member of the amino amide class of local anesthetics) was inadvertently rapidly injected intravenously. prior to receiving major blocks the general condition of the patient should be optimized and the patient should have an iv line inserted. all necessary precautions should be taken to avoid intravascular injection. local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate (without delay) 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 , precautions and management of local anesthetic emergencies ). 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. solutions of naropin should not be used for the production of obstetrical paracervical block anesthesia, retrobulbar block, or spinal anesthesia (subarachnoid block) due to insufficient data to support such use. intravenous regional anesthesia (bier block) should not be performed due to a lack of clinical experience and the risk of attaining toxic blood levels of ropivacaine. 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 2 nd 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. a well-known risk of epidural anesthesia may be an unintentional subarachnoid injection of local anesthetic. two clinical studies have been performed to verify the safety of naropin at a volume of 3 ml injected into the subarachnoid space since this dose represents an incremental epidural volume that could be unintentionally injected. the 15 and 22.5 mg doses injected resulted in sensory levels as high as t5 and t4, respectively. anesthesia to pinprick started in the sacral dermatomes in 2 to 3 minutes, extended to the t10 level in 10 to 13 minutes and lasted for approximately 2 hours. the results of these two clinical studies showed that a 3 ml dose did not produce any serious adverse events when spinal anesthesia blockade was achieved. naropin should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. patients treated with class iii antiarrhythmic drugs (e.g., amiodarone) should be under close surveillance and ecg monitoring considered, since cardiac effects may be additive. 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 central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. discontinue naropin 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.

on before proceeding. when clinical conditions permit, consideration should be given to employing local anesthetic solutions, which contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. an intravascular injection is still possible even if aspirations for blood are negative. administration of higher than recommended doses of naropin to achieve greater motor blockade or increased duration of sensory blockade may result in cardiovascular depression, particularly in the event of inadvertent intravascular injection. tolerance to elevated blood levels varies with the physical condition of the patient. debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical condition. local anesthetics should also be used with caution in patients with hypotension, hypovolemia or heart block. careful and constant monitoring of cardiovascular and respiratory vital signs (adequacy of ventilation) 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, light-headedness, 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. because amide-type local anesthetics such as ropivacaine are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a 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 a-v conduction produced by these drugs. many drugs used during the conduct of anesthesia are considered potential triggering agents for malignant hyperthermia (mh). amide-type local anesthetics are not known to trigger this reaction. however, since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for mh management should be available.

conduction block, advanced liver disease or severe renal dysfunction require special attention although regional anesthesia is frequently indicated in these patients. to reduce the risk of potentially serious adverse reactions, attempts should be made to optimize the patient's condition before major blocks are performed, and the dosage should be adjusted accordingly. use an adequate test dose (3 to 5 ml of a short acting local anesthetic solution containing epinephrine) prior to induction of complete block. this test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter. allow adequate time for onset of anesthesia following administration of each test dose. parenteral drug products 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. table 7 dosage recommendations conc. volume dose onset duration mg/ml (%) ml mg min hours surgical anesthesia lumbar epidural 5 (0.5%) 15 to 30 75 to 150 15 to 30 2 to 4 administration 7.5 (0.75%) 15 to 25 113 to 188 10 to 20 3 to 5 surgery 10 (1%) 15 to 20 150 to 200 10 to 20 4 to 6 lumbar epidural 5 (0.5%) 20 to 30 100 to 150 15 to 25 2 to 4 administration 7.5 (0.75%) 15 to 20 113 to 150 10 to 20 3 to 5 cesarean section thoracic epidural 5 (0.5%) 5 to 15 25 to 75 10 to 20 n/a* administration 7.5 (0.75%) 5 to 15 38 to 113 10 to 20 n/a* surgery major nerve block † 5 (0.5%) 35 to 50 175 to 250 15 to 30 5 to 8 (e.g., brachial plexus block) 7.5 (0.75%) 10 to 40 75 to 300 10 to 25 6 to 10 field block 5 (0.5%) 1 to 40 5 to 200 1 to 15 2 to 6 (e.g., minor nerve blocks and infiltration) labor pain management lumbar epidural administration initial dose 2 (0.2%) 10 to 20 20 to 40 10 to 15 0.5 to 1.5 continuous infusion ‡ 2 (0.2%) 6 to 14 ml/h 12 to 28 mg/h n/a* n/a* incremental injections (top-up) ‡ 2 (0.2%) 10 to 15 ml/h 20 to 30 mg/h n/a* n/a* postoperative pain management lumbar epidural administration continuous infusion § 2 (0.2%) 6 to 14 ml/h 12 to 28 mg/h n/a* n/a* thoracic epidural administration 2 (0.2%) 6 to 14 ml/h 12 to 28 mg/h n/a* n/a* continuous infusion § infiltration 2 (0.2%) 1 to 100 2 to 200 1 to 5 2 to 6 (e.g., minor nerve block) 5 (0.5%) 1 to 40 5 to 200 1 to 5 2 to 6 * = not applicable † = the dose for a major nerve block must be adjusted according to site of administration and patient status. supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used (see precautions ). ‡ = median dose of 21 mg per hour was administered by continuous infusion or by incremental injections (top-ups) over a median delivery time of 5.5 hours. § = cumulative doses up to 770 mg of naropin over 24 hours (intraoperative block plus postoperative infusion); continuous epidural infusion at rates up to 28 mg per hour for 72 hours have been well tolerated in adults, i.e., 2016 mg plus surgical dose of approximately 100 to 150 mg as top-up. the doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. individual variations in onset and duration occur. the figures reflect the expected average dose range needed. for other local anesthetic techniques standard current textbooks should be consulted. when prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. experience to date indicates that a cumulative dose of up to 770 mg naropin administered over 24 hours is well tolerated in adults when used for postoperative pain management: i.e., 2016 mg. caution should be exercised when administering naropin for prolonged periods of time, e.g., > 70 hours in debilitated patients. for treatment of postoperative pain, the following technique can be recommended: if regional anesthesia was not used intraoperatively, then an initial epidural block with 5 to 7 ml naropin is induced via an epidural catheter. analgesia is maintained with an infusion of naropin, 2 mg/ml (0.2%). clinical studies have demonstrated that infusion rates of 6 to 14 ml (12 to 28 mg) per hour provide adequate analgesia with nonprogressive motor block. with this technique a significant reduction in the need for opioids was demonstrated. clinical experience supports the use of naropin epidural infusions for up to 72 hours.

anagement, peripheral nerve block, and local infiltration, the following treatment-emergent adverse events were reported with an incidence of ≥5% in all clinical studies (n=3988): hypotension (37%), nausea (24.8%), vomiting (11.6%), bradycardia (9.3%), fever (9.2%), pain (8%), postoperative complications (7.1%), anemia (6.1%), paresthesia (5.6%), headache (5.1%), pruritus (5.1%), and back pain (5%). incidence 1 to 5% urinary retention, dizziness, rigors, hypertension, tachycardia, anxiety, oliguria, hypoesthesia, chest pain, hypokalemia, dyspnea, cramps, and urinary tract infection. incidence in controlled clinical trials the reported adverse events are derived from controlled clinical studies with naropin (concentrations ranged from 0.125% to 1% for naropin and 0.25% to 0.75% for bupivacaine) in the u.s. and other countries involving 3,094 patients. table 3a and 3b list adverse events (number and percentage) that occurred in at least 1% of naropin-treated patients in these studies. the majority of patients receiving concentrations higher than 5 mg/ml (0.5%) were treated with naropin. table 3a adverse events reported in ≥1% of adult patients receiving regional or local anesthesia (surgery, labor, cesarean section, postoperative pain management, peripheral nerve block and local infiltration) adverse reaction naropin total n=1661 bupivacaine total n=1433 n (%) n (%) hypotension 536 (32.3) 408 (28.5) nausea 283 (17) 207 (14.4) vomiting 117 (7) 88 (6.1) bradycardia 96 (5.8) 73 (5.1) headache 84 (5.1) 68 (4.7) paresthesia 82 (4.9) 57 (4) back pain 73 (4.4) 75 (5.2) pain 71 (4.3) 71 (5) pruritus 63 (3.8) 40 (2.8) fever 61 (3.7) 37 (2.6) dizziness 42 (2.5) 23 (1.6) rigors (chills) 42 (2.5) 24 (1.7) postoperative complications 41 (2.5) 44 (3.1) hypoesthesia 27 (1.6) 24 (1.7) urinary retention 23 (1.4) 20 (1.4) progression of labor poor/failed 23 (1.4) 22 (1.5) anxiety 21 (1.3) 11 (0.8) breast disorder, breast-feeding 21 (1.3) 12 (0.8) rhinitis 18 (1.1) 13 (0.9) table 3b adverse events reported in ≥ 1% of fetuses or neonates of mothers who received regional anesthesia (cesarean section and labor studies) adverse reaction naropin total n=639 bupivacaine total n=573 n (%) n (%) fetal bradycardia 77 (12.1) 68 (11.9) neonatal jaundice 49 (7.7) 47 (8.2) neonatal complication-nos 42 (6.6) 38 (6.6) apgar score low 18 (2.8) 14 (2.4) neonatal respiratory disorder 17 (2.7) 18 (3.1) neonatal tachypnea 14 (2.2) 15 (2.6) neonatal fever 13 (2) 14 (2.4) fetal tachycardia 13 (2) 12 (2.1) fetal distress 11 (1.7) 10 (1.7) neonatal infection 10 (1.6) 8 (1.4) neonatal hypoglycemia 8 (1.3) 16 (2.8) incidence <1% the following adverse events were reported during the naropin clinical program in more than one patient (n=3988), occurred at an overall incidence of <1%, and were considered relevant: application site reactions - injection site pain cardiovascular system - vasovagal reaction, syncope, postural hypotension, non-specific ecg abnormalities female reproductive - poor progression of labor, uterine atony gastrointestinal system - fecal incontinence, tenesmus, neonatal vomiting general and other disorders - hypothermia, malaise, asthenia, accident and/or injury hearing and vestibular - tinnitus, hearing abnormalities heart rate and rhythm - extrasystoles, non-specific arrhythmias, atrial fibrillation liver and biliary system - jaundice metabolic disorders - hypomagnesemia musculoskeletal system - myalgia myo/endo/pericardium - st segment changes, myocardial infarction nervous system - tremor, horner’s syndrome, paresis, dyskinesia, neuropathy, vertigo, coma, convulsion, hypokinesia, hypotonia, ptosis, stupor psychiatric disorders - agitation, confusion, somnolence, nervousness, amnesia, hallucination, emotional lability, insomnia, nightmares respiratory system - bronchospasm, coughing skin disorders - rash, urticaria urinary system disorders - urinary incontinence, micturition disorder vascular - deep vein thrombosis, phlebitis, pulmonary embolism vision - vision abnormalities for the indication epidural anesthesia for surgery, the 15 most common adverse events were compared between different concentrations of naropin and bupivacaine. table 4 is based on data from trials in the u.s. and other countries where naropin was administered as an epidural anesthetic for surgery. table 4 common events (epidural administration) adverse reaction naropin bupivacaine 5 mg/ml total n=256 7.5 mg/ml total n=297 10 mg/ml total n=207 5 mg/ml total n=236 7.5 mg/ml total n=174 n (%) n (%) n (%) n (%) n (%) hypotension 99 (38.7) 146 (49.2) 113 (54.6) 91 (38.6) 89 (51.1) nausea 34 (13.3) 68 (22.9) 41 (17.4) 36 (20.7) bradycardia 29 (11.3) 58 (19.5) 40 (19.3) 32 (13.6) 25 (14.4) back pain 18 (7) 23 (7.7) 34 (16.4) 21 (8.9) 23 (13.2) vomiting 18 (7) 33 (11.1) 23 (11.1) 19 (8.1) 14 (8) headache 12 (4.7) 20 (6.7) 16 (7.7) 13 (5.5) 9 (5.2) fever 8 (3.1) 5 (1.7) 18 (8.7) 11 (4.7) chills 6 (2.3) 7 (2.4) 6 (2.9) 4 (1.7) 3 (1.7) urinary retention 5 (2) 8 (2.7) 10 (4.8) 10 (4.2) paresthesia 5 (2) 10 (3.4) 5 (2.4) 7 (3) pruritus 14 (4.7) 3 (1.4) 7 (4) using data from the same studies, the number (%) of patients experiencing hypotension is displayed by patient age, drug and concentration in table 5. in table 6, the adverse events for naropin are broken down by gender. table 5 effects of age on hypotension (epidural administration) total n: naropin = 760, bupivacaine = 410 age naropin bupivacaine 5 mg/ml 7.5 mg/ml 10 mg/ml 5 mg/ml 7.5 mg/ml n (%) n (%) n (%) n (%) n (%) <65 68 (32.2) 99 (43.2) 87 (51.5) 64 (33.5) 73 (48.3) ≥65 31 (68.9) 47 (69.1) 26 (68.4) 27 (60) 16 (69.6) table 6 most common adverse events by gender (epidural administration) total n: females = 405, males = 355 adverse reaction female male n (%) n (%) hypotension 220 (54.3) 138 (38.9) nausea 119 (29.4) 23 (6.5) bradycardia 65 (16) 56 (15.8) vomiting 59 (14.6) 8 (2.3) back pain 41 (10.1) 23 (6.5) headache 33 (8.1) 17 (4.8) chills 18 (4.4) 5 (1.4) fever 16 (4) 3 (0.8) pruritus 16 (4) 1 (0.3) pain 12 (3) 4 (1.1) urinary retention 11 (2.7) 7 (2) dizziness 9 (2.2) 4 (1.1) hypoesthesia 8 (2) 2 (0.6) paresthesia 8 (2) 10 (2.8) systemic reactions the most commonly encountered acute adverse experiences that 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 that 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 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 that alter protein production or competition with other drugs for protein binding sites, may diminish individual tolerance. epidural administration of naropin has, in some cases, as with other local anesthetics, been associated with transient increases in temperature to >38.5°c. this occurred more frequently at doses of naropin >16 mg/h. neurologic 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 route of administration 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. the incidence of adverse neurological reactions associated with the use of local anesthetics may be related to the total dose and concentration 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 observations may be related to local anesthetic techniques, with or without a contribution from the drug. during 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 as well as the physiological and physical effects of a dural puncture. these observations may include spinal block of varying magnitude (including high or total spinal block), hypotension secondary to spinal block, urinary retention, loss of bladder and bowel control (fecal and urinary incontinence), and loss of perineal sensation and sexual function. signs and symptoms of subarachnoid block typically start within 2 to 3 minutes of injection. doses of 15 and 22.5 mg of naropin resulted in sensory levels as high as t5 and t4, respectively. analgesia started in the sacral dermatomes in 2 to 3 minutes and extended to the t10 level in 10 to 13 minutes and lasted for approximately 2 hours. other neurological effects following unintentional subarachnoid administration during epidural anesthesia may include 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, septic meningitis, meningismus, slowing of labor, increased incidence of forceps delivery, or cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid have been reported (see dosage and administration discussion of lumbar epidural block). a high spinal is characterized by paralysis of the arms, loss of consciousness, respiratory paralysis and bradycardia. cardiovascular system reactions high doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and possibly cardiac arrest (see warnings , precautions , and overdosage ). allergic reactions allergic type reactions are rare and may occur as a result of sensitivity to the local anesthetic (see warnings ). 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 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 definitively established.

) pain 71 (4.3) 71 (5) pruritus 63 (3.8) 40 (2.8) fever 61 (3.7) 37 (2.6) dizziness 42 (2.5) 23 (1.6) rigors (chills) 42 (2.5) 24 (1.7) postoperative complications 41 (2.5) 44 (3.1) hypoesthesia 27 (1.6) 24 (1.7) urinary retention 23 (1.4) 20 (1.4) progression of labor poor/failed 23 (1.4) 22 (1.5) anxiety 21 (1.3) 11 (0.8) breast disorder, breast-feeding 21 (1.3) 12 (0.8) rhinitis 18 (1.1) 13 (0.9) table 3b adverse events reported in ≥ 1% of fetuses or neonates of mothers who received regional anesthesia (cesarean section and labor studies) adverse reaction naropin total n=639 bupivacaine total n=573 n (%) n (%) fetal bradycardia 77 (12.1) 68 (11.9) neonatal jaundice 49 (7.7) 47 (8.2) neonatal complication-nos 42 (6.6) 38 (6.6) apgar score low 18 (2.8) 14 (2.4) neonatal respiratory disorder 17 (2.7) 18 (3.1) neonatal tachypnea 14 (2.2) 15 (2.6) neonatal fever 13 (2) 14 (2.4) fetal tachycardia 13 (2) 12 (2.1) fetal distress 11 (1.7) 10 (1.7) neonatal infection 10 (1.6) 8 (1.4) neonatal hypoglycemia 8 (1.3) 16 (2.8)

pokinesia, hypotonia, ptosis, stupor psychiatric disorders - agitation, confusion, somnolence, nervousness, amnesia, hallucination, emotional lability, insomnia, nightmares respiratory system - bronchospasm, coughing skin disorders - rash, urticaria urinary system disorders - urinary incontinence, micturition disorder vascular - deep vein thrombosis, phlebitis, pulmonary embolism vision - vision abnormalities for the indication epidural anesthesia for surgery, the 15 most common adverse events were compared between different concentrations of naropin and bupivacaine. table 4 is based on data from trials in the u.s. and other countries where naropin was administered as an epidural anesthetic for surgery. table 4 common events (epidural administration) adverse reaction naropin bupivacaine 5 mg/ml total n=256 7.5 mg/ml total n=297 10 mg/ml total n=207 5 mg/ml total n=236 7.5 mg/ml total n=174 n (%) n (%) n (%) n (%) n (%) hypotension 99 (38.7) 146 (49.2) 113 (54.6) 91 (38.6) 89 (51.1) nausea 34 (13.3) 68 (22.9) 41 (17.4) 36 (20.7) bradycardia 29 (11.3) 58 (19.5) 40 (19.3) 32 (13.6) 25 (14.4) back pain 18 (7) 23 (7.7) 34 (16.4) 21 (8.9) 23 (13.2) vomiting 18 (7) 33 (11.1) 23 (11.1) 19 (8.1) 14 (8) headache 12 (4.7) 20 (6.7) 16 (7.7) 13 (5.5) 9 (5.2) fever 8 (3.1) 5 (1.7) 18 (8.7) 11 (4.7) chills 6 (2.3) 7 (2.4) 6 (2.9) 4 (1.7) 3 (1.7) urinary retention 5 (2) 8 (2.7) 10 (4.8) 10 (4.2) paresthesia 5 (2) 10 (3.4) 5 (2.4) 7 (3) pruritus 14 (4.7) 3 (1.4) 7 (4) using data from the same studies, the number (%) of patients experiencing hypotension is displayed by patient age, drug and concentration in table 5. in table 6, the adverse events for naropin are broken down by gender. table 5 effects of age on hypotension (epidural administration) total n: naropin = 760, bupivacaine = 410 age naropin bupivacaine 5 mg/ml 7.5 mg/ml 10 mg/ml 5 mg/ml 7.5 mg/ml n (%) n (%) n (%) n (%) n (%) <65 68 (32.2) 99 (43.2) 87 (51.5) 64 (33.5) 73 (48.3) ≥65 31 (68.9) 47 (69.1) 26 (68.4) 27 (60) 16 (69.6) table 6 most common adverse events by gender (epidural administration) total n: females = 405, males = 355 adverse reaction female male n (%) n (%) hypotension 220 (54.3) 138 (38.9) nausea 119 (29.4) 23 (6.5) bradycardia 65 (16) 56 (15.8) vomiting 59 (14.6) 8 (2.3) back pain 41 (10.1) 23 (6.5) headache 33 (8.1) 17 (4.8) chills 18 (4.4) 5 (1.4) fever 16 (4) 3 (0.8) pruritus 16 (4) 1 (0.3) pain 12 (3) 4 (1.1) urinary retention 11 (2.7) 7 (2) dizziness 9 (2.2) 4 (1.1) hypoesthesia 8 (2) 2 (0.6) paresthesia 8 (2) 10 (2.8)

binding, such as acidosis, systemic diseases that alter protein production or competition with other drugs for protein binding sites, may diminish individual tolerance. epidural administration of naropin has, in some cases, as with other local anesthetics, been associated with transient increases in temperature to >38.5°c. this occurred more frequently at doses of naropin >16 mg/h.

also dependent upon the particular drug used, the route of administration, and the physical status of the patient. many of these observations may be related to local anesthetic techniques, with or without a contribution from the drug. during 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 as well as the physiological and physical effects of a dural puncture. these observations may include spinal block of varying magnitude (including high or total spinal block), hypotension secondary to spinal block, urinary retention, loss of bladder and bowel control (fecal and urinary incontinence), and loss of perineal sensation and sexual function. signs and symptoms of subarachnoid block typically start within 2 to 3 minutes of injection. doses of 15 and 22.5 mg of naropin resulted in sensory levels as high as t5 and t4, respectively. analgesia started in the sacral dermatomes in 2 to 3 minutes and extended to the t10 level in 10 to 13 minutes and lasted for approximately 2 hours. other neurological effects following unintentional subarachnoid administration during epidural anesthesia may include 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, septic meningitis, meningismus, slowing of labor, increased incidence of forceps delivery, or cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid have been reported (see dosage and administration discussion of lumbar epidural block). a high spinal is characterized by paralysis of the arms, loss of consciousness, respiratory paralysis and bradycardia.

sion § dose (mg) 1493 ± 10 2075 ± 206 1217 ± 277 150 187.5 300 40 n 12 12 11 8 8 10 12 c max (mg/l) 2.4 ± 1 ¶ 2.8 ± 0.5 ¶ 2.3 ± 1.1 ¶ 1.1 ± 0.2 1.6 ± 0.6 2.3 ± 0.8 1.2 ± 0.2 # t max (min) n/a ♠ n/a n/a 43 ± 14 34 ± 9 54 ± 22 n/a auc 0 - (mg.h/l) 135.5 ± 50 145 ± 34 161 ± 90 7.2 ± 2 11.3 ± 4 13 ± 3.3 1.8 ± 0.6 cl (l/h) 11.03 13.7 n/a 5.5 ± 2 5 ± 2.6 n/a 21.2 ± 7 t 1/2 (hr) ♥ 5 ± 2.5 5.7 ± 3 6 ± 3 5.7 ± 2 7.1 ± 3 6.8 ± 3.2 1.9 ± 0.5 * continuous 72 hour epidural infusion after an epidural block with 5 or 10 mg/ml. † epidural anesthesia with 7.5 mg/ml (0.75%) for cesarean delivery. ‡ brachial plexus block with 7.5 mg/ml (0.75%) ropivacaine. § 20 minute iv infusion to volunteers (40 mg). ¶ c max measured at the end of infusion (i.e., at 72 hr). # c max measured at the end of infusion (i.e., at 20 minutes). ♠ n/a=not applicable ♥ t ½ is the true terminal elimination half-life. on the other hand, t ½ follows absorption‑dependent elimination (flip-flop) after non-intravenous administration. in some patients after a 300 mg dose for brachial plexus block, free plasma concentrations of ropivacaine may approach the threshold for cns toxicity (see precautions ). at a dose of greater than 300 mg, for local infiltration, the terminal half-life may be longer (>30 hours). distribution after intravascular infusion, ropivacaine has a steady-state volume of distribution of 41 ± 7 liters. ropivacaine is 94% protein bound, mainly to α 1 -acid glycoprotein. an increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of α 1 -acid glycoprotein. variations in unbound, i.e., pharmacologically active, concentrations have been less than in total plasma concentration. ropivacaine readily crosses the placenta and equilibrium in regard to unbound concentration will be rapidly reached (see precautions , labor and delivery ). metabolism ropivacaine is extensively metabolized in the liver, predominantly by aromatic hydroxylation mediated by cytochrome p4501a to 3-hydroxy ropivacaine. after a single iv dose approximately 37% of the total dose is excreted in the urine as both free and conjugated 3-hydroxy ropivacaine. low concentrations of 3-hydroxy ropivacaine have been found in the plasma. urinary excretion of the 4-hydroxy ropivacaine, and both the 3-hydroxy n-de-alkylated (3-oh-ppx) and 4-hydroxy n-de-alkylated (4-oh-ppx) metabolites account for less than 3% of the dose. an additional metabolite, 2-hydroxy-methyl-ropivacaine, has been identified but not quantified in the urine. the n-de-alkylated metabolite of ropivacaine (ppx) and 3-oh-ropivacaine are the major metabolites excreted in the urine during epidural infusion. total ppx concentration in the plasma was about half as that of total ropivacaine; however, mean unbound concentrations of ppx were about 7 to 9 times higher than that of unbound ropivacaine following continuous epidural infusion up to 72 hours. unbound ppx, 3-hydroxy and 4-hydroxy ropivacaine, have a pharmacological activity in animal models less than that of ropivacaine. there is no evidence of in vivo racemization in urine of ropivacaine. elimination the kidney is the main excretory organ for most local anesthetic metabolites. in total, 86% of the ropivacaine dose is excreted in the urine after intravenous administration of which only 1% relates to unchanged drug. after intravenous administration ropivacaine has a mean ± sd total plasma clearance of 387 ± 107 ml/min, an unbound plasma clearance of 7.2 ± 1.6 l/min, and a renal clearance of 1 ml/min. the mean ± sd terminal half-life is 1.8 ± 0.7 h after intravascular administration and 4.2 ± 1 h after epidural administration (see absorption ). pharmacodynamics studies in humans have demonstrated that, unlike most other local anesthetics, the presence of epinephrine has no major effect on either the time of onset or the duration of action of ropivacaine. likewise, addition of epinephrine to ropivacaine has no effect on limiting systemic absorption of ropivacaine. systemic absorption of local anesthetics can produce effects on the central nervous and cardiovascular systems. at blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance have been reported. toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. 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 usually 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. in 2 clinical pharmacology studies (total n=24) ropivacaine and bupivacaine were infused (10 mg/min) in human volunteers until the appearance of cns symptoms, e.g., visual or hearing disturbances, perioral numbness, tingling and others. similar symptoms were seen with both drugs. in 1 study, the mean ± sd maximum tolerated intravenous dose of ropivacaine infused (124 ± 38 mg) was significantly higher than that of bupivacaine (99 ± 30 mg) while in the other study the doses were not different (115 ± 29 mg of ropivacaine and 103 ± 30 mg of bupivacaine). in the latter study, the number of subjects reporting each symptom was similar for both drugs with the exception of muscle twitching, which was reported by more subjects with bupivacaine than ropivacaine at comparable intravenous doses. at the end of the infusion, ropivacaine in both studies caused significantly less depression of cardiac conductivity (less qrs widening) than bupivacaine. ropivacaine and bupivacaine caused evidence of depression of cardiac contractility, but there were no changes in cardiac output. clinical data in one published article indicate that differences in various pharmacodynamic measures were observed with increasing age. in one study, the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (map) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age. however, no pharmacokinetic differences were observed between elderly and younger patients. in non-clinical pharmacology studies comparing ropivacaine and bupivacaine in several animal species, the cardiac toxicity of ropivacaine was less than that of bupivacaine, although both were considerably more toxic than lidocaine. arrhythmogenic and cardio-depressant effects were seen in animals at significantly higher doses of ropivacaine than bupivacaine. the incidence of successful resuscitation was not significantly different between the ropivacaine and bupivacaine groups. clinical trials ropivacaine was studied as a local anesthetic both for surgical anesthesia and for acute pain management (see dosage and administration ). the onset, depth and duration of sensory block are, in general, similar to bupivacaine. however, the depth and duration of motor block, in general, are less than that with bupivacaine. epidural administration in surgery there were 25 clinical studies performed in 900 patients to evaluate naropin epidural injection for general surgery. naropin was used in doses ranging from 75 to 250 mg. in doses of 100 to 200 mg, the median (1st to 3rd quartile) onset time to achieve a t10 sensory block was 10 (5 to 13) minutes and the median (1st to 3rd quartile) duration at the t10 level was 4 (3 to 5) hours (see dosage and administration ). higher doses produced a more profound block with a greater duration of effect. epidural administration in cesarean section a total of 12 studies were performed with epidural administration of naropin for cesarean section. eight of these studies involved 218 patients using the concentration of 5 mg/ml (0.5%) in doses up to 150 mg. median onset measured at t6 ranged from 11 to 26 minutes. median duration of sensory block at t6 ranged from 1.7 to 3.2 h, and duration of motor block ranged from 1.4 to 2.9 h. naropin provided adequate muscle relaxation for surgery in all cases. in addition, 4 active controlled studies for cesarean section were performed in 264 patients at a concentration of 7.5 mg/ml (0.75%) in doses up to 187.5 mg. median onset measured at t6 ranged from 4 to 15 minutes. seventy-seven to 96% of naropin-exposed patients reported no pain at delivery. some patients received other anesthetic, analgesic, or sedative modalities during the course of the operative procedure. epidural administration in labor and delivery a total of 9 double-blind clinical studies, involving 240 patients were performed to evaluate naropin for epidural block for management of labor pain. when administered in doses up to 278 mg as intermittent injections or as a continuous infusion, naropin produced adequate pain relief. a prospective meta-analysis on 6 of these studies provided detailed evaluation of the delivered newborns and showed no difference in clinical outcomes compared to bupivacaine. there were significantly fewer instrumental deliveries in mothers receiving ropivacaine as compared to bupivacaine. table 2 labor and delivery meta-analysis: mode of delivery delivery mode naropin n=199 bupivacaine n=188 n % n % spontaneous vertex 116 58 92 49 vacuum extractor 26 33 }27* }40 forceps 28 42 cesarean section 29 15 21 11 * p=0.004 versus bupivacaine epidural administration in postoperative pain management there were 8 clinical studies performed in 382 patients to evaluate naropin 2 mg/ml (0.2%) for postoperative pain management after upper and lower abdominal surgery and after orthopedic surgery. the studies utilized intravascular morphine via pca as a rescue medication and quantified as an efficacy variable. epidural anesthesia with naropin 5 mg/ml, (0.5%) was used intraoperatively for each of these procedures prior to initiation of postoperative naropin. the incidence and intensity of the motor block were dependent on the dose rate of naropin and the site of injection. cumulative doses of up to 770 mg of ropivacaine were administered over 24 hours (intraoperative block plus postoperative continuous infusion). the overall quality of pain relief, as judged by the patients, in the ropivacaine groups was rated as good or excellent (73% to 100%). the frequency of motor block was greatest at 4 hours and decreased during the infusion period in all groups. at least 80% of patients in the upper and lower abdominal studies and 42% in the orthopedic studies had no motor block at the end of the 21-hour infusion period. sensory block was also dose rate-dependent and a decrease in spread was observed during the infusion period. a double blind, randomized, clinical trial compared lumbar epidural infusion of naropin (n=26) and bupivacaine (n=26) at 2 mg/ml (8 ml/h), for 24 hours after knee replacement. in this study, the pain scores were higher in the naropin group, but the incidence and the intensity of motor block were lower. continuous epidural infusion of naropin 2 mg/ml (0.2%) during up to 72 hours for postoperative pain management after major abdominal surgery was studied in 2 multicenter, double-blind studies. a total of 391 patients received a low thoracic epidural catheter, and naropin 7.5 mg/l (0.75%) was given for surgery, in combination with ga. postoperatively, naropin 2 mg/ml (0.2%), 4 to 14 ml/h, alone or with fentanyl 1, 2, or 4 mcg/ml was infused through the epidural catheter and adjusted according to the patient’s needs. these studies support the use of naropin 2 mg/ml (0.2%) for epidural infusion at 6 to 14 ml/h (12 to 28 mg) for up to 72 hours and demonstrated adequate analgesia with only slight and nonprogressive motor block in cases of moderate to severe postoperative pain. clinical studies with 2 mg/ml (0.2%) naropin have demonstrated that infusion rates of 6 to 14 ml (12 to 28 mg) per hour provide adequate analgesia with nonprogressive motor block in cases of moderate to severe postoperative pain. in these studies, this technique resulted in a significant reduction in patients’ morphine rescue dose requirement. clinical experience supports the use of naropin epidural infusions for up to 72 hours. peripheral nerve block naropin, 5 mg/ml (0.5%), was evaluated for its ability to provide anesthesia for surgery using the techniques of peripheral nerve block. there were 13 studies performed including a series of 4 pharmacodynamic and pharmacokinetic studies performed on minor nerve blocks. from these, 235 naropin treated patients were evaluable for efficacy. naropin was used in doses up to 275 mg. when used for brachial plexus block, onset depended on technique used. supraclavicular blocks were consistently more successful than axillary blocks. the median onset of sensory block (anesthesia) produced by ropivacaine 0.5% via axillary block ranged from 10 minutes (medial brachial cutaneous nerve) to 45 minutes (musculocutaneous nerve). median duration ranged from 3.7 hours (medial brachial cutaneous nerve) to 8.7 hours (ulnar nerve). the 5 mg/ml (0.5%) naropin solution gave success rates from 56% to 86% for axillary blocks, compared with 92% for supraclavicular blocks. in addition, naropin, 7.5 mg/ml (0.75%), was evaluated in 99 naropin treated patients, in 2 double-blind studies, performed to provide anesthesia for surgery using the techniques of brachial plexus block. naropin 7.5 mg/ml was compared to bupivacaine 5 mg/ml. in 1 study, patients underwent axillary brachial plexus block using injections of 40 ml (300 mg) of naropin, 7.5 mg/ml (0.75%) or 40 ml injections of bupivacaine, 5 mg/ml (200 mg). in a second study, patients underwent subclavian perivascular brachial plexus block using 30 ml (225 mg) of naropin, 7.5 mg/ml (0.75%) or 30 ml of bupivacaine 5 mg/ml (150 mg). there was no significant difference between the naropin and bupivacaine groups in either study with regard to onset of anesthesia, duration of sensory blockade, or duration of anesthesia. the median duration of anesthesia varied between 11.4 and 14.4 hours with both techniques. in one study, using the axillary technique, the quality of analgesia and muscle relaxation in the naropin group was judged to be significantly superior to bupivacaine by both investigator and surgeon. however, using the subclavian perivascular technique, no statistically significant difference was found in the quality of analgesia and muscle relaxation as judged by both the investigator and surgeon. the use of naropin 7.5 mg/ml for block of the brachial plexus via either the subclavian perivascular approach using 30 ml (225 mg) or via the axillary approach using 40 ml (300 mg) both provided effective and reliable anesthesia. local infiltration a total of 7 clinical studies were performed to evaluate the local infiltration of naropin to produce anesthesia for surgery and analgesia in postoperative pain management. in these studies 297 patients who received naropin in doses up to 200 mg (concentrations up to 5 mg/ml, 0.5%) were evaluable for efficacy. with infiltration of 100 to 200 mg naropin, the time to first request for analgesic was 2 to 6 hours. when compared to placebo, naropin produced lower pain scores and a reduction of analgesic consumption.

