PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.
Principal Display Panel Text for Container Label:NDC 17478-081-30Ropivacaine HClInjection, USP0.5%150 mg/30 mL(5 mg/mL)For Infiltration, Nerve Block andEpidural Administration Only.Not for Intravenous Administration.30 mL Single-dose Vial. Principal Display Panel Text for Container Label.
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PEDIATRIC USE SECTION.
Pediatric Use. The safety and efficacy of ropivacaine hydrochloride in pediatric patients have not been established.
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PHARMACODYNAMICS SECTION.
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 primary depressant effect on the medulla and on higher centers. The depressed stage may occur without prior excited stage.In clinical pharmacology studies (total n=24) ropivacaine and bupivacaine were infused (10 mg/min) in human volunteers until the appearance of CNS symptoms, eg, visual or hearing disturbances, perioral numbness, tingling and others. Similar symptoms were seen with both drugs. In 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 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.
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PHARMACOKINETICS SECTION.
PHARMACOKINETICS. Absorption. The systemic concentration of ropivacaine is dependent on the total dose and concentration of drug administered, the route of administration, the patients hemodynamic/circulatory condition, and the vascularity of the administration site.From the epidural space, ropivacaine shows complete and biphasic absorption. The half-lives of the phases, (mean +- SD) are 14 +- minutes and 4.2 +- 0.9 h, respectively. The slow absorption is the rate limiting factor in the elimination of ropivacaine that explains why the terminal half-life is longer after epidural than after intravenous administration. Ropivacaine shows dose-proportionality up to the highest intravenous dose studied, 80 mg, corresponding to mean +- SD peak plasma concentration of 1.9 +- 0.3 mcg/mL.Table Pharmacokinetic (plasma concentration-time) data from clinical trials Continuous 72 hour epidural infusion after an epidural block with 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). Cmax measured at the end of infusion (ie, at 72 hr). Cmax measured at the end of infusion (ie, at 20 minutes). n/a=not applicable 1/2 is the true terminal elimination half-life. On the other hand, 1/2 follows absorption-dependent elimination (flip-flop) after non-intravenous administration.RouteEpidural InfusionEpidural InfusionEpidural Block+ Epidural Block+ Plexus Block IV Infusion Dose (mg)1493 +- 102075 +- 2061217 +- 277150187.530040N121211881012Cmax (mg/L)2.4 +- 2.8 +- 0.5 2.3 +- 1.1 1.1 +- 0.21.6 +- 0.62.3 +- 0.81.2 +- 0.2 Tmax (min)n/a n/an/a43 +- 1434 +- 954 +- 22n/aAUC0- (mg.h/L)135.5 +- 50145 +- 34161 +- 907.2 +- 211.3 +- 413 +- 3.31.8 +- 0.6CL (L/h)11.0313.7n/a5.5 +- 25 +- 2.6n/a21.2 +- 7t1/2 (hr) +- 2.55.7 +- 36 +- 35.7 +- 27.1 +- 36.8 +- 3.21.9 +- 0.5In some patients after 300 mg dose for brachial plexus block, free plasma concentrations of ropivacaine may approach the threshold for CNS toxicity (see PRECAUTIONS). At dose of greater than 300 mg, for local infiltration, the terminal half-life may be longer (>30 hours).. Distribution. After intravascular infusion, ropivacaine has steady-state volume of distribution of 41 +- liters. Ropivacaine is 94% protein bound, mainly to 1-acid glycoprotein. An increase in total plasma concentrations during continuous epidural infusion has been observed, related to postoperative increase of 1-acid glycoprotein. Variations in unbound, ie, 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 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 to times higher than that of unbound ropivacaine following continuous epidural infusion up to 72 hours. Unbound PPX, 3-hydroxy and 4-hydroxy ropivacaine, have 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 mean +- SD total plasma clearance of 387 +- 107 mL/min, an unbound plasma clearance of 7.2 +- 1.6 L/min, and renal clearance of mL/min. The mean +- SD terminal half-life is 1.8 +- 0.7 after intravascular administration and 4.2 +- h after epidural administration (see Absorption).
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PRECAUTIONS SECTION.
PRECAUTIONS. General. The safe and effective use of local anesthetics depends 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). The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse events. Injections should be made slowly and incrementally, with frequent aspirations before and during the injection to avoid intravascular injection. When continuous catheter technique is used, syringe aspirations should also be performed before and during each supplemental injection. During the administration of epidural anesthesia, it is recommended that test dose of local anesthetic with fast onset be administered initially and that the patient be monitored for central nervous system and cardiovascular toxicity, as well as for signs of unintended intrathecal administration 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 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 ropivacaine hydrochloride 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 patients 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 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 standard protocol for MH management should be available.. Epidural Anesthesia. During epidural administration, ropivacaine hydrochloride should be administered in incremental doses of to mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal 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 test dose be administered initially and the effects monitored before the full dose is given. When clinical conditions permit, the test dose should contain an appropriate dose of epinephrine to serve as warning of unintentional intravascular injection. If injected into blood vessel, this amount of epinephrine is likely to produce transient epinephrine response within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart should be continuously monitored for heart rate increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect rise in systolic blood pressure. test dose of short-acting amide anesthetic such as lidocaine is recommended to detect an unintentional intrathecal administration. This will be manifested within 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). An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects.. Use in Brachial Plexus Block. Ropivacaine plasma concentrations may approach the threshold for central nervous system toxicity after the administration of 300 mg of ropivacaine for brachial plexus block. Caution should be exercised when using the 300 mg dose (see OVERDOSAGE).The dose for major nerve block must be adjusted according to the site of administration and patient status. Supraclavicular brachial plexus blocks may be associated with higher frequency of serious adverse reactions, regardless of the local anesthetic used.. Use in Peripheral Nerve Block. Major peripheral nerve blocks may result in the administration of large volume of local anesthetic in highly vascularized areas, often close to large vessels where there is an increased risk of intravascular injection and/or rapid systemic absorption, which can lead to high plasma concentrations.. 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. Dosage recommendations should not be exceeded (see DOSAGE AND ADMINISTRATION).. Use in Ophthalmic Surgery. The use of ropivacaine hydrochloride in retrobulbar blocks for ophthalmic surgery has not been studied. Until appropriate experience is gained, the use of ropivacaine hydrochloride for such surgery is not recommended.. Information for Patients. When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity in the anesthetized part of the body following proper administration of lumbar epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the ropivacaine hydrochloride package insert.Inform patients that use of local anesthetics may cause methemoglobinemia, 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.. Drug Interactions. Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (eg, amiodarone) have not been performed, but caution is advised (see WARNINGS).Ropivacaine hydrochloride 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. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for days), selective and potent CYPIA2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as tluvoxamine, given concomitantly during administration of ropivacaine hydrochloride, can interact with ropivacaine hydrochloride leading to increased ropivacaine plasma levels. Caution should be exercised when CYPlA2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYPlA2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for days with ropivacaine infusion administered hour after ketoconazole) caused 15% reduction in in vivo plasma clearance of ropivacaine.Patients that 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:ClassExamplesNitrates/Nitritesnitric oxide, nitroglycerin, nitroprusside, nitrous oxideLocal anestheticsarticaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracineAntineoplastic agentscyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicaseAntibioticsdapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamidesAntimalarialschloroquine, primaquineAnticonvulsantsphenobarbital, phenytoin, sodium valproateOther drugsacetaminophen, metoclopramide, quinine, sulfasalazine. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals of most local anesthetics, including ropivacaine, to evaluate the carcinogenic potential have not been conducted.Weak mutagenic activity was seen in the mouse lymphoma test. Mutagenicity was not noted in the other assays, demonstrating that the weak signs of in vitro activity in the mouse lymphoma test were not manifest under diverse in vivo conditions.Studies performed with ropivacaine in rats did not demonstrate an effect on fertility or general reproductive performance over generations.. Pregnancy Category B. Reproduction toxicity studies have been performed in pregnant New Zealand white rabbits and Sprague-Dawley rats. During gestation days to 18, rabbits received 1.3, 4.2, or 13 mg/kg/day subcutaneously. In rats, subcutaneous doses of 5.3, 11 and 26 mg/kg/day were administered during gestation days to 15. No teratogenic effects were observed in rats and rabbits at the highest doses tested. The highest doses of 13 mg/kg/day (rabbits) and 26 mg/kg/day (rats) are approximately 1/3 of the maximum recommended human dose (epidural, 770 mg/24 hours) based on mg/m2 basis. In prenatal and postnatal studies, the female rats were dosed daily from day 15 of gestation to day 20 postpartum. The doses were 5.3, 11 and 26 mg/kg/day subcutaneously. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring.In another study with rats, the males were dosed daily for weeks before mating and during mating. The females were dosed daily for weeks before mating and then during the mating, pregnancy, and lactation, up to day 42 post coitus. At 23 mg/kg/day, an increased loss of pups was observed during the first days postpartum. The effect was considered secondary to impaired maternal care due to maternal toxicity.There are no adequate or well-controlled studies in pregnant women of the effects of ropivacaine hydrochloride on the developing fetus. Ropivacaine hydrochloride should only be used during pregnancy if the benefits outweigh the risk.Teratogenicity studies in rats and rabbits did not show evidence of any adverse effects on organogenesis or early fetal development in rats (26 mg/kg sc) or rabbits (13 mg/kg). The doses used were approximately equal to total daily dose based on body surface area. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring in perinatal and postnatal studies in rats, at dose levels equivalent to the maximum recommended human dose based on body surface area. In another study at 23 mg/kg, an increased pup loss was seen during the first days postpartum, which was considered secondary to impaired maternal care due to maternal toxicity.. Labor and Delivery. Local anesthetics, including ropivacaine, rapidly cross the placenta, and when used for epidural block can cause varying degrees of maternal, fetal and neonatal toxicity (see CLINICAL PHARMACOLOGY and 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 with ropivacaine hydrochloride for obstetrical pain relief. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patients 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 anesthesia has been reported to prolong the second stage of labor by removing the patients reflex urge to bear down or by interfering with motor function. Spontaneous vertex delivery occurred more frequently in patients receiving ropivacaine hydrochloride than in those receiving bupivacaine.. Nursing Mothers. Some local anesthetic drugs are excreted in human milk and caution should be exercised when they are administered to nursing woman. The excretion of ropivacaine or its metabolites in human milk has not been studied. Based on the milk/plasma concentration ratio in rats, the estimated daily dose to pup will be about 4% of the dose given to the mother. Assuming that the milk/plasma concentration in humans is of the same order, the total ropivacaine hydrochloride dose to which the baby is exposed by breast-feeding is far lower than by exposure in utero in pregnant women at term (see PRECAUTIONS).. Pediatric Use. The safety and efficacy of ropivacaine hydrochloride in pediatric patients have not been established.. Geriatric Use. Of the 2,978 subjects that were administered ropivacaine hydrochloride injection in 71 controlled and uncontrolled clinical studies, 803 patients (27%) were 65 years of age or older which includes 127 patients (4%) 75 years of age and over. Ropivacaine hydrochloride injection was found to be safe and effective in the patients in these studies. 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.This drug and its metabolites are known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased hepatic, renal, or cardiac function, as well as concomitant disease. Therefore, care should be taken in dose selection, starting at the low end of the dosage range, and it may be useful to monitor renal function (see PHARMACOKINETICS, Elimination).
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MECHANISM OF ACTION SECTION.
Mechanism of Action. Ropivacaine is member of the amino amide class of local anesthetics and is supplied as the pure S-(-)-enantiomer. 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: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.
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ADVERSE REACTIONS SECTION.
ADVERSE REACTIONS:. Reactions to ropivacaine are characteristic of those associated with other amide-type local anesthetics. major cause of adverse reactions to this group of drugs may be associated with excessive plasma levels, which may be due to overdosage, unintentional intravascular injection or slow metabolic degradation.The reported adverse events are derived from clinical studies conducted in the U.S. and other countries. The reference drug was usually bupivacaine. The studies used variety of premedications, sedatives, and surgical procedures of varying length. total of 3,988 patients have been exposed to ropivacaine hydrochloride at concentrations up to 1% in clinical trials. Each patient was counted once for each type of adverse event.. Incidence >= 5%. For the indications of epidural administration in surgery, cesarean section, postoperative pain management, 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 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 ropivacaine hydrochloride (concentrations ranged from 0.125% to 1% for ropivacaine hydrochloride 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 ropivacaine hydrochloride-treated patients in these studies. The majority of patients receiving concentrations higher than mg/mL (0.5%) were treated with ropivacaine hydrochloride.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 ReactionRopivacaine Hydrochloride total N=1661Bupivacainetotal N=1433N(%)N(%)Hypotension536(32.3)408(28.5)Nausea283(17)207(14.4)Vomiting117(7)88(6.1)Bradycardia96(5.8)73(5.1)Headache84(5.1)68(4.7)Paresthesia82(4.9)57(4)Back pain73(4.4)75(5.2)Pain71(4.3)71(5)Pruritus63(3.8)40(2.8)Fever61(3.7)37(2.6)Dizziness42(2.5)23(1.6)Rigors (Chills)42(2.5)24(1.7)Postoperative complications41(2.5)44(3.1)Hypoesthesia27(1.6)24(1.7)Urinary retention23(1.4)20(1.4)Progression of labor poor/failed23(1.4)22(1.5)Anxiety21(1.3)11(0.8)Breast disorder, breast-feeding21(1.3)12(0.8)Rhinitis18(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 ReactionRopivacaine Hydrochloride total N=639Bupivacainetotal N=573N(%)N(%)Fetal bradycardia77(12.1)68(11.9)Neonatal jaundice49(7.7)47(8.2)Neonatal complication-NOS42(6.6)38(6.6)Apgar score low18(2.8)14(2.4)Neonatal respiratory disorder17(2.7)18(3.1)Neonatal tachypnea14(2.2)15(2.6)Neonatal fever13(2)14(2.4)Fetal tachycardia13(2)12(2.1)Fetal distress11(1.7)10(1.7)Neonatal infection10(1.6)8(1.4)Neonatal hypoglycemia8(1.3)16(2.8). Incidence 1%. The following adverse events were reported during the ropivacaine hydrochloride 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 painCardiovascular System vasovagal reaction, syncope, postural hypotension, non-specific ECG abnormalitiesFemale Reproductive poor progression of labor, uterine atonyGastrointestinal System fecal incontinence, tenesmus, neonatal vomitingGeneral and Other Disorders hypothermia, malaise, asthenia, accident and/or injuryHearing and Vestibular tinnitus, hearing abnormalitiesHeart Rate and Rhythm extrasystoles, non-specific arrhythmias, atrial fibrillationLiver and Biliary System jaundiceMetabolic Disorders hypomagnesemiaMusculoskeletal System myalgiaMyo/Endo/Pericardium ST segment changes, myocardial infarctionNervous System tremor, Horners syndrome, paresis, dyskinesia, neuropathy, vertigo, coma, convulsion, hypokinesia, hypotonia, ptosis, stuporPsychiatric Disorders agitation, confusion, somnolence, nervousness, amnesia, hallucination, emotional lability, insomnia, nightmaresRespiratory System bronchospasm, coughingSkin Disorders rash, urticariaUrinary System Disorders urinary incontinence, micturition disorderVascular deep vein thrombosis, phlebitis, pulmonary embolismVision vision abnormalitiesFor the indication epidural anesthesia for surgery, the 15 most common adverse events were compared between different concentrations of ropivacaine hydrochloride and bupivacaine. Table is based on data from trials in the U.S. and other countries where ropivacaine hydrochloride was administered as an epidural anesthetic for surgery.Table Common Events (Epidural Administration)Adverse ReactionRopivacaine HydrochlorideBupivacaine5 mg/mL totalN=2565 mg/mLtotal N=236N(%)N(%)hypotension99(38.7)91(38.6)nausea34(13.3)41(17.4)bradycardia29(11.3)32(13.6)back pain18(7)21(8.9)vomiting18(7)19(8.1)headache12(4.7)13(5.5)fever8(3.1)11(4.7)chills6(2.3)4(1.7)urinary retention5(2)10(4.2)paresthesia5(2)7(3)pruritusUsing 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 ropivacaine hydrochloride are broken down by gender.Table Effects of Age on Hypotension (Epidural Administration) Total N: Ropivacaine Hydrochloride 760, Bupivacaine 410AGERopivacaine HydrochlorideBupivacaine5 mg/mL5 mg/mLN(%)N(%)<6568(32.2)64(33.5)>=6531(68.9)27(60)Table Most Common Adverse Events by Gender (Epidural Administration) Total N: Females 405, Males 355Adverse ReactionFemaleMaleN(%)N(%)hypotension220(54.3)138(38.9)nausea119(29.4)23(6.5)bradycardia65(16)56(15.8)vomiting59(14.6)8(2.3)back pain41(10.1)23(6.5)headache33(8.1)17(4.8)chills18(4.4)5(1.4)fever16(4)3(0.8)pruritus16(4)1(0.3)pain12(3)4(1.1)urinary retention11(2.7)7(2)dizziness9(2.2)4(1.1)hypoesthesia8(2)2(0.6)paresthesia8(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 ropivacaine hydrochloride has, in some cases, as with other local anesthetics, been associated with transient increases in temperature to >38.5C. This occurred more frequently at doses of ropivacaine hydrochloride >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, exctextent 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 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 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 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 to minutes of injection. Doses of 15 and 22.5 mg of ropivacaine hydrochloride resulted in sensory levels as high as T5 and T4, respectively. Analgesia started in the sacral dermatomes in to minutes and extended to the T10 level in 10 to 13 minutes and lasted for approximately 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). 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 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.
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CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.
Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals of most local anesthetics, including ropivacaine, to evaluate the carcinogenic potential have not been conducted.Weak mutagenic activity was seen in the mouse lymphoma test. Mutagenicity was not noted in the other assays, demonstrating that the weak signs of in vitro activity in the mouse lymphoma test were not manifest under diverse in vivo conditions.Studies performed with ropivacaine in rats did not demonstrate an effect on fertility or general reproductive performance over generations.
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CLINICAL PHARMACOLOGY SECTION.
CLINICAL PHARMACOLOGY. Mechanism of Action. Ropivacaine is member of the amino amide class of local anesthetics and is supplied as the pure S-(-)-enantiomer. 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: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.
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CLINICAL STUDIES SECTION.
Incidence in Controlled Clinical Trials. The reported adverse events are derived from controlled clinical studies with ropivacaine hydrochloride (concentrations ranged from 0.125% to 1% for ropivacaine hydrochloride 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 ropivacaine hydrochloride-treated patients in these studies. The majority of patients receiving concentrations higher than mg/mL (0.5%) were treated with ropivacaine hydrochloride.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 ReactionRopivacaine Hydrochloride total N=1661Bupivacainetotal N=1433N(%)N(%)Hypotension536(32.3)408(28.5)Nausea283(17)207(14.4)Vomiting117(7)88(6.1)Bradycardia96(5.8)73(5.1)Headache84(5.1)68(4.7)Paresthesia82(4.9)57(4)Back pain73(4.4)75(5.2)Pain71(4.3)71(5)Pruritus63(3.8)40(2.8)Fever61(3.7)37(2.6)Dizziness42(2.5)23(1.6)Rigors (Chills)42(2.5)24(1.7)Postoperative complications41(2.5)44(3.1)Hypoesthesia27(1.6)24(1.7)Urinary retention23(1.4)20(1.4)Progression of labor poor/failed23(1.4)22(1.5)Anxiety21(1.3)11(0.8)Breast disorder, breast-feeding21(1.3)12(0.8)Rhinitis18(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 ReactionRopivacaine Hydrochloride total N=639Bupivacainetotal N=573N(%)N(%)Fetal bradycardia77(12.1)68(11.9)Neonatal jaundice49(7.7)47(8.2)Neonatal complication-NOS42(6.6)38(6.6)Apgar score low18(2.8)14(2.4)Neonatal respiratory disorder17(2.7)18(3.1)Neonatal tachypnea14(2.2)15(2.6)Neonatal fever13(2)14(2.4)Fetal tachycardia13(2)12(2.1)Fetal distress11(1.7)10(1.7)Neonatal infection10(1.6)8(1.4)Neonatal hypoglycemia8(1.3)16(2.8).
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CONTRAINDICATIONS SECTION.
CONTRAINDICATIONS. Ropivacaine Hydrochloride is contraindicated in patients with known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide type.
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DESCRIPTION SECTION.
DESCRIPTION. Ropivacaine Hydrochloride Injection contains ropivacaine HCl which is member of the amino amide class of local anesthetics. Ropivacaine Hydrochloride Injection is sterile, isotonic solution that contains the enantiomerically pure drug substance, sodium chloride for isotonicity and water for injection. Sodium hydroxide and/or hydrochloric acid may be used for pH adjustment. It is administered parenterally.Ropivacaine HCl is chemically described as S-(-)-1-propyl-2,6-pipecoloxylidide hydrochloride monohydrate. The drug substance is white crystalline powder, with the following structural formula:At 25C ropivacaine HCl has solubility of 53.8 mg/mL in water, distribution ratio between n-octanol and phosphate buffer at pH 7.4 of 14:1 and pKa of 8.07 in 0.1 KCl solution. The pKa of ropivacaine is approximately the same as bupivacaine (8.1) and is similar to that of mepivacaine (7.7). However, ropivacaine has an intermediate degree of lipid solubility compared to bupivacaine and mepivacaine.Ropivacaine Hydrochloride Injection is preservative-free and is available in single dose container in mg/mL (0.5%) concentration. The specific gravity of Ropivacaine Hydrochloride Injection solutions range from 1.002 to 1.005 at 25C.. Structural Formula.
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DOSAGE & ADMINISTRATION SECTION.
