their weight and physical status. Mepivacaine should be used with caution in patients with a history of severe disturbances of cardiac rhythm or heart block. INJECTIONS SHOULD ALWAYS BE MADE SLOWLY WITH ASPIRATION TO AVOID INTRAVASCULAR INJECTION AND THEREFORE SYSTEMIC REACTION TO BOTH LOCAL ANESTHETIC AND VASOCONSTRICTOR. If sedatives are employed to reduce patient apprehension, use reduced doses, since local anesthetic agents, like sedatives, are central nervous system depressants which in combination may have an additive effect. Young children should be given minimal doses of each agent. Changes in sensorium such as excitation, disorientation or drowsiness may be early indications of a high blood level of the drug and may occur following inadvertent intravascular administration or rapid absorption of mepivacaine. Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection. Information for Patients/Patient Counseling Information The patient should be cautioned against loss of sensation and possibility of biting trauma should the patient attempt to eat or chew gum prior to return of sensation. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue. Clinically Significant Drug Interactions The administration of local anesthetic solutions containing vasopressors, such as Neo-Cobefrin, Epinephrine or Norepinephrine, to patients receiving tricyclic antidepressants or monoamine oxidase inhibitors may produce severe, prolonged 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 and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of Epinephrine. Solutions containing a vasoconstrictor should be used cautiously in the presence of disease which may adversely affect the patient's cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics.

ning a vasoconstrictor should be used cautiously in the presence of disease which may adversely affect the patient's cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprus-side, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hy-droxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient's prior experience with Mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ). Patients allergic to methylparaben or para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as Mepivacaine. Since Mepivacaine is metabolized in the liver and excreted by the kidneys, it should be used cautiously in patients with liver and renal disease. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of Mepivacaine HCl in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. Pregnacy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can effect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed. 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 this solution is administered to a nursing woman. Pediatric Use Great care must be exercised in adhering to safe concentrations and dosages for pedodontic administration (see DOSAGE AND ADMINISTRATION ).

<table border="8" width="100%"><caption>EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: </caption><tbody><tr><td styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold"> Class</content></td><td styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">Examples</content></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Nitrates/Nitrites</td><td styleCode="Lrule Rrule Toprule Botrule"> nitric oxide, nitroglycerin, nitroprus-side, nitrous oxide</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Local anesthetics</td><td styleCode="Lrule Rrule Toprule Botrule"> articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Antineoplastic Agents</td><td styleCode="Lrule Rrule Toprule Botrule"> cyclophosphamide, flutamide, hy-droxyurea, ifosfamide, rasburicase</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Antibiotics</td><td styleCode="Lrule Rrule Toprule Botrule"> dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Antimalarials</td><td styleCode="Lrule Rrule Toprule Botrule"> chloroquine, primaquine</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Anticonvulsants</td><td styleCode="Lrule Rrule Toprule Botrule"> phenobarbital, phenytoin, sodium valproate</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Other drugs</td><td styleCode="Lrule Rrule Toprule Botrule"> acetaminophen, metoclopramide, quinine, sulfasalazine</td></tr></tbody></table>

Information for Patients/Patient Counseling Information The patient should be cautioned against loss of sensation and possibility of biting trauma should the patient attempt to eat or chew gum prior to return of sensation. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

Clinically Significant Drug Interactions The administration of local anesthetic solutions containing vasopressors, such as Neo-Cobefrin, Epinephrine or Norepinephrine, to patients receiving tricyclic antidepressants or monoamine oxidase inhibitors may produce severe, prolonged 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 and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of Epinephrine. Solutions containing a vasoconstrictor should be used cautiously in the presence of disease which may adversely affect the patient's cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprus-side, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hy-droxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient's prior experience with Mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ). Patients allergic to methylparaben or para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as Mepivacaine. Since Mepivacaine is metabolized in the liver and excreted by the kidneys, it should be used cautiously in patients with liver and renal disease.

Pregnacy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can effect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed.

Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can effect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed.

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 this solution is administered to a nursing woman.

ADVERSE REACTIONS Reactions to CARBOCAINE are characteristic of those associated with other amide-type local anesthetics. Systemic adverse reactions involving the central nervous system and the cardiovascular system usually result from high plasma levels (which may be due to excessive dosage, rapid absorption, inadvertent intravascular injection, or slow metabolic degradation), injection technique, or volume of injection. A small number of reactions may result from hypersensitivity, idiosyncrasy or diminished tolerance to normal dosage on the part of the patient. Persistent paresthesias of the lips, tongue, and oral tissues have been reported with the use of mepivacaine, with slow, incomplete, or no recovery. These post-markeing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches. Reactions involving the central nervous system are characterized by excitation and/or depression. Nervousness, dizziness, blurred vision, or tremors may occur followed by drowsiness, convulsions, unconsciousness, and possible respiratory arrest. Since excitement may be transient or absent, the first manifestations may be drowsiness merging into unconsciousness and respiratory arrest. Cardiovascular reactions are depressant. They may be the result of direct drug effect or more commonly in dental practice, the result of vasovagal reaction, particularly if the patient is in the sitting position. Failure to recognize premonitory signs such as sweating, feeling of faintness, changes in pulse or sensorium may result in progressive cerebral hypoxia and seizure or serious cardiovascular catastrophe. Management consists of placing the patient in the recumbent position and administration of oxygen. Vasoactive drugs such as Ephedrine or Methoxamine may be administered intravenously. Allergic reactions are rare and may occur as a result of sensitivity to the local anesthetic and are characterized by cutaneous lesions of delayed onset or urticaria, edema and other manifestations of allergy. The detection of sensitivity by skin testing is of limited value. As with other local anesthetics, anaphylactoid reactions to Mepivacaine have occurred rarely. The reaction may be abrupt and severe and is not usually dose related. Localized puffiness and swelling may occur.

OVERDOSAGE Treatment of a patient with toxic manifestations consists of assuring and maintaining a patent airway and supporting ventilation (respiration) as required. This usually will be sufficient in the management of most reactions. Should a convulsion persist despite ventilatory therapy, small increments of anticonvulsive agents may be given intravenously, such as benzodiazephine (e.g., diazepam) or ultrashort-acting barbiturates (e.g., thiopental or thiamylal) or short-acting barbiturates (e.g., pentobarbital or secobarbital). Cardiovascular depression may require circulatory assistance with intravenous fluids and/or vasopressor (e.g., Ephedrine) as dictated by the clinical situation. Allergic reactions should be managed by conventional means. IV and SC LD 50 's in mice for Mepivacaine Hydrochloride 3% are 33 and 258 mg/kg, respectively. The acute IV and SC LD 50 's in mice for Mepivacaine Hydrochloride 2% with Levonordefrin 1:20,000 are 30 and 184 mg/kg, respectively.

DOSAGE AND ADMINISTRATION As with all local anesthetics, the dose varies and depends upon the area to be anesthetized, the vascularity of the tissues, individual tolerance and the technique of anesthesia. The lowest dose needed to provide effective anesthesia should be administered. For specific techniques and procedures refer to standard dental manuals and textbooks. For infiltration and block injections in the upper or lower jaw, the average dose of 1 cartridge will usually suffice. Each cartridge contains 1.7 mL (34 mg of 2% or 51 mg of 3%). 5.3 cartridges (180 mg of the 2% solution or 270 mg of the 3% solution) are usually adequate to effect anesthesia of the entire oral cavity. Whenever a larger dose seems to be necessary for an extensive procedure, the maximum dose should be calculated according to the patient's weight. A dose of up to 3 mg per pound of body weight may be administered. At any single dental sitting the total dose for all injected sites should not exceed 400 mg in adults. The maximum pediatric dose should be carefully calculated. Maximum dose for pediatric population = Child's Weight (lbs.) × Maximum Recommended Dose for Adults (400 mg) 150 The following table, approximating these calculations, may also be used as a guide. This table is based upon a recommended maximum for larger pediatric population of 5.3 cartridges (the maximum recommended adult dose) during any single dental sitting, regardless of the pediatric patient's weight or (for 2% mepivacaine) calculated maximum amount of drug: Maximum Allowable Dosage Adapted from Malamed, Stanley F: Handbook of medical emergencies in the dental office, ed. 2, St. Louis, 1982. The C.V. Mosby Co. 3% Mepivacaine (Plain) 2% Mepivacaine 1:20,000 Levonordefrin 3 mg/lb (270 mg max.) 3mg/lb (180 mg max.) Weight (lb.) mg Number of Cartridges mg Number of Cartridges 20 60 1.2 60 1.8 30 90 1.8 90 2.6 40 120 2.3 120 3.5 50 150 2.9 150 4.4 60 180 3.5 180 5.3 80 240 4.7 180 5.3 100 270 5.3 180 5.3 120 270 5.3 180 5.3 When using CARBOCAINE for infiltration or regional block anesthesia, injection should always be made slowly and with frequent aspiration. Any unused portion of a cartridge should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED CARBOCAINE 3% (30 mg/mL) injection (mepivacaine hydrocholoride injection, USP) is available in cartons containing 5 blisters of 10 × 1.7 mL single-dose dental cartridges, 50 per carton (NDC 0362-0753-05). CARBOCAINE 2% (20 mg/mL) with NEO-COBEFRIN 1:20,000 injection, USP (mepivacaine hydrochloride and levonordefrin injection, USP) is available in cartons containing 5 blisters of 10 × 1.7 mL single-dose dental cartridges, 50 per carton (NDC 0362-0931-05). Both solutions should be stored at controlled room temperature, below 25° C (77° F). Protect from light. Do not permit to freeze. For protection from light, retain in box until time of use. Once opened, the box should be reclosed by closing the flap. The mepivacaine 2% (20 mg/mL) solution should not be used if its color is pinkish or darker than slightly yellow or it contains a precipitate. Cartridge warmers should not be used with CARBOCAINE products.

Both solutions should be stored at controlled room temperature, below 25° C (77° F). Protect from light. Do not permit to freeze. For protection from light, retain in box until time of use. Once opened, the box should be reclosed by closing the flap. The mepivacaine 2% (20 mg/mL) solution should not be used if its color is pinkish or darker than slightly yellow or it contains a precipitate. Cartridge warmers should not be used with CARBOCAINE products.

Rx Only THESE SOLUTIONS ARE INTENDED FOR DENTAL USE ONLY. DISINFECTION OF CARTRIDGES As in the case of any cartridge, the diaphragm should be disinfected before needle puncture. The diaphragm should be thoroughly swabbed with either pure 91% isopropyl alcohol or 70% ethyl alcohol, USP, just prior to use. Many commercially available alcohol solutions contain ingredients which are injurious to container components, and therefore should not be used. Cartridges should not be immersed in any solution. Manufactured for Dentsply Pharmaceutical, York, PA 17404 by Novocol Pharmaceutical of Canada, Inc. Cambridge, Ontario N1R 6X3 Dentsply Sirona Rev 07/2020 (2624-3)

DESCRIPTION Mepivacaine Hydrochloride, a tertiary amine used as a local anesthetic, is 1-methyl-2,' 6' - pipecoloxylidide monohydrochloride with the following structural formula: It is a white, crystalline, odorless powder soluble in water, but very resistant to both acid and alkaline hydrolysis. Levonordefrin, a sympathomimetic amine used as a vasoconstrictor in local anesthetic solution, is (-)-α-(1-Aminoethyl)-3, 4-dihydroxybenzyl alcohol with the following structural formula: It is a white or buff-colored crystalline solid, freely soluble in aqueous solutions of mineral acids, but practically insoluble in water. DENTAL CARTRIDGES MAY NOT BE AUTOCLAVED. 3% (30 mg/mL) Polocaine ® DENTAL (mepivacaine hydrochloride injection 3% (30 mg/mL)) and 2% (20 mg/mL) Polocaine ® DENTAL with Levonordefrin 1:20,000 (mepivacaine hydrochloride 2% (20 mg/mL) with levonordefrin 1:20,000 injection) are sterile solutions for injection. COMPOSITION: CARTRIDGE The pH of the 2% cartridge solution is adjusted between 3.3 and 5.5 with NaOH. The pH of the 3% cartridge solution is adjusted between 4.5 and 6.8 with NaOH. Each mL contains: 2% 3% Mepivacaine Hydrochloride 20 mg 30 mg Levonordefrin 0.05 mg - Sodium Chloride 4 mg 6 mg Potassium metabisulfite 1.2 mg - Edetate disodium 0.25 mg - Sodium Hydroxide q.s. ad pH; Hydrochloric Acid 0.5 mg - Water For Injection, qs. ad. 1 mL 1 mL Chemical Structure Chemical Structure

<table width="75%"><colgroup><col width="70%" align="left" valign="top"/><col width="15%" align="left" valign="top"/><col width="15%" align="left" valign="top"/></colgroup><thead><tr styleCode="First Last"><th align="left">COMPOSITION:</th><th colspan="2" align="center">CARTRIDGE</th></tr></thead><tfoot><tr><td colspan="2" align="left">The pH of the 2% cartridge solution is adjusted between 3.3 and 5.5 with NaOH.</td></tr><tr><td colspan="2" align="left">The pH of the 3% cartridge solution is adjusted between 4.5 and 6.8 with NaOH.</td></tr></tfoot><tbody><tr><td align="left">Each mL contains:</td><td align="left">2%</td><td align="left">3%</td></tr><tr><td align="left">Mepivacaine Hydrochloride</td><td align="left">20 mg</td><td align="left">30 mg</td></tr><tr><td align="left">Levonordefrin</td><td align="left">0.05 mg</td><td align="left">-</td></tr><tr><td align="left">Sodium Chloride</td><td align="left">4 mg</td><td align="left">6 mg</td></tr><tr><td align="left">Potassium metabisulfite</td><td align="left">1.2 mg</td><td align="left">-</td></tr><tr><td align="left">Edetate disodium</td><td align="left">0.25 mg</td><td align="left">-</td></tr><tr><td align="left">Sodium Hydroxide q.s. ad pH; Hydrochloric Acid</td><td align="left">0.5 mg</td><td align="left">-</td></tr><tr><td align="left">Water For Injection, qs. ad.</td><td align="left">1 mL</td><td align="left">1 mL</td></tr></tbody></table>