) 1493 ± 10 2075 ± 206 1217 ± 277 150 187.5 300 40 n 12 12 11 8 8 10 12 c max (mg/l) 2.4 ± 1 ¶ 2.8 ± 0.5 ¶ 2.3 ± 1.1 ¶ 1.1 ± 0.2 1.6 ± 0.6 2.3 ± 0.8 1.2 ± 0.2 # t max (min) n/a ♠ n/a n/a 43 ± 14 34 ± 9 54 ± 22 n/a auc 0 - (mg.h/l) 135.5 ± 50 145 ± 34 161 ± 90 7.2 ± 2 11.3 ± 4 13 ± 3.3 1.8 ± 0.6 cl (l/h) 11.03 13.7 n/a 5.5 ± 2 5 ± 2.6 n/a 21.2 ± 7 t 1/2 (hr) ♥ 5 ± 2.5 5.7 ± 3 6 ± 3 5.7 ± 2 7.1 ± 3 6.8 ± 3.2 1.9 ± 0.5 * continuous 72 hour epidural infusion after an epidural block with 5 or 10 mg/ml. † epidural anesthesia with 7.5 mg/ml (0.75%) for cesarean delivery. ‡ brachial plexus block with 7.5 mg/ml (0.75%) ropivacaine. § 20 minute iv infusion to volunteers (40 mg). ¶ c max measured at the end of infusion (i.e., at 72 hr). # c max measured at the end of infusion (i.e., at 20 minutes). ♠ n/a=not applicable ♥ t ½ is the true terminal elimination half-life. on the other hand, t ½ follows absorption‑dependent elimination (flip-flop) after non-intravenous administration. in some patients after a 300 mg dose for brachial plexus block, free plasma concentrations of ropivacaine may approach the threshold for cns toxicity (see precautions ). at a dose of greater than 300 mg, for local infiltration, the terminal half-life may be longer (>30 hours).

ne following continuous epidural infusion up to 72 hours. unbound ppx, 3-hydroxy and 4-hydroxy ropivacaine, have a pharmacological activity in animal models less than that of ropivacaine. there is no evidence of in vivo racemization in urine of ropivacaine.

an section. eight of these studies involved 218 patients using the concentration of 5 mg/ml (0.5%) in doses up to 150 mg. median onset measured at t6 ranged from 11 to 26 minutes. median duration of sensory block at t6 ranged from 1.7 to 3.2 h, and duration of motor block ranged from 1.4 to 2.9 h. naropin provided adequate muscle relaxation for surgery in all cases. in addition, 4 active controlled studies for cesarean section were performed in 264 patients at a concentration of 7.5 mg/ml (0.75%) in doses up to 187.5 mg. median onset measured at t6 ranged from 4 to 15 minutes. seventy-seven to 96% of naropin-exposed patients reported no pain at delivery. some patients received other anesthetic, analgesic, or sedative modalities during the course of the operative procedure. epidural administration in labor and delivery a total of 9 double-blind clinical studies, involving 240 patients were performed to evaluate naropin for epidural block for management of labor pain. when administered in doses up to 278 mg as intermittent injections or as a continuous infusion, naropin produced adequate pain relief. a prospective meta-analysis on 6 of these studies provided detailed evaluation of the delivered newborns and showed no difference in clinical outcomes compared to bupivacaine. there were significantly fewer instrumental deliveries in mothers receiving ropivacaine as compared to bupivacaine. table 2 labor and delivery meta-analysis: mode of delivery delivery mode naropin n=199 bupivacaine n=188 n % n % spontaneous vertex 116 58 92 49 vacuum extractor 26 33 }27* }40 forceps 28 42 cesarean section 29 15 21 11 * p=0.004 versus bupivacaine epidural administration in postoperative pain management there were 8 clinical studies performed in 382 patients to evaluate naropin 2 mg/ml (0.2%) for postoperative pain management after upper and lower abdominal surgery and after orthopedic surgery. the studies utilized intravascular morphine via pca as a rescue medication and quantified as an efficacy variable. epidural anesthesia with naropin 5 mg/ml, (0.5%) was used intraoperatively for each of these procedures prior to initiation of postoperative naropin. the incidence and intensity of the motor block were dependent on the dose rate of naropin and the site of injection. cumulative doses of up to 770 mg of ropivacaine were administered over 24 hours (intraoperative block plus postoperative continuous infusion). the overall quality of pain relief, as judged by the patients, in the ropivacaine groups was rated as good or excellent (73% to 100%). the frequency of motor block was greatest at 4 hours and decreased during the infusion period in all groups. at least 80% of patients in the upper and lower abdominal studies and 42% in the orthopedic studies had no motor block at the end of the 21-hour infusion period. sensory block was also dose rate-dependent and a decrease in spread was observed during the infusion period. a double blind, randomized, clinical trial compared lumbar epidural infusion of naropin (n=26) and bupivacaine (n=26) at 2 mg/ml (8 ml/h), for 24 hours after knee replacement. in this study, the pain scores were higher in the naropin group, but the incidence and the intensity of motor block were lower. continuous epidural infusion of naropin 2 mg/ml (0.2%) during up to 72 hours for postoperative pain management after major abdominal surgery was studied in 2 multicenter, double-blind studies. a total of 391 patients received a low thoracic epidural catheter, and naropin 7.5 mg/l (0.75%) was given for surgery, in combination