DOSAGE AND ADMINISTRATION. The rapid injection of large volume of local anesthetic solution should be avoided and fractional (incremental) doses should always be used. The smallest dose and concentration required to produce the desired result should be administered.There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Ropivacaine hydrochloride is not approved for this use (see WARNINGS and 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. Patients in poor general condition due to aging or other compromising factors such as partial or complete heart 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 patients condition before major blocks are performed, and the dosage should be adjusted accordingly.Use an adequate test dose (3 to mL of 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 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 Dosage Recommendations Not Applicable+= The dose for major nerve block must be adjusted according to site of administration and patient status. Supraclavicular brachial plexus blocks may be associated with 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 median delivery time of 5.5 hours.= Cumulative doses up to 770 mg of ropivacaine hydrochloride 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, ie, 2016 mg plus surgical dose of approximately 100 to 150 mg as top-up.Conc.VolumeDoseOnsetDurationmg/mL(%)mLmgminhoursSURGICAL ANESTHESIALumbar Epidural5(0.5%)15 to 3075 to 15015 to 302 to 4Administration7.5(0.75%)15 to 25113 to 18810 to 203 to 5Surgery10(1%)15 to 20150 to 20010 to 204 to 6Lumbar Epidural5(0.5%)20 to 30100 to 15015 to 252 to 4Administration7.5(0.75%)15 to 20113 to 15010 to 203 to 5Cesarean SectionThoracic Epidural5(0.5%)5 to 1525 to 7510 to 20n/aAdministration7.5(0.75%)5 to 1538 to 11310 to 20n/aSurgeryMajor Nerve Block+5(0.5%)35 to 50175 to 25015 to 305 to 8(eg, brachial plexus block)7.5(0.75%)10 to 4075 to 30010 to 256 to 10Field Block5(0.5%)1 to 405 to 2001 to 152 to 6(eg, minor nerve blocks and infiltration)Labor Pain ManagementLumbar Epidural AdministrationInitial Dose2(0.2%)10 to 2020 to 4010 to 150.5 to 1.5Continuous Infusion 2(0.2%)6 to 14 mL/h12 to 28 mg/hn/an/aIncremental injections (top-up) 2(0.2%)10 to 15 mL/h20 to 30 mg/hn/an/aPOSTOPERATIVE PAIN MANAGEMENTLumbar Epidural AdministrationContinuous Infusion 2(0.2%)6 to 14 mL/h12 to 28 mg/hn/an/aThoracic Epidural AdministrationContinuous Infusion 2(0.2%)6 to 14 mL/h12 to 28 mg/hn/an/aInfiltration2(0.2%)1 to 1002 to 2001 to 52 to 6(eg, minor nerve block)5(0.5%)1 to 405 to 2001 to 52 to 6The doses in the table are those considered to be necessary to produce 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 toxic plasma concentration or inducing local neural injury must be considered. Experience to date indicates that cumulative dose of up to 770 mg ropivacaine hydrochloride administered over 24 hours is well tolerated in adults when used for postoperative pain management: ie, 2016 mg. Caution should be exercised when administering ropivacaine hydrochloride for prolonged periods of time, eg, 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 to mL ropivacaine hydrochloride is induced via an epidural catheter. Analgesia is maintained with an infusion of ropivacaine hydrochloride, mg/ mL (0.2%). Clinical studies have demonstrated that infusion rates of to 14 mL (12 to 28 mg) per hour provide adequate analgesia with nonprogressive motor block. With this technique significant reduction in the need for opioids was demonstrated. Clinical experience supports the use of ropivacaine hydrochloride epidural infusions for up to 72 hours.
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NURSING MOTHERS SECTION.
Nursing Mothers. Some local anesthetic drugs are excreted in human milk and caution should be exercised when they are administered to nursing woman. The excretion of ropivacaine or its metabolites in human milk has not been studied. Based on the milk/plasma concentration ratio in rats, the estimated daily dose to pup will be about 4% of the dose given to the mother. Assuming that the milk/plasma concentration in humans is of the same order, the total ropivacaine hydrochloride dose to which the baby is exposed by breast-feeding is far lower than by exposure in utero in pregnant women at term (see PRECAUTIONS).
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DRUG INTERACTIONS SECTION.
Drug Interactions. Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (eg, amiodarone) have not been performed, but caution is advised (see WARNINGS).Ropivacaine hydrochloride 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. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for days), selective and potent CYPIA2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as tluvoxamine, given concomitantly during administration of ropivacaine hydrochloride, can interact with ropivacaine hydrochloride leading to increased ropivacaine plasma levels. Caution should be exercised when CYPlA2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYPlA2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for days with ropivacaine infusion administered hour after ketoconazole) caused 15% reduction in in vivo plasma clearance of ropivacaine.Patients that 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:ClassExamplesNitrates/Nitritesnitric oxide, nitroglycerin, nitroprusside, nitrous oxideLocal anestheticsarticaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracineAntineoplastic agentscyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicaseAntibioticsdapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamidesAntimalarialschloroquine, primaquineAnticonvulsantsphenobarbital, phenytoin, sodium valproateOther drugsacetaminophen, metoclopramide, quinine, sulfasalazine.
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GENERAL PRECAUTIONS SECTION.