CLINICAL PHARMACOLOGY Polocaine ® stabilizes the neuronal membrane and prevents the initiation and transmission of nerve impulses, thereby effecting local anesthesia. Polocaine ® is rapidly metabolized, with only a small percentage of the anesthetic (5 to 10 percent) being excreted unchanged in the urine. Polocaine ® because of its amide structure, is not detoxified by the circulating plasma esterases. The liver is the principal site of metabolism, with over 50 percent of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of mepivacaine have been identified from adult humans: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2,' 6' - pipecoloxylidide). The onset of action is rapid (30 to 120 seconds in the upper jaw; 1 to 4 minutes in the lower jaw) and 3% (30 mg/mL) Polocaine ® DENTAL will ordinarily provide operating anesthesia of 20 minutes in the upper jaw and 40 minutes in the lower jaw . 2% (20 mg/mL) Polocaine ® DENTAL with Levonordefrin 1:20,000 provides anesthesia of longer duration for more prolonged procedures, 1 hour to 2.5 hours in the upper jaw and 2.5 hours to 5.5 hours in the lower jaw . Polocaine ® does not ordinarily produce irritation or tissue damage. Levonordefrin is a sympathomimetic amine used as a vasoconstrictor in local anesthetic solutions. It has pharmacologic activity similar to that of Epinephrine but it is more stable than Epinephrine. In equal concentrations, Levonordefrin is less potent than Epinephrine in raising blood pressure, and as a vasoconstrictor.

WARNINGS RESUSCITATIVE EQUIPMENT AND DRUGS SHOULD BE IMMEDIATELY AVAILABLE. (See ADVERSE REACTIONS ). Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics, even in the absence of a history of hypersensitivity. Fatalities may occur with use of local anesthetics in the head and neck region as the result of retrograde arterial flow to vital CNS areas even when maximum recommended doses are observed. The practitioner should be alert to early evidences of alteration in sensorium or vital signs. The solution which contains a vasoconstrictor (2% (20 mg/mL) Polocaine ® DENTAL with Levonordefrin 1:20,000) should be used with extreme caution for patients whose medical history and physical evaluation suggest the existence of hypertension, arteriosclerotic heart disease, cerebral vascular insufficiency, heart block, thyrotoxicosis and diabetes, etc. The solution which contains a vasoconstrictor (2% (20 mg/mL) Polocaine ® DENTAL with Levonordefrin 1:20,000) also contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. 3% (30 mg/mL) Polocaine ® DENTAL is SULFITE FREE. The American Heart Association has made the following recommendations regarding the use of local anesthetics with vasoconstrictors in patients with ischemic heart disease: "Vasoconstrictor agents should be used in local anesthesia solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection. The minimum possible amount of vasoconstrictor should be used." (Kaplan, EL, editor: Cardiovascular disease in dental practice, Dallas 1986, American Heart Association.) Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use; Polocaine ® , along with other local anesthetics, is capable of producing this condition. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by cyanosis of the skin, nail beds and lips, and/or abnormal coloration of the blood, fatigue and weakness. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Polocaine ® and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration.

quired to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Polocaine ® and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. If methemoglobinemia does not respond to administration of oxygen, a more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

PRECAUTIONS The safety and effectiveness of mepivacaine depend upon proper dosage, correct technique, adequate precautions, and readiness for emergencies. The lowest dose that results in effective anesthesia should be used to avoid high plasma levels and possible adverse effects. Injection of repeated doses of mepivacaine may cause significant increase in blood levels with each repeated dose due to slow accumulation of the drug or its metabolites, or due to slower metabolic degradation than normal. Tolerance varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their weight and physical status. Mepivacaine should be used with caution in patients with a history of severe disturbances of cardiac rhythm or heart block. INJECTIONS SHOULD ALWAYS BE MADE SLOWLY WITH ASPIRATION TO AVOID INTRAVASCULAR INJECTION AND THEREFORE SYSTEMIC REACTION TO BOTH LOCAL ANESTHETIC AND VASOCONSTRICTOR. If sedatives are employed to reduce patient apprehension, use reduced doses, since local anesthetic agents, like sedatives, are central nervous system depressants which in combination may have an additive effect. Young children should be given minimal doses of each agent. Changes in sensorium such as excitation, disorientation or drowsiness may be early indications of a high blood level of the drug and may occur following inadvertent intravascular administration or rapid absorption of mepivacaine. Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection. Information for Patients/Patient Counseling Information The patient should be cautioned against loss of sensation and possibility of biting trauma should the patient attempt to eat or chew gum prior to return of sensation. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue. Clinically Significant Drug Interactions The administration of local anesthetic solutions containing vasopressors, such as Levonordefrin, Epinephrine or Norepinephrine, to patients receiving tricyclic antidepressants or monoamine oxidase inhibitors may produce severe, prolonged 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 and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of Epinephrine. Solutions containing a vasoconstrictor should be used cautiously in the presence of diseases which may adversely affect the patient's cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics.

ing a vasoconstrictor should be used cautiously in the presence of diseases which may adversely affect the patient's cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: 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 acetaminophen, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient's prior experience with mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ). Patients allergic to methylparaben or para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as mepivacaine. Since mepivacaine is metabolized in the liver and excreted by the kidneys, it should be used cautiously in patients with liver and renal disease. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of mepivacaine HCl in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed. 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 this solution is administered to a nursing woman. Pediatric Use Great care must be exercised in adhering to safe concentrations and dosages for pedodontic administration (see DOSAGE AND ADMINISTRATION ).

<table width="90%"><caption>EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA:</caption><col width="25%" align="left" valign="top"/><col width="75%" align="left" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Class</th><th styleCode="Rrule">Examples</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nitrates/Nitrites</td><td styleCode="Rrule">nitric oxide, nitroglycerin, nitroprusside, nitrous oxide</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Local anesthetics</td><td styleCode="Rrule">articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Antineoplastic Agents</td><td styleCode="Rrule">cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Antibiotics</td><td styleCode="Rrule">dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Antimalarials</td><td styleCode="Rrule">chloroquine, primaquine</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anticonvulsants</td><td styleCode="Rrule">phenobarbital, phenytoin, sodium valproate</td></tr><tr><td styleCode="Lrule Rrule">Other drugs</td><td styleCode="Rrule">acetaminophen, metoclopramide, quinine, sulfasalazine</td></tr></tbody></table>

Clinically Significant Drug Interactions The administration of local anesthetic solutions containing vasopressors, such as Levonordefrin, Epinephrine or Norepinephrine, to patients receiving tricyclic antidepressants or monoamine oxidase inhibitors may produce severe, prolonged 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 and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of Epinephrine. Solutions containing a vasoconstrictor should be used cautiously in the presence of diseases which may adversely affect the patient's cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: 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 acetaminophen, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient's prior experience with mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ). Patients allergic to methylparaben or para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as mepivacaine. Since mepivacaine is metabolized in the liver and excreted by the kidneys, it should be used cautiously in patients with liver and renal disease.

Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed. 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 this solution is administered to a nursing woman. Pediatric Use Great care must be exercised in adhering to safe concentrations and dosages for pedodontic administration (see DOSAGE AND ADMINISTRATION ).

Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed.