with ga. postoperatively, naropin 2 mg/ml (0.2%), 4 to 14 ml/h, alone or with fentanyl 1, 2, or 4 mcg/ml was infused through the epidural catheter and adjusted according to the patient’s needs. these studies support the use of naropin 2 mg/ml (0.2%) for epidural infusion at 6 to 14 ml/h (12 to 28 mg) for up to 72 hours and demonstrated adequate analgesia with only slight and nonprogressive motor block in cases of moderate to severe postoperative pain. clinical studies with 2 mg/ml (0.2%) naropin have demonstrated that infusion rates of 6 to 14 ml (12 to 28 mg) per hour provide adequate analgesia with nonprogressive motor block in cases of moderate to severe postoperative pain. in these studies, this technique resulted in a significant reduction in patients’ morphine rescue dose requirement. clinical experience supports the use of naropin epidural infusions for up to 72 hours. peripheral nerve block naropin, 5 mg/ml (0.5%), was evaluated for its ability to provide anesthesia for surgery using the techniques of peripheral nerve block. there were 13 studies performed including a series of 4 pharmacodynamic and pharmacokinetic studies performed on minor nerve blocks. from these, 235 naropin treated patients were evaluable for efficacy. naropin was used in doses up to 275 mg. when used for brachial plexus block, onset depended on technique used. supraclavicular blocks were consistently more successful than axillary blocks. the median onset of sensory block (anesthesia) produced by ropivacaine 0.5% via axillary block ranged from 10 minutes (medial brachial cutaneous nerve) to 45 minutes (musculocutaneous nerve). median duration ranged from 3.7 hours (medial brachial cutaneous nerve) to 8.7 hours (ulnar nerve). the 5 mg/ml (0.5%) naropin solution gave success rates from 56% to 86% for axillary blocks, compared with 92% for supraclavicular blocks. in addition, naropin, 7.5 mg/ml (0.75%), was evaluated in 99 naropin treated patients, in 2 double-blind studies, performed to provide anesthesia for surgery using the techniques of brachial plexus block. naropin 7.5 mg/ml was compared to bupivacaine 5 mg/ml. in 1 study, patients underwent axillary brachial plexus block using injections of 40 ml (300 mg) of naropin, 7.5 mg/ml (0.75%) or 40 ml injections of bupivacaine, 5 mg/ml (200 mg). in a second study, patients underwent subclavian perivascular brachial plexus block using 30 ml (225 mg) of naropin, 7.5 mg/ml (0.75%) or 30 ml of bupivacaine 5 mg/ml (150 mg). there was no significant difference between the naropin and bupivacaine groups in either study with regard to onset of anesthesia, duration of sensory blockade, or duration of anesthesia. the median duration of anesthesia varied between 11.4 and 14.4 hours with both techniques. in one study, using the axillary technique, the quality of analgesia and muscle relaxation in the naropin group was judged to be significantly superior to bupivacaine by both investigator and surgeon. however, using the subclavian perivascular technique, no statistically significant difference was found in the quality of analgesia and muscle relaxation as judged by both the investigator and surgeon. the use of naropin 7.5 mg/ml for block of the brachial plexus via either the subclavian perivascular approach using 30 ml (225 mg) or via the axillary approach using 40 ml (300 mg) both provided effective and reliable anesthesia. local infiltration a total of 7 clinical studies were performed to evaluate the local infiltration of naropin to produce anesthesia for surgery and analgesia in postoperative pain management. in these studies 297 patients who received naropin in doses up to 200 mg (concentrations up to 5 mg/ml, 0.5%) were evaluable for efficacy. with infiltration of 100 to 200 mg naropin, the time to first request for analgesic was 2 to 6 hours. when compared to placebo, naropin produced lower pain scores and a reduction of analgesic consumption.

n of the container surface is desired, either isopropyl alcohol (91%) or ethyl alcohol (70%) is recommended. it is recommended that chemical disinfection be accomplished by wiping the ampule or vial stopper thoroughly with cotton or gauze that has been moistened with the recommended alcohol just prior to use. when a container is required to have a sterile outside, a sterile-pak should be chosen. glass containers may, as an alternative, be autoclaved once. stability has been demonstrated using a targeted f 0 of 7 minutes at 121°c. solutions should be stored at 20º to 25°c (68º to 77°f) [see usp controlled room temperature]. the container closure is not made with natural rubber latex. these products are intended for single dose and are free from preservatives. any solution remaining from an opened container should be discarded promptly. in addition, continuous infusion bottles should not be left in place for more than 24 hours. naropin is a trademark of fresenius kabi usa, llc. novaplus is a registered trademark of vizient, inc. manufactured by: fresenius kabi lake zurich, il 60047 www.fresenius-kabi.com/us 451113f revised: june 2020 logo