General. The safe and effective use of local anesthetics depends 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). The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse events. Injections should be made slowly and incrementally, with frequent aspirations before and during the injection to avoid intravascular injection. When continuous catheter technique is used, syringe aspirations should also be performed before and during each supplemental injection. During the administration of epidural anesthesia, it is recommended that test dose of local anesthetic with fast onset be administered initially and that the patient be monitored for central nervous system and cardiovascular toxicity, as well as for signs of unintended intrathecal administration 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 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 ropivacaine hydrochloride 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 patients 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 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 standard protocol for MH management should be available.
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GERIATRIC USE SECTION.
Geriatric Use. Of the 2,978 subjects that were administered ropivacaine hydrochloride injection in 71 controlled and uncontrolled clinical studies, 803 patients (27%) were 65 years of age or older which includes 127 patients (4%) 75 years of age and over. Ropivacaine hydrochloride injection was found to be safe and effective in the patients in these studies. 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.This drug and its metabolites are known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased hepatic, renal, or cardiac function, as well as concomitant disease. Therefore, care should be taken in dose selection, starting at the low end of the dosage range, and it may be useful to monitor renal function (see PHARMACOKINETICS, Elimination).
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HOW SUPPLIED SECTION.
HOW SUPPLIED. Ropivacaine Hydrochloride Injection USP, 0.5% (5 mg/mL) is clear, colorless solution supplied in 30 mL single-dose vial packaged individually as follows:NDC 17478-081-30 mg/mL; 30 mL single dose vialThe solubility of ropivacaine is limited at pH above 6. Thus, care must be taken as precipitation may occur if Ropivacaine Hydrochloride is mixed with alkaline solutions.Disinfecting agents containing heavy metals, which cause release of respective ions (mercury, zinc, copper, etc.) should not be used for skin or mucous membrane disinfection since they have been related to incidents of swelling and edema.When chemical disinfection 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 container is required to have sterile outside, Sterile-Pak should be chosen. Glass containers may, as an alternative, be autoclaved once. Stability has been demonstrated using targeted F0 of minutes at 121C.Solutions should be stored at 20o to 25C (68o to 77F) [see USP Controlled Room Temperature].These products are intended for single use 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.AKORNManufactured by: Akorn, Inc. Lake Forest, IL 60045RP00N Rev. 11/19.
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INDICATIONS & USAGE SECTION.
INDICATIONS AND USAGE. Ropivacaine Hydrochloride is indicated for the production of local or regional anesthesia for surgery and for acute pain management.Surgical Anesthesia: epidural block for surgery including cesarean section; major nerve block; local infiltrationAcute Pain Management: epidural continuous infusion or intermittent bolus, eg, postoperative or labor; local infiltration.
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INFORMATION FOR PATIENTS SECTION.
Information for Patients. When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity in the anesthetized part of the body following proper administration of lumbar epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the ropivacaine hydrochloride package insert.Inform patients that use of local anesthetics may cause methemoglobinemia, 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.
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LABOR & DELIVERY SECTION.
Labor and Delivery. Local anesthetics, including ropivacaine, rapidly cross the placenta, and when used for epidural block can cause varying degrees of maternal, fetal and neonatal toxicity (see CLINICAL PHARMACOLOGY and 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 with ropivacaine hydrochloride for obstetrical pain relief. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patients 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 anesthesia has been reported to prolong the second stage of labor by removing the patients reflex urge to bear down or by interfering with motor function. Spontaneous vertex delivery occurred more frequently in patients receiving ropivacaine hydrochloride than in those receiving bupivacaine.
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OVERDOSAGE SECTION.
OVERDOSAGE. Acute emergencies from local anesthetics are generally related to high plasma levels encountered or large doses administered, during therapeutic use of local anesthetics or to unintended subarachnoid or intravascular injection of local anesthetic solution (see ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS).
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PREGNANCY SECTION.