ADVERSE REACTIONS Reactions to Polocaine ® are characteristic of those associated with other amide-type local anesthetics. Systemic adverse reactions involving the central nervous system and the cardiovascular system usually result from high plasma levels (which may be due to excessive dosage, rapid absorption, inadvertent intravascular injection, or slow metabolic degradation), injection technique, or volume of injection. A small number of reactions may result from hypersensitivity, idiosyncrasy or diminished tolerance to normal dosage on the part of the patient. Persistent paresthesias of the lips, tongue, and oral tissues have been reported with the use of mepivacaine, with slow, incomplete, or no recovery. These post-marketing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches. Reactions involving the central nervous system are characterized by excitation and/or depression. Nervousness, dizziness, blurred vision, or tremors may occur followed by drowsiness, convulsions, unconsciousness, and possible respiratory arrest. Since excitement may be transient or absent, the first manifestations may be drowsiness merging into unconsciousness and respiratory arrest. Cardiovascular reactions are depressant. They may be the result of direct drug effect or more commonly in dental practice, the result of vasovagal reaction, particularly if the patient is in the sitting position. Failure to recognize premonitory signs such as sweating, feeling of faintness, changes in pulse or sensorium may result in progressive cerebral hypoxia and seizure or serious cardiovascular catastrophe. Management consists of placing the patient in the recumbent position and administration of oxygen. Vasoactive drugs such as Ephedrine or Methoxamine may be administered intravenously. Allergic reactions are rare and may occur as a result of sensitivity to the local anesthetic and are characterized by cutaneous lesions of delayed onset or urticaria, edema and other manifestations of allergy. The detection of sensitivity by skin testing is of limited value. As with other local anesthetics, anaphylactoid reactions to mepivacaine have occurred rarely. The reaction may be abrupt and severe and is not usually dose related. Localized puffiness and swelling may occur.

OVERDOSAGE Treatment of a patient with toxic manifestations consists of assuring and maintaining a patent airway and supporting ventilation (respiration) as required. This usually will be sufficient in the management of most reactions. Should a convulsion persist despite ventilatory therapy, small increments of anticonvulsive agents may be given intravenously, such as benzodiazephine (e.g., diazepam) or ultrashort-acting barbiturates (e.g., thiopental or thiamylal) or short-acting barbiturates (e.g., pentobarbital or secobarbital). Cardiovascular depression may require circulatory assistance with intravenous fluids and/or vasopressor (e.g., Ephedrine) as dictated by the clinical situation. Allergic reactions should be managed by conventional means. Intravenous and subcutaneous LD50's in mice for mepivacaine hydrochloride 3% are 33 and 258 mg/kg, respectively. The acute IV and SC LD50's in mice for mepivacaine hydrochloride 2% with levonordefrin 1:20,000 are 30 and 184 mg/kg, respectively.

DOSAGE AND ADMINISTRATION As with all local anesthetics, the dose varies and depends upon the area to be anesthetized, the vascularity of the tissues, individual tolerance and the technique of anesthesia. The lowest dose needed to provide effective anesthesia should be administered. For specific techniques and procedures refer to standard dental manuals and textbooks. For infiltration and block injections in the upper or lower jaw, the average dose of 1 cartridge will usually suffice. Each cartridge contains 1.7 mL (34 mg of 2% or 51 mg of 3%). 5.3 cartridges (180 mg of the 2% solution or 270 mg of the 3% solution) are usually adequate to effect anesthesia of the entire oral cavity. Whenever a larger dose seems to be necessary for an extensive procedure, the maximum dose should be calculated according to the patient's weight. A dose of up to 3 mg per pound of body weight may be administered. At any single dental sitting the total dose for all injected sites should not exceed 400 mg in adults. The maximum pediatric dose should be carefully calculated . Maximum dose for pediatric population = Child's Weight (lbs.) × Maximum Recommended Dose for Adults (400 mg) 150 The following table, approximating these calculations, may also be used as a guide. This table is based upon a recommended maximum for larger pediatric population of 5.3 cartridges (the maximum recommended adult dose) during any single dental sitting, regardless of the pediatric patient's weight or (for 2% mepivacaine) calculated maximum amount of drug: Maximum Allowable Dosage Adapted from Malamed, Stanley F: Handbook of medical emergencies in the dental office, ed. 2, St. Louis, 1982. The C.V. Mosby Co. 3% Mepivacaine Plain 2% Mepivacaine 1:20,000 Levonordefrin 3 mg/lb (270 mg max.) 3 mg/lb (180 mg max.) Weight (lb.) mg Number of Cartridges mg Number of Cartridges 20 60 1.2 60 1.8 30 90 1.8 90 2.6 40 120 2.3 120 3.5 50 150 2.9 150 4.4 60 180 3.5 180 5.3 80 240 4.7 180 5.3 100 270 5.3 180 5.3 120 270 5.3 180 5.3 When using Polocaine ® for infiltration or regional block anesthesia, injection should always be made slowly and with frequent aspiration. Any unused portion of a cartridge should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED 3% (30 mg/mL) Polocaine ® DENTAL (Mepivacaine Hydrochloride Injection USP) (NDC 66312-441-16) is available in cardboard boxes containing 5 blisters of 10 × 1.7 mL single-dose dental cartridges, 50 per carton. 2% (20 mg/mL) Polocaine ® DENTAL with Levonordefrin 1:20,000 (Mepivacaine Hydrochloride and Levonordefrin Injection USP) (NDC 66312-461-16) is available in cardboard boxes containing 5 blisters of 10 × 1.7 mL single-dose dental cartridges, 50 per carton. Both solutions should be stored at controlled room temperature, below 25° C (77° F). Protect from light . Do not permit to freeze. BOXES For protection from light, retain in box until time of use. Once opened, the box should be reclosed by closing the top flap. The 2% (20 mg/mL) Polocaine ® DENTAL with Levonordefrin 1:20,000 solution should not be used if its color is pinkish or darker than slightly yellow or it contains a precipitate. Cartridge warmers should not be used with Polocaine ® products.

Both solutions should be stored at controlled room temperature, below 25° C (77° F). Protect from light . Do not permit to freeze. BOXES For protection from light, retain in box until time of use. Once opened, the box should be reclosed by closing the top flap. The 2% (20 mg/mL) Polocaine ® DENTAL with Levonordefrin 1:20,000 solution should not be used if its color is pinkish or darker than slightly yellow or it contains a precipitate. Cartridge warmers should not be used with Polocaine ® products.

