Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Ropivacaine Hydrochloride Injection, USP is a clear colorless, and preservative-free solution, available in single-dose containers in 2 mg/mL(0.2%), 5 mg/mL (0.5%), and 10 mg/mL (1%) concentrations. Storage Solutions should be stored at 20ºC to 25°C (68 ºF to 77 °F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Ropivacaine Hydrochloride Injection, USP Single Dose Vials Unit of Sale Product Code Strength Each NDC 83854-013-26 Unit of 25 032 0.2% 20 mg per 10 mL (2 mg per mL) NDC 83854-013-02 10 mL single dose vial NDC 83854-013-10 Unit of 10 033 0.2% 40 mg per 20 mL (2 mg per mL) NDC 83854-013-01 20 mL single dose vial NDC 83854-013-25 Unit of 25 NDC 83854-014-26 Unit of 10 34 0.5% 100 mg per 20 mL (5 mg per mL) NDC 83854-014-02 20 mL single dose vial NDC 83854-014-25 Unit of 25 NDC 83854-014-05 Unit of 5 035 0.5% 150 mg per 30 mL (5 mg per mL) NDC 83854-014-01 30 mL single dose vial NDC 83854-014-10 Unit of 10 NDC 83854-014-06 Unit of 25 NDC 83854-015-25 Unit of 25 036 1% 200 mg per 20 mL (10 mg per mL) NDC 83854-015-01 20 mL single dose vial Ropivacaine Hydrochloride injection container closure is not made with natural rubber latex. Single Dose Only - Discard unused portion.; PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection, USP 10 mL Single Dose Vial Label NDC 83854-013-02 Ropivacaine Hydrochloride Injection, USP 0.2% 20 mg per 10 mL (2 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. 10 mL Single Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection, USP 10 mL Single Dose Carton Label Panel NDC 83854-013-26 Ropivacaine Hydrochloride Injection, USP 0.2% 20 mg per 10 mL (2 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. Rx only Twenty-five 10 mL Single Dose Vials PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 20 mL Single-Dose Vial Label NDC 83854-013-01 Ropivacaine Hydrochloride Injection USP, 0.2% 40 mg per 20 mL (2 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. 20 mL Single-Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 20 mL Single Dose Carton Label Panel NDC 83854-013-25 Ropivacaine Hydrochloride Injection USP, 0.2% 40 mg per 20 mL (2 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. Rx only Twenty-five 20 mL Single-Dose Vials PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection, USP 20 mL Single Dose Vial Label NDC 83854-014-02 Ropivacaine Hydrochloride Injection, USP 0.5% 100 mg per 20 mL (5 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. 20 mL Single Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection, USP 20 mL Single Dose Carton Label Panel NDC 83854-014-25 Ropivacaine Hydrochloride Injection, USP 0.5% 100 mg per 20 mL (5 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. Rx only Twenty-five 20 mL Single Dose Vials PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 30 mL Single Dose Vial Label NDC 83854-014-01 Ropivacaine Hydrochloride Injection USP, 0.5% 150 mg per 30 mL (5 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. 30 mL Single Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 30 mL Single Dose Vial Carton Panel NDC 83854-014-05 Ropivacaine Hydrochloride Injection USP, 0.5% 150 mg per 30 mL (5 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. Rx only Contains Five Presterilized 30 mL Single Dose Vials PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 20 mL Single Dose Vial Label NDC 83854-015-01 Ropivacaine Hydrochloride Injection USP, 1% 200 mg per 20 mL (10 mg per mL) For Epidural Administration Only. Not for Intravenous Administration. 20 mL Single Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 20 mL Single Dose Carton Label Panel NDC 83854-015-25 Ropivacaine Hydrochloride Injection USP, 1% 200 mg per 20 mL (10 mg per mL) For Epidural Administration Only. Not for Intravenous Administration. Rx only Twenty-five 20 mL Single Dose Vials "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description"
- 16 HOW SUPPLIED/STORAGE AND HANDLING Ropivacaine Hydrochloride Injection, USP is a clear colorless, and preservative-free solution, available in single-dose containers in 2 mg/mL(0.2%), 5 mg/mL (0.5%), and 10 mg/mL (1%) concentrations. Storage Solutions should be stored at 20ºC to 25°C (68 ºF to 77 °F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Ropivacaine Hydrochloride Injection, USP Single Dose Vials Unit of Sale Product Code Strength Each NDC 83854-013-26 Unit of 25 032 0.2% 20 mg per 10 mL (2 mg per mL) NDC 83854-013-02 10 mL single dose vial NDC 83854-013-10 Unit of 10 033 0.2% 40 mg per 20 mL (2 mg per mL) NDC 83854-013-01 20 mL single dose vial NDC 83854-013-25 Unit of 25 NDC 83854-014-26 Unit of 10 34 0.5% 100 mg per 20 mL (5 mg per mL) NDC 83854-014-02 20 mL single dose vial NDC 83854-014-25 Unit of 25 NDC 83854-014-05 Unit of 5 035 0.5% 150 mg per 30 mL (5 mg per mL) NDC 83854-014-01 30 mL single dose vial NDC 83854-014-10 Unit of 10 NDC 83854-014-06 Unit of 25 NDC 83854-015-25 Unit of 25 036 1% 200 mg per 20 mL (10 mg per mL) NDC 83854-015-01 20 mL single dose vial Ropivacaine Hydrochloride injection container closure is not made with natural rubber latex. Single Dose Only - Discard unused portion.
- PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection, USP 10 mL Single Dose Vial Label NDC 83854-013-02 Ropivacaine Hydrochloride Injection, USP 0.2% 20 mg per 10 mL (2 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. 10 mL Single Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection, USP 10 mL Single Dose Carton Label Panel NDC 83854-013-26 Ropivacaine Hydrochloride Injection, USP 0.2% 20 mg per 10 mL (2 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. Rx only Twenty-five 10 mL Single Dose Vials PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 20 mL Single-Dose Vial Label NDC 83854-013-01 Ropivacaine Hydrochloride Injection USP, 0.2% 40 mg per 20 mL (2 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. 20 mL Single-Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 20 mL Single Dose Carton Label Panel NDC 83854-013-25 Ropivacaine Hydrochloride Injection USP, 0.2% 40 mg per 20 mL (2 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. Rx only Twenty-five 20 mL Single-Dose Vials PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection, USP 20 mL Single Dose Vial Label NDC 83854-014-02 Ropivacaine Hydrochloride Injection, USP 0.5% 100 mg per 20 mL (5 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. 20 mL Single Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection, USP 20 mL Single Dose Carton Label Panel NDC 83854-014-25 Ropivacaine Hydrochloride Injection, USP 0.5% 100 mg per 20 mL (5 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. Rx only Twenty-five 20 mL Single Dose Vials PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 30 mL Single Dose Vial Label NDC 83854-014-01 Ropivacaine Hydrochloride Injection USP, 0.5% 150 mg per 30 mL (5 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. 30 mL Single Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 30 mL Single Dose Vial Carton Panel NDC 83854-014-05 Ropivacaine Hydrochloride Injection USP, 0.5% 150 mg per 30 mL (5 mg per mL) For Infiltration, Nerve Block, and Epidural Administration Only. Not for Intravenous Administration. Rx only Contains Five Presterilized 30 mL Single Dose Vials PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 20 mL Single Dose Vial Label NDC 83854-015-01 Ropivacaine Hydrochloride Injection USP, 1% 200 mg per 20 mL (10 mg per mL) For Epidural Administration Only. Not for Intravenous Administration. 20 mL Single Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Ropivacaine Hydrochloride Injection 20 mL Single Dose Carton Label Panel NDC 83854-015-25 Ropivacaine Hydrochloride Injection USP, 1% 200 mg per 20 mL (10 mg per mL) For Epidural Administration Only. Not for Intravenous Administration. Rx only Twenty-five 20 mL Single Dose Vials "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description"
Overview
Ropivacaine Hydrochloride Injection, USP is a sterile, isotonic solution that contains ropivacaine hydrochloride as the active pharmaceutical ingredient. Ropivacaine hydrochloride is a member of the amino amide class of local anesthetics. Ropivacaine Hydrochloride Injection,USP is administered parenterally by for infiltration, epidural, and nerve block. Ropivacaine hydrochloride 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: C 17 H 26 N 2 O•HCl•H 2 O M.W. 328.89 At 25 °C ropivacaine hydrochloride 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, USP is a clear, colorless, and preservative-free solution. Each mL contains 2.1 mg, 5.3 mg or 10.6 mg ropivacaine hydrochloride monohydrate (equivalent to 2.0 mg, 5.0 mg or 10 mg of ropivacaine hydrochloride anhydrous), and 8.6 mg, 8.0 mg or 7.1 mg of sodium chloride; respectively, and sodium hydroxide and hydrochloric acid as pH adjusters, in water for injection. The pH is adjusted between 4.0 to 6.0. The specific gravity of Ropivacaine Hydrochloride Injection, USP solutions range from 1.002 to 1.005 at 25°C. "Image Description"
Indications & Usage
Ropivacaine Hydrochloride Injection 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, e.g., postoperative or labor; local infiltration Ropivacaine Hydrochloride is an amide local anesthetic indicated in adults for the production of local or regional anesthesia for surgery and for acute pain management. ( 1 ) Surgical Anesthesia: epidural block for surgery including cesarean section; major nerve block; local infiltration. ( 1 ) Acute Pain Management: epidural continuous infusion or intermittent bolus, e.g., postoperative or labor; local infiltration. ( 1 )
Dosage & Administration
See Table 1 for Dosage Recommendations. ( 2.2 ) 2.1 Important Administration Instructions 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 Injection is not approved for this use [see Warnings and Precautions ( 5.3 )]. 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. 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 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. These products are intended for single-dose and are free from preservatives. Any solution remaining from an opened container should be discarded promptly. 2.2 Dosage Recommendations Table 1 Dosage Recommendations SURGICAL ANESTHESIA Conc. Volume mL Dose mg Onset min Duration hours mg/mL (%) Lumbar Epidural Administration Surgery 5 (0.5%) 15 to 30 75 to 150 15 to 30 2 to 4 10 (1%) 15 to 20 150 to 200 10 to 20 4 to 6 Lumbar Epidural Administration Cesarean Section 5 (0.5%) 20 to 30 100 to 150 15 to 25 2 to 4 Thoracic Epