Mepivacaine

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.

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 . 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.

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. 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.

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.

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.

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. 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.

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. 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).