Rx Only THIS SOLUTION IS INTENDED FOR DENTAL USE ONLY. COMPOSITION: CARTRIDGE Each mL contains: 3% Mepivacaine Hydrochloride 30 mg Sodium Chloride 6 mg Sodium Hydroxide or Hydrochloric Acid q.s. to adjust pH Water For Injection, qs. ad. 1 mL The pH of the 3% cartridge solution is adjusted between 4.5 and 6.8 with NaOH. DISINFECTION OF CARTRIDGES: As in the case of any cartridge, the diaphragm should be disinfected before needle puncture. The diaphragm should be thoroughly swabbed with either pure 91% isopropyl alcohol or 70% ethyl alcohol, USP, just prior to use. Many commercially available alcohol solutions contain ingredients which are injurious to container components, and therefore, should not be used. Cartridges should not be immersed in any solution. Manufactured for SEPTODONT, Inc., 205 Granite Run Dr., Suite 150, Lancaster, PA, USA 17601 by Novocol ® Pharmaceutical of Canada Inc., 25 Wolseley Court, Cambridge, Ontario, Canada N1R 6X3 Rev. 04/2025 (2558-10)

DESCRIPTION: Mepivacaine Hydrochloride, a tertiary amine used as a local anesthetic, is 1-methyl-2', 6' - pipecoloxylidide monohydrochloride with the following structural formula: C 15 H 22 N 2 O • HCI M.W. 282.81 It is a white, crystalline, odorless powder soluble in water, but very resistant to both acid and alkaline hydrolysis. DENTAL CARTRIDGES MAY NOT BE AUTOCLAVED. SCANDONEST ® 3% Plain (mepivacaine hydrochloride injection 3% (51 mg/1.7 mL) (30 mg/mL)) is a sterile solution for injection. Mepivacaine Hydrochloride

<table width="50%"><caption/><tbody><tr><td/><td align="center"><content styleCode="bold"> CARTRIDGE</content></td></tr><tr><td><content styleCode="bold"> Each mL contains:</content></td><td align="center"><content styleCode="bold"> 3%</content></td></tr><tr><td> Mepivacaine Hydrochloride</td><td align="center"> 30 mg</td></tr><tr><td> Sodium Chloride</td><td align="center"> 6 mg</td></tr><tr><td> Sodium Hydroxide or Hydrochloric Acid q.s. to adjust pH</td><td/></tr><tr><td> Water For Injection, qs. ad.</td><td align="center"> 1 mL</td></tr><tr><td> The pH of the 3% cartridge solution is adjusted between 4.5 and 6.8 with NaOH.</td><td/></tr></tbody></table>

CLINICAL PHARMACOLOGY: SCANDONEST ® stabilizes the neuronal membrane and prevents the initiation and transmission of nerve impulses, thereby effecting local anesthesia. SCANDONEST ® is rapidly metabolized, with only a small percentage of the anesthetic (5 to 10 percent) being excreted unchanged in the urine. SCANDONEST ® because of its amide structure, is not detoxified by the circulating plasma esterases. The liver is the principal site of metabolism, with over 50 percent of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of mepivacaine have been identified from adult humans: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2’, 6’- pipecoloxylidide). The onset of action is rapid (30 to 120 seconds in the upper jaw; 1 to 4 minutes in the lower jaw) and SCANDONEST ® 3% Plain will ordinarily provide operating anesthesia of 20 minutes in the upper jaw and 40 minutes in the lower jaw . SCANDONEST ® does not ordinarily produce irritation or tissue damage.

WARNINGS: RESUSCITATIVE EQUIPMENT AND DRUGS SHOULD BE IMMEDIATELY AVAILABLE. (See ADVERSE REACTIONS ). Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics, even in the absence of a history of hypersensitivity. Fatalities may occur with use of local anesthetics in the head and neck region as the result of retrograde arterial flow to vital CNS areas even when maximum recommended doses are observed. The practitioner should be alert to early evidences of alteration in sensorium or vital signs. SCANDONEST ® 3% Plain is SULFITE FREE. Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use; SCANDONEST ® , along with other local anesthetics, is capable of producing this condition. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by cyanosis of the skin, nail beds and lips, and/or abnormal coloration of the blood, fatigue and weakness. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue SCANDONEST ® and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. If methemoglobinemia does not respond to administration of oxygen, a more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

PRECAUTIONS: The safety and effectiveness of mepivacaine depend upon proper dosage, correct technique, adequate precautions, and readiness for emergencies. The lowest dose that results in effective anesthesia should be used to avoid high plasma levels and possible adverse effects. Injection of repeated doses of mepivacaine may cause significant increase in blood levels with each repeated dose due to slow accumulation of the drug or its metabolites, or due to slower metabolic degradation than normal. Tolerance varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their weight and physical status. Mepivacaine should be used with caution in patients with a history of severe disturbances of cardiac rhythm or heart block. INJECTIONS SHOULD ALWAYS BE MADE SLOWLY WITH ASPIRATION TO AVOID INTRAVASCULAR INJECTION AND THEREFORE SYSTEMIC REACTION. If sedatives are employed to reduce patient apprehension, use reduced doses, since local anesthetic agents, like sedatives, are central nervous system depressants which in combination may have an additive effect. Young children should be given minimal doses of each agent. Changes in sensorium such as excitation, disorientation or drowsiness may be early indications of a high blood level of the drug and may occur following inadvertent intravascular administration or rapid absorption of mepivacaine. Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection. Information for Patients/Patient Counseling Information: The patient should be cautioned against loss of sensation and possibility of biting trauma should the patient attempt to eat or chew gum prior to return of sensation. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue. Clinically Significant Drug Interactions: Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: 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 acetaminophen, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient’s prior experience with mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ).

en, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient’s prior experience with mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ). Patients allergic to methylparaben or para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as mepivacaine. Since mepivacaine is metabolized in the liver and excreted by the kidneys, it should be used cautiously in patients with liver and renal disease. Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies of mepivacaine HCl in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. Pregnancy: Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed. 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 this solution is administered to a nursing woman. Pediatric Use: Great care must be exercised in adhering to safe concentrations and dosages for pedodontic administration (see DOSAGE AND ADMINISTRATION ).

<table width="70%"><caption>EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA:</caption><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold"> Class</content></td><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold"> Examples</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Nitrates/Nitrites</td><td styleCode="Botrule Lrule Rrule Toprule"> nitric oxide, nitroglycerin, nitroprusside, nitrous oxide</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Local anesthetics</td><td styleCode="Botrule Lrule Rrule Toprule"> articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Antineoplastic Agents</td><td styleCode="Botrule Lrule Rrule Toprule"> cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Antibiotics</td><td styleCode="Botrule Lrule Rrule Toprule"> dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Antimalarials</td><td styleCode="Botrule Lrule Rrule Toprule"> chloroquine, primaquine</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Anticonvulsants</td><td styleCode="Botrule Lrule Rrule Toprule"> phenobarbital, phenytoin, sodium valproate</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Other drugs</td><td styleCode="Botrule Lrule Rrule Toprule"> acetaminophen, metoclopramide, quinine, sulfasalazine</td></tr></tbody></table>

Information for Patients/Patient Counseling Information: The patient should be cautioned against loss of sensation and possibility of biting trauma should the patient attempt to eat or chew gum prior to return of sensation. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

Clinically Significant Drug Interactions: Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: 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 acetaminophen, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient’s prior experience with mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ). Patients allergic to methylparaben or para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as mepivacaine. Since mepivacaine is metabolized in the liver and excreted by the kidneys, it should be used cautiously in patients with liver and renal disease.

Pregnancy: Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed.

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 this solution is administered to a nursing woman.