Pregnancy Category B. Reproduction toxicity studies have been performed in pregnant New Zealand white rabbits and Sprague-Dawley rats. During gestation days to 18, rabbits received 1.3, 4.2, or 13 mg/kg/day subcutaneously. In rats, subcutaneous doses of 5.3, 11 and 26 mg/kg/day were administered during gestation days to 15. No teratogenic effects were observed in rats and rabbits at the highest doses tested. The highest doses of 13 mg/kg/day (rabbits) and 26 mg/kg/day (rats) are approximately 1/3 of the maximum recommended human dose (epidural, 770 mg/24 hours) based on mg/m2 basis. In prenatal and postnatal studies, the female rats were dosed daily from day 15 of gestation to day 20 postpartum. The doses were 5.3, 11 and 26 mg/kg/day subcutaneously. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring.In another study with rats, the males were dosed daily for weeks before mating and during mating. The females were dosed daily for weeks before mating and then during the mating, pregnancy, and lactation, up to day 42 post coitus. At 23 mg/kg/day, an increased loss of pups was observed during the first days postpartum. The effect was considered secondary to impaired maternal care due to maternal toxicity.There are no adequate or well-controlled studies in pregnant women of the effects of ropivacaine hydrochloride on the developing fetus. Ropivacaine hydrochloride should only be used during pregnancy if the benefits outweigh the risk.Teratogenicity studies in rats and rabbits did not show evidence of any adverse effects on organogenesis or early fetal development in rats (26 mg/kg sc) or rabbits (13 mg/kg). The doses used were approximately equal to total daily dose based on body surface area. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring in perinatal and postnatal studies in rats, at dose levels equivalent to the maximum recommended human dose based on body surface area. In another study at 23 mg/kg, an increased pup loss was seen during the first days postpartum, which was considered secondary to impaired maternal care due to maternal toxicity.
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SPL UNCLASSIFIED SECTION.
Absorption. The systemic concentration of ropivacaine is dependent on the total dose and concentration of drug administered, the route of administration, the patients hemodynamic/circulatory condition, and the vascularity of the administration site.From the epidural space, ropivacaine shows complete and biphasic absorption. The half-lives of the phases, (mean +- SD) are 14 +- minutes and 4.2 +- 0.9 h, respectively. The slow absorption is the rate limiting factor in the elimination of ropivacaine that explains why the terminal half-life is longer after epidural than after intravenous administration. Ropivacaine shows dose-proportionality up to the highest intravenous dose studied, 80 mg, corresponding to mean +- SD peak plasma concentration of 1.9 +- 0.3 mcg/mL.Table Pharmacokinetic (plasma concentration-time) data from clinical trials Continuous 72 hour epidural infusion after an epidural block with 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). Cmax measured at the end of infusion (ie, at 72 hr). Cmax measured at the end of infusion (ie, at 20 minutes). n/a=not applicable 1/2 is the true terminal elimination half-life. On the other hand, 1/2 follows absorption-dependent elimination (flip-flop) after non-intravenous administration.RouteEpidural InfusionEpidural InfusionEpidural Block+ Epidural Block+ Plexus Block IV Infusion Dose (mg)1493 +- 102075 +- 2061217 +- 277150187.530040N121211881012Cmax (mg/L)2.4 +- 2.8 +- 0.5 2.3 +- 1.1 1.1 +- 0.21.6 +- 0.62.3 +- 0.81.2 +- 0.2 Tmax (min)n/a n/an/a43 +- 1434 +- 954 +- 22n/aAUC0- (mg.h/L)135.5 +- 50145 +- 34161 +- 907.2 +- 211.3 +- 413 +- 3.31.8 +- 0.6CL (L/h)11.0313.7n/a5.5 +- 25 +- 2.6n/a21.2 +- 7t1/2 (hr) +- 2.55.7 +- 36 +- 35.7 +- 27.1 +- 36.8 +- 3.21.9 +- 0.5In some patients after 300 mg dose for brachial plexus block, free plasma concentrations of ropivacaine may approach the threshold for CNS toxicity (see PRECAUTIONS). At dose of greater than 300 mg, for local infiltration, the terminal half-life may be longer (>30 hours).
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WARNINGS SECTION.
WARNINGS. In performing ropivacaine hydrochloride blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardiac arrest. The potential for successful resuscitation has not been studied in humans. There have been rare reports of cardiac arrest during the use of ropivacaine hydrochloride for epidural anesthesia or peripheral nerve blockade, the majority of which occurred after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of successful outcome.Ropivacaine hydrochloride should be administered in incremental doses. It is not recommended for emergency situations, where fast onset of surgical anesthesia is necessary. Historically, pregnant patients were reported to have high risk for cardiac arrhythmias, cardiac/circulatory arrest and death when 0.75% bupivacaine (another 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 that which might 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 ropivacaine hydrochloride 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 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 glenohumeral 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, 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 ropivacaine hydrochloride at volume of 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 to minutes, extended to the T10 level in 10 to 13 minutes and lasted for approximately hours. The results of these two clinical studies showed that 3 mL dose did not produce any serious adverse events when spinal anesthesia blockade was achieved.Ropivacaine hydrochloride 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 (eg, 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 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 and symptoms of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by 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 ropivacaine hydrochloride 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. more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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