Ropivacaine Hydrochloride


Akorn
Human Prescription Drug
NDC 17478-081
Ropivacaine Hydrochloride is a human prescription drug labeled by 'Akorn'. National Drug Code (NDC) number for Ropivacaine Hydrochloride is 17478-081. This drug is available in dosage form of Injection, Solution. The names of the active, medicinal ingredients in Ropivacaine Hydrochloride drug includes Ropivacaine Hydrochloride - 5 mg/mL . The currest status of Ropivacaine Hydrochloride drug is Active.

Drug Information:

Drug NDC: 17478-081
The labeler code and product code segments of the National Drug Code number, separated by a hyphen. Asterisks are no longer used or included within the product code segment to indicate certain configurations of the NDC.
Proprietary Name: Ropivacaine Hydrochloride
Also known as the trade name. It is the name of the product chosen by the labeler.
Product Type: Human Prescription Drug
Indicates the type of product, such as Human Prescription Drug or Human OTC Drug. This data element corresponds to the “Document Type” of the SPL submission for the listing.
Non Proprietary Name: Ropivacaine Hydrochloride
Also known as the generic name, this is usually the active ingredient(s) of the product.
Labeler Name: Akorn
Name of Company corresponding to the labeler code segment of the ProductNDC.
Dosage Form: Injection, Solution
The translation of the DosageForm Code submitted by the firm. There is no standard, but values may include terms like `tablet` or `solution for injection`.The complete list of codes and translations can be found www.fda.gov/edrls under Structured Product Labeling Resources.
Status: Active
FDA does not review and approve unfinished products. Therefore, all products in this file are considered unapproved.
Substance Name:ROPIVACAINE HYDROCHLORIDE - 5 mg/mL
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.
Route Details:EPIDURAL
INFILTRATION
PERINEURAL
The translation of the Route Code submitted by the firm, indicating route of administration. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Marketing Information:

An openfda section: An annotation with additional product identifiers, such as NUII and UPC, of the drug product, if available.
Marketing Category: ANDA
Product types are broken down into several potential Marketing Categories, such as New Drug Application (NDA), Abbreviated New Drug Application (ANDA), BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.
Marketing Start Date: 11 Apr, 2016
This is the date that the labeler indicates was the start of its marketing of the drug product.
Marketing End Date: 31 Dec, 2025
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.
Application Number: ANDA203955
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.
Listing Expiration Date: 31 Dec, 2023
This is the date when the listing record will expire if not updated or certified by the firm.

OpenFDA Information:

An openfda section: An annotation with additional product identifiers, such as NUII and UPC, of the drug product, if available.
Manufacturer Name:Akorn
Name of manufacturer or company that makes this drug product, corresponding to the labeler code segment of the NDC.
RxCUI:1734475
The RxNorm Concept Unique Identifier. RxCUI is a unique number that describes a semantic concept about the drug product, including its ingredients, strength, and dose forms.
Original Packager:Yes
Whether or not the drug has been repackaged for distribution.
UPC:0317478081302
UPC stands for Universal Product Code.
UNII:V910P86109
Unique Ingredient Identifier, which is a non-proprietary, free, unique, unambiguous, non-semantic, alphanumeric identifier based on a substance’s molecular structure and/or descriptive information.
Pharmacologic Class:Amide Local Anesthetic [EPC]
Amides [CS]
Local Anesthesia [PE]
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

Packaging Information:

Package NDCDescriptionMarketing Start DateMarketing End DateSample Available
17478-081-301 VIAL, SINGLE-DOSE in 1 CARTON (17478-081-30) / 30 mL in 1 VIAL, SINGLE-DOSE11 Apr, 2016N/ANo
Package NDC number, known as the NDC, identifies the labeler, product, and trade package size. The first segment, the labeler code, is assigned by the FDA. Description tells the size and type of packaging in sentence form. Multilevel packages will have the descriptions concatenated together.

Product Elements:

Ropivacaine hydrochloride ropivacaine hydrochloride ropivacaine hydrochloride ropivacaine sodium chloride water sodium hydroxide hydrochloric acid

Drug Interactions:

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 2 days), a 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 i
nteractions with drugs known to be metabolized by cypla2 via competitive inhibition such as theophylline and imipramine may also occur. coadministration of a selective and potent inhibitor of cyp3a4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 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: class examples nitrates/nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracine antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides antimalarials chloroquine, primaquine anticonvulsants phenobarbital, phenytoin, sodium valproate other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

Indications and Usage:

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 infiltration acute pain management: epidural continuous infusion or intermittent bolus, eg, postoperative or labor; local infiltration

Warnings:

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 a successful outcome. ropivacaine hydrochloride should be administered in incremental doses. it is not recommended for emergency situations, where a fast onset of surgical anesthesia is necessary. historically, pregnant patients were reported to have a high risk for cardiac arrhythmias, cardiac/circula
tory 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 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 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 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 ropivacaine hydrochloride 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. 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 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 and symptoms 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 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. a more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

General 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 a 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 a test dose of a local anesthetic with a 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 administrati
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 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 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.

Dosage and Administration:

Dosage and administration the rapid injection of a 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 par
tial 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 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 * = 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 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. 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 (eg, 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 (eg, 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 continuous infusion § 2 (0.2%) 6 to 14 ml/h 12 to 28 mg/h n/a* n/a* infiltration 2 (0.2%) 1 to 100 2 to 200 1 to 5 2 to 6 (eg, minor nerve block) 5 (0.5%) 1 to 40 5 to 200 1 to 5 2 to 6 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 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 5 to 7 ml ropivacaine hydrochloride is induced via an epidural catheter. analgesia is maintained with an infusion of ropivacaine hydrochloride, 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 ropivacaine hydrochloride epidural infusions for up to 72 hours.

Contraindications:

Contraindications ropivacaine hydrochloride is contraindicated in patients with a known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide type.

Adverse Reactions:

Adverse reactions: reactions to ropivacaine are characteristic of those associated with other amide‑type local anesthetics. a 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 a variety of premedications, sedatives, and surgical procedures of varying length. a 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 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 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 5 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 reaction ropivacaine hydrochloride 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 ropivacaine hydrochloride 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 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 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 ropivacaine hydrochloride and bupivacaine. table 4 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 4 common events (epidural administration) adverse reaction ropivacaine hydrochloride bupivacaine 5 mg/ml total n=256 5 mg/ml total n=236 n (%) n (%) hypotension 99 (38.7) 91 (38.6) nausea 34 (13.3) 41 (17.4) bradycardia 29 (11.3) 32 (13.6) back pain 18 (7) 21 (8.9) vomiting 18 (7) 19 (8.1) headache 12 (4.7) 13 (5.5) fever 8 (3.1) 11 (4.7) chills 6 (2.3) 4 (1.7) urinary retention 5 (2) 10 (4.2) paresthesia 5 (2) 7 (3) pruritus 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 ropivacaine hydrochloride are broken down by gender. table 5 effects of age on hypotension (epidural administration) total n: ropivacaine hydrochloride = 760, bupivacaine = 410 age ropivacaine hydrochloride bupivacaine 5 mg/ml 5 mg/ml n (%) n (%) <65 68 (32.2) 64 (33.5) ≥65 31 (68.9) 27 (60) 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 ropivacaine hydrochloride 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 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, 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 ropivacaine hydrochloride 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.

Adverse Reactions Table:

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=1661Bupivacaine 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 ReactionRopivacaine Hydrochloride total N=639Bupivacaine 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)

Table 4 Common Events (Epidural Administration)
Adverse ReactionRopivacaine HydrochlorideBupivacaine
5 mg/mL total N=2565 mg/mL total N=236
N(%)N(%)
hypotension 99 (38.7) 91 (38.6)
nausea 34 (13.3) 41 (17.4)
bradycardia 29 (11.3) 32 (13.6)
back pain 18 (7) 21 (8.9)
vomiting 18 (7) 19 (8.1)
headache 12 (4.7) 13 (5.5)
fever 8 (3.1) 11 (4.7)
chills 6 (2.3) 4 (1.7)
urinary retention 5 (2) 10 (4.2)
paresthesia 5 (2) 7 (3)
pruritus

Table 5 Effects of Age on Hypotension (Epidural Administration) Total N: Ropivacaine Hydrochloride = 760, Bupivacaine = 410
AGERopivacaine HydrochlorideBupivacaine
5 mg/mL5 mg/mL
N (%) N (%)
<65 68 (32.2) 64 (33.5)
≥65 31 (68.9) 27 (60)

Table 6 Most Common Adverse Events by Gender (Epidural Administration) Total N: Females = 405, Males = 355
Adverse ReactionFemaleMale
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)

Drug Interactions:

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 2 days), a 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 i
nteractions with drugs known to be metabolized by cypla2 via competitive inhibition such as theophylline and imipramine may also occur. coadministration of a selective and potent inhibitor of cyp3a4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 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: class examples nitrates/nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracine antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides antimalarials chloroquine, primaquine anticonvulsants phenobarbital, phenytoin, sodium valproate other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

Use in Pregnancy:

Pregnancy category b reproduction toxicity studies have been performed in pregnant new zealand white rabbits and sprague‑dawley rats. during gestation days 6 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 6 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 a mg/m 2 basis. in 2 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 9 weeks before mating a
nd during mating. the females were dosed daily for 2 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 3 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 2 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 3 days postpartum, which was considered secondary to impaired maternal care due to maternal toxicity.

Pediatric Use:

Pediatric use the safety and efficacy of ropivacaine hydrochloride in pediatric patients have not been established.

Geriatric Use:

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 ).

Overdosage:

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 ).

Description:

Description ropivacaine hydrochloride injection contains ropivacaine hcl which is a member of the amino amide class of local anesthetics. ropivacaine hydrochloride injection is a 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 a white crystalline powder, with the following structural formula: at 25°c ropivacaine hcl has a solubility of 53.8 mg/ml in water, a distribution ratio between n‑octanol and phosphate buffer at ph 7.4 of 14:1 and a pka of 8.07 in 0.1 m 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 a single dose container in 5 mg/ml (0.5%) concentration. the specific gravity of ropivacaine hydrochloride injection solutions range from 1.002 to 1.005 at 25°c. structural formula

Clinical Pharmacology:

Clinical pharmacology mechanism of action ropivacaine is a 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.

Mechanism of Action:

Mechanism of action ropivacaine is a 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.

Pharmacodynamics:

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, eg, 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.

Pharmacokinetics:

Pharmacokinetics absorption the systemic concentration of ropivacaine is dependent on the total dose and concentration of drug administered, the route of administration, the patient's 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 2 phases, (mean ± sd) are 14 ± 7 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 a mean ± sd peak plasma concentration of 1.9 ± 0.3 mcg/ml. table 1 pharmacokinetic (plasma concentration-time) data from clinical trials * continuous 72 hour epidural infusion after an epidural block with 5 or 10 mg/ml. † epidural anesthe
sia 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 (ie, at 72 hr). # c max measured at the end of infusion (ie, 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. route epidural infusion* epidural infusion* epidural block † epidural block † plexus block ‡ iv infusion § 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 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, 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 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 ).

Carcinogenesis and Mutagenesis and Impairment of Fertility:

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 2 generations.

Clinical Studies:

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 5 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 reaction ropivacaine hydrochloride 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 ropivacaine hydrochloride 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)

How Supplied:

How supplied ropivacaine hydrochloride injection usp, 0.5% (5 mg/ml) is a clear, colorless solution supplied in 30 ml single-dose vial packaged individually as follows: ndc 17478‑081‑30 5 mg/ml; 30 ml single dose vial the 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 a container is requir
ed 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]. 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. akorn manufactured by: akorn, inc. lake forest, il 60045 rp00n rev. 11/19

Information for Patients:

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, a serious condition that must be treated promptly. advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

Package Label Principal Display Panel:

Principal display panel text for container label: ndc 17478-081-30 ropivacaine hcl injection, usp 0.5% 150 mg/30 ml (5 mg/ml) for infiltration, nerve block and epidural administration only. not for intravenous administration. 30 ml single-dose vial principal display panel text for container label

Principal display panel text for carton label: ndc 17478-081-30 ropivacaine hcl injection, usp 0.5% 150 mg/30 ml (5 mg/ml) for infiltration, nerve block and epidural administration only. not for intravenous administration. 30 ml single-dose vial rx only akorn logo principal display panel text for carton label


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