ADVERSE REACTIONS: Reactions to SCANDONEST ® are characteristic of those associated with other amide-type local anesthetics. Systemic adverse reactions involving the central nervous system and the cardiovascular system usually result from high plasma levels (which may be due to excessive dosage, rapid absorption, inadvertent intravascular injection, or slow metabolic degradation), injection technique, or volume of injection. A small number of reactions may result from hypersensitivity, idiosyncrasy or diminished tolerance to normal dosage on the part of the patient. Persistent paresthesias of the lips, tongue, and oral tissues have been reported with the use of mepivacaine, with slow, incomplete, or no recovery. These post-marketing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches. Reactions involving the central nervous system are characterized by excitation and/or depression. Nervousness, dizziness, blurred vision, or tremors may occur followed by drowsiness, convulsions, unconsciousness, and possible respiratory arrest. Since excitement may be transient or absent, the first manifestations may be drowsiness merging into unconsciousness and respiratory arrest. Cardiovascular reactions are depressant. They may be the result of direct drug effect or more commonly in dental practice, the result of vasovagal reaction, particularly if the patient is in the sitting position. Failure to recognize premonitory signs such as sweating, feeling of faintness, changes in pulse or sensorium may result in progressive cerebral hypoxia and seizure or serious cardiovascular catastrophe. Management consists of placing the patient in the recumbent position and administration of oxygen. Vasoactive drugs such as Ephedrine or Methoxamine may be administered intravenously. Allergic reactions are rare and may occur as a result of sensitivity to the local anesthetic and are characterized by cutaneous lesions of delayed onset or urticaria, edema and other manifestations of allergy. The detection of sensitivity by skin testing is of limited value. As with other local anesthetics, anaphylactoid reactions to mepivacaine have occurred rarely. The reaction may be abrupt and severe and is not usually dose related. Localized puffiness and swelling may occur0

OVERDOSAGE: Treatment of a patient with toxic manifestations consists of assuring and maintaining a patent airway and supporting ventilation (respiration) as required. This usually will be sufficient in the management of most reactions. Should a convulsion persist despite ventilatory therapy, small increments of anticonvulsive agents may be given intravenously, such as benzodiazepine (e.g., diazepam) or ultrashort-acting barbiturates (e.g., thiopental or thiamylal) or short-acting barbiturates (e.g., pentobarbital or secobarbital). Cardiovascular depression may require circulatory assistance with intravenous fluids and/or vasopressor (e.g., Ephedrine) as dictated by the clinical situation. Allergic reactions should be managed by conventional means. Intravenous and subcutaneous LD 50 ’s in mice for mepivacaine hydrochloride 3% are 33 and 258 mg/kg, respectively.

DOSAGE AND ADMINISTRATION: As with all local anesthetics, the dose varies and depends upon the area to be anesthetized, the vascularity of the tissues, individual tolerance and the technique of anesthesia. The lowest dose needed to provide effective anesthesia should be administered. For specific techniques and procedures refer to standard dental manuals and textbooks. For infiltration and block injections in the upper or lower jaw, the average dose of 1 cartridge will usually suffice. Each cartridge contains 1.7 mL (51 mg of mepivacaine). 270 mg of mepivacaine (5.3 cartridges of Scandonest 3%) is usually adequate to effect anesthesia of the entire oral cavity. Whenever a larger dose seems to be necessary for an extensive procedure, the maximum dose should be calculated according to the patient’s weight. A dose of up to 3 mg per pound of body weight may be administered. At any single dental sitting the total dose for all injected sites should not exceed 400 mg in adults. The maximum pediatric dose should be carefully calculated . Maximum dose for pediatric population = Child’s Weight (lbs.) X Maximum Recommended Dose 150 for Adults (400 mg) The following table, approximating these calculations, may also be used as a guide. This table is based upon a recommended maximum for larger pediatric population of 5.3 cartridges (the maximum recommended adult dose) during any single dental sitting, regardless of the pediatric patient’s weight or calculated maximum amount of drug: Maximum Allowable Dosage* 3% Mepivacaine Plain 3 mg/lb (270 mg max.) Weight (lb) mg Number of Cartridges 20 60 1.2 30 90 1.8 40 120 2.3 50 150 2.9 60 180 3.5 80 240 4.7 100 270 5.3 120 270 5.3 *Adapted from Malamed, Stanley F: Handbook of medical emergencies in the dental office, ed. 2, St. Louis, 1982. The C.V. Mosby Co. When using SCANDONEST ® for infiltration or regional block anesthesia, injection should always be made slowly and with frequent aspiration. Any unused portion of a cartridge should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED: SCANDONEST ® 3% Plain; (Mepivacaine Hydrocholoride Injection USP) (NDC 0362-1098-90) is available in cardboard boxes containing 5 blisters of 10 x 1.7 mL single-dose dental cartridges, 50 per carton. Solution should be stored at controlled room temperature, below 25°C (77°F). Protect from light. Do not permit to freeze. BOXES: For protection from light, retain in box until time of use. Once opened, the box should be reclosed by closing the top flap. Cartridge warmers should not be used with SCANDONEST ® product.

Solution should be stored at controlled room temperature, below 25°C (77°F). Protect from light. Do not permit to freeze. BOXES: For protection from light, retain in box until time of use. Once opened, the box should be reclosed by closing the top flap. Cartridge warmers should not be used with SCANDONEST ® product.

Rx Only THESE SOLUTIONS ARE INTENDED FOR DENTAL USE ONLY. COMPOSITION CARTRIDGE Each mL contains: 2% 3% Mepivacaine Hydrochloride 20 mg 30 mg Levonordefrin 0.05 mg - Sodium Chloride 4 mg 6 mg Potassium metabisulfite 1.2 mg - Edetate disodium 0.25 mg - Sodium Hydroxide q.s. ad pH; Hydrochloric Acid 0.5 mg - Water For Injection, qs. ad. 1 mL 1 mL The pH of the 2% cartridge solution is adjusted between 3.3 and 5.5 with NaOH. The pH of the 3% cartridge solution is adjusted between 4.5 and 6.8 with NaOH. DISINFECTION OF CARTRIDGES As in the case of any cartridge, the diaphragm should be disinfected before needle puncture. The diaphragm should be thoroughly swabbed with either pure 91% isopropyl alcohol or 70% ethyl alcohol, USP, just prior to use. Many commercially available alcohol solutions contain ingredients which are injurious to container components, and therefore, should not be used. Cartridges should not be immersed in any solution. Manufactured and Distributed by Novocol Pharmaceutical of Canada, Inc. Cambridge, Ontario, N1R 6X3, Canada Rev. 03/2020 (2780-3)

DESCRIPTION Mepivacaine Hydrochloride, a tertiary amine used as a local anesthetic, is 1-methyl-2', 6' - pipecoloxylidide monohydrochloride with the following structural formula: It is a white, crystalline, odorless powder soluble in water, but very resistant to both acid and alkaline hydrolysis. Levonordefrin, a sympathomimetic amine used as a vasoconstrictor in local anesthetic solution, is (-)- -(1-Aminoethyl)-3, 4-dihydroxybenzyl alcohol with the following structural formula: It is a white or buff-colored crystalline solid, freely soluble in aqueous solutions of mineral acids, but practically insoluble in water; DENTAL CARTRIDGES MAY NOT BE AUTOCLAVED. Mepivacaine hydrochloride injection 3% (30 mg/mL) and Mepivacaine hydrochloride 2% (20 mg/mL) with levonordefrin 1:20,000 injection are sterile solutions for injection. Chemical Structure Chemical Structure Chemical Structure

<table width="100%"><colgroup><col width="75%" align="left" valign="top"/><col width="12%" align="center" valign="top"/><col width="13%" align="center" valign="top"/></colgroup><thead><tr><th align="left"/><th align="center">CARTRIDGE</th></tr><tr><th align="left">Each mL contains:</th><th align="center">2%</th><th align="center">3%</th></tr></thead><tbody><tr><td align="left"> Mepivacaine Hydrochloride</td><td align="center">20 mg</td><td align="center">30 mg</td></tr><tr><td align="left"> Levonordefrin</td><td align="center">0.05 mg</td><td align="center">-</td></tr><tr><td align="left"> Sodium Chloride</td><td align="center">4 mg</td><td align="center">6 mg</td></tr><tr><td align="left"> Potassium metabisulfite</td><td align="center">1.2 mg</td><td align="center">-</td></tr><tr><td align="left"> Edetate disodium</td><td align="center">0.25 mg</td><td align="center">-</td></tr><tr><td align="left"> Sodium Hydroxide q.s. ad pH; Hydrochloric Acid</td><td align="center">0.5 mg</td><td align="center">-</td></tr><tr><td align="left"> Water For Injection, qs. ad.</td><td align="center">1 mL</td><td align="center">1 mL</td></tr><tr><td align="left"> The pH of the 2% cartridge solution is adjusted between 3.3 and 5.5 with NaOH.</td><td align="center"/><td align="center"/></tr><tr><td align="left"> The pH of the 3% cartridge solution is adjusted between 4.5 and 6.8 with NaOH.</td><td align="center"/><td align="center"/></tr></tbody></table>

CLINICAL PHARMACOLOGY Mepivacaine stabilizes the neuronal membrane and prevents the initiation and transmission of nerve impulses, thereby effecting local anesthesia. Mepivacaine is rapidly metabolized, with only a small percentage of the anesthetic (5 to 10 percent) being excreted unchanged in the urine. Mepivacaine because of its amide structure, is not detoxified by the circulating plasma esterases. The liver is the principal site of metabolism, with over 50 percent of the administered dose being excreted into the bile as metabolites. Most of the metabolized Mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of Mepivacaine have been identified from adult humans: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2’, 6’ - pipecoloxylidide). The onset of action is rapid (30 to 120 seconds in the upper jaw; 1 to 4 minutes in the lower jaw) and Mepivacaine HCl 3% (30 mg/mL) will ordinarily provide operating anesthesia of 20 minutes in the upper jaw and 40 minutes in the lower jaw. Mepivacaine HCl 2% (20 mg/mL) with Levonordefrin 1:20,000 provides anesthesia of longer duration for more prolonged procedures, 1 hour to 2.5 hours in the upper jaw and 2.5 hours to 5.5 hours in the lower jaw. Mepivacaine does not ordinarily produce irritation or tissue damage. Levonordefrin is a sympathomimetic amine used as a vasoconstrictor in local anesthetic solutions. It has pharmacologic activity similar to that of Epinephrine but it is more stable than Epinephrine. In equal concentrations, Levonordefrin is less potent than Epinephrine in raising blood pressure, and as a vasoconstrictor.

WARNINGS RESUSCITATIVE EQUIPMENT AND DRUGS SHOULD BE IMMEDIATELY AVAILABLE. (See ADVERSE REACTIONS). Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics, even in the absence of a history of hypersensitivity. Fatalities may occur with use of local anesthetics in the head and neck region as the result of retrograde arterial flow to vital CNS areas even when maximum recommended doses are observed. The practitioner should be alert to early evidence of alteration in sensorium or vital signs. The solution which contains a vasoconstrictor (Mepivacaine HCl 2% (20 mg/mL)) should be used with extreme caution for patients whose medical history and physical evaluation suggest the existence of hypertension, arteriosclerotic heart disease, cerebral vascular insufficiency, heart block, thyrotoxicosis and diabetes, etc. The solution which contains a vasoconstrictor (Mepivacaine HCl 2% (20 mg/mL)) also contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and lifethreatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. Mepivacaine HCl 3% (30 mg/mL) is SULFITE FREE. Mepivacaine, along with other local anesthetics, is capable of producing methemoglobinemia. The clinical signs of methemoglobinemia are cyanosis of the nail beds and lips, fatigue and weakness. If methemoglobinemia does not respond to administration of oxygen, administration of methylene blue intravenously 1-2 mg/kg body weight over a 5 minute period is recommended. The American Heart Association has made the following recommendations regarding the use of local anesthetics with vasoconstrictors in patients with ischemic heart disease: “Vasoconstrictor agents should be used in local anesthesia solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection. The minimum possible amount of vasoconstrictor should be used.” (Kaplan, EL, editor: Cardiovascular disease in dental practice, Dallas 1986, American Heart Association.) Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use; MEPIVACAINE, along with other local anesthetics, is capable of producing this condition. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by cyanosis of the skin, nail beds and lips, and/or abnormal coloration of the blood, fatigue and weakness.

in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by cyanosis of the skin, nail beds and lips, and/or abnormal coloration of the blood, fatigue and weakness. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue MEPIVACAINE and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. If methemoglobinemia does not respond to administration of oxygen, a more severe clinical presentation may require treatment with methylene blue exchange transfusion, or hyperbaric oxygen.

PRECAUTIONS The safety and effectiveness of Mepivacaine depend upon proper dosage, correct technique, adequate precautions, and readiness for emergencies. The lowest dose that results in effective anesthesia should be used to avoid high plasma levels and possible adverse effects. Injection of repeated doses of Mepivacaine may cause significant increases in blood levels with each repeated dose due to slow accumulation of the drug or its metabolites, or due to slower metabolic degradation than normal. Tolerance varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their weight and physical status. Mepivacaine should be used with caution in patients with a history of severe disturbances of cardiac rhythm or heart block. INJECTIONS SHOULD ALWAYS BE MADE SLOWLY WITH ASPIRATION TO AVOID INTRAVASCULAR INJECTION AND THEREFORE SYSTEMIC REACTION TO BOTH LOCAL ANESTHETIC AND VASOCONSTRICTOR. If sedatives are employed to reduce patient apprehension, use reduced doses, since local anesthetic agents, like sedatives, are central nervous system depressants which in combination may have an additive effect. Young children should be given minimal doses of each agent. Changes in sensorium such as excitation, disorientation or drowsiness may be early indications of a high blood level of the drug and may occur following inadvertent intravascular administration or rapid absorption of Mepivacaine. Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection. Information for Patients/Patient Counseling Information: The patient should be cautioned against loss of sensation and possibility of biting trauma should the patient attempt to eat or chew gum prior to return of sensation. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue. Clinically Significant Drug Interactions The administration of local anesthetic solutions containing vasopressors, such as Levonordefrin, Epinephrine or Norepinephrine, to patients receiving tricyclic antidepressants or monoamine oxidase inhibitors may produce severe, prolonged 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 and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of Epinephrine. Solutions containing a vasoconstrictor should be used cautiously in the presence of disease which may adversely affect the patient's cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics.

ning a vasoconstrictor should be used cautiously in the presence of disease which may adversely affect the patient's cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprus-side, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hy-droxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient's prior experience with Mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ). Patients allergic to methylparaben or para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as Mepivacaine. Since Mepivacaine is metabolized in the liver and excreted by the kidneys, it should be used cautiously in patients with liver and renal disease. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of Mepivacaine HCl in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. Pregnancy Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can effect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed. 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 this solution is administered to a nursing woman. Pediatric Use Great care must be exercised in adhering to safe concentrations and dosages for pedodontic administration (see DOSAGE AND ADMINISTRATION ).

<table width="100%"><caption>EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: </caption><tbody><tr><td styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold"> Class</content></td><td styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">Examples</content></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Nitrates/Nitrites</td><td styleCode="Lrule Rrule Toprule Botrule"> nitric oxide, nitroglycerin, nitroprus-side, nitrous oxide</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Local anesthetics</td><td styleCode="Lrule Rrule Toprule Botrule"> articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Antineoplastic Agents</td><td styleCode="Lrule Rrule Toprule Botrule"> cyclophosphamide, flutamide, hy-droxyurea, ifosfamide, rasburicase</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Antibiotics</td><td styleCode="Lrule Rrule Toprule Botrule"> dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Antimalarials</td><td styleCode="Lrule Rrule Toprule Botrule"> chloroquine, primaquine</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Anticonvulsants</td><td styleCode="Lrule Rrule Toprule Botrule"> Phenobarbital, phenytoin, sodium valproate</td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule"> Other drugs</td><td styleCode="Lrule Rrule Toprule Botrule"> acetaminophen, metoclopramide, quinine, sulfasalazine</td></tr></tbody></table>

Clinically Significant Drug Interactions The administration of local anesthetic solutions containing vasopressors, such as Levonordefrin, Epinephrine or Norepinephrine, to patients receiving tricyclic antidepressants or monoamine oxidase inhibitors may produce severe, prolonged 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 and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of Epinephrine. Solutions containing a vasoconstrictor should be used cautiously in the presence of disease which may adversely affect the patient's cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprus-side, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hy-droxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient's prior experience with Mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ). Patients allergic to methylparaben or para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as Mepivacaine. Since Mepivacaine is metabolized in the liver and excreted by the kidneys, it should be used cautiously in patients with liver and renal disease.

Pregnancy Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can effect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed.

ADVERSE REACTIONS Reactions to Mepivacaine are characteristic of those associated with other amide-type local anesthetics. Systemic adverse reactions involving the central nervous system and the cardiovascular system usually result from high plasma levels (which may be due to excessive dosage, rapid absorption, inadvertent intravascular injection, or slow metabolic degradation), injection technique, or volume of injection. A small number of reactions may result from hypersensitivity, idiosyncrasy or diminished tolerance to normal dosage on the part of the patient. Persistent paresthesias of the lips, tongue, and oral tissues have been reported with the use of mepivacaine, with slow, incomplete, or no recovery. These post-marketing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches. Reactions involving the central nervous system are characterized by excitation and/or depression. Nervousness, dizziness, blurred vision, or tremors may occur followed by drowsiness, convulsions, unconsciousness, and possible respiratory arrest. Since excitement may be transient or absent, the first manifestations may be drowsiness merging into unconsciousness and respiratory arrest. Cardiovascular reactions are depressant. They may be the result of direct drug effect or more commonly in dental practice, the result of vasovagal reaction, particularly if the patient is in the sitting position. Failure to recognize premonitory signs such as sweating, feeling of faintness, changes in pulse or sensorium may result in progressive cerebral hypoxia and seizure or serious cardiovascular catastrophe. Management consists of placing the patient in the recumbent position and administration of oxygen. Vasoactive drugs such as Ephedrine or Methoxamine may be administered intravenously. Allergic reactions are rare and may occur as a result of sensitivity to the local anesthetic and are characterized by cutaneous lesions of delayed onset or urticaria, edema and other manifestations of allergy. The detection of sensitivity by skin testing is of limited value. As with other local anesthetics, anaphylactoid reactions to Mepivacaine have occurred rarely. The reaction may be abrupt and severe and is not usually dose related. Localized puffiness and swelling may occur.

DOSAGE AND ADMINISTRATION As with all local anesthetics, the dose varies and depends upon the area to be anesthetized, the vascularity of the tissues, individual tolerance and the technique of anesthesia. The lowest dose needed to provide effective anesthesia should be administered. For specific techniques and procedures refer to standard dental manuals and textbooks. For infiltration and block injections in the upper or lower jaw, the average dose of 1 cartridge will usually suffice. Each cartridge contains 1.7 mL (34 mg of 2% or 51 mg of 3%). 5.3 cartridges (180 mg of the 2% solution or 270 mg of the 3% solution) are usually adequate to effect anesthesia of the entire oral cavity. Whenever a larger dose seems to be necessary for an extensive procedure, the maximum dose should be calculated according to the patient's weight. A dose of up to 3 mg per pound of body weight may be administered. At any single dental sitting the total dose for all injected sites should not exceed 400 mg in adults. The maximum pediatric dose should be carefully calculated. Maximum dose for pediatric population = Child's Weight (lbs.) 150 × Maximum Recommended Dose for Adults (400 mg) The following table, approximating these calculations, may also be used as a guide. This table is based upon a recommended maximum for larger pediatric population of 5.3 cartridges (the maximum recommended adult dose) during any single dental sitting, regardless of the pediatric patient's weight or (for 2% mepivacaine) calulated maximum amount of drug: Maximum Allowable Dosage* 3% Mepivacaine 2% Mepivacaine 1:20,000 Levonordefrin 3 mg/lb 3mg/lb (270 mg max.) (180 mg max.) Weight (lb.) mg Number of Cartridges mg Number of Cartridges 20 60 1.2 60 1.8 30 90 1.8 90 2.6 40 120 2.3 120 3.5 50 150 2.9 150 4.4 60 180 3.5 180 5.3 80 240 4.7 180 5.3 100 270 5.3 180 5.3 120 270 5.3 180 5.3 *Adapted from Malamed, Stanley F. Handbook of medical emergencies in the dental office, ed. 2, St. Louis, 1982. The C.V. Mosby Co. When using Mepivacine HCl Injection USP for infiltration or regional block anesthesia, injection should always be made slowly and with frequent aspiration. Any unused portion of a cartridge should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED Mepivacaine HCl 3% (30 mg/mL); (Mepivacaine Hydrocholoride Injection USP) is available in cardboard boxes containing 5 blisters of 10 x 1.7 mL single-dose dental cartridges, 50 per carton. Mepivacaine HCl 2% (20 mg/mL) (Mepivacaine Hydrochloride and Levonordefrin Injection; USP) is available in cardboard boxes containing 5 blisters of 10 x 1.7 mL single-dose dental cartridges, 50 per carton. Both solutions should be stored at controlled room temperature, below 25° C (77° F). Protect from light. Do not permit to freeze. BOXES: For protection from light, retain in box until time of use. Once opened, the box should be reclosed by closing the top flap. The Mepivacaine 2% (20 mg/mL) solution should not be used if its color is pinkish or darker than slightly yellow or it contains a precipitate. Cartridge warmers should not be used with Mepivacaine HCl Injection USP products.

Both solutions should be stored at controlled room temperature, below 25° C (77° F). Protect from light. Do not permit to freeze. BOXES: For protection from light, retain in box until time of use. Once opened, the box should be reclosed by closing the top flap. The Mepivacaine 2% (20 mg/mL) solution should not be used if its color is pinkish or darker than slightly yellow or it contains a precipitate. Cartridge warmers should not be used with Mepivacaine HCl Injection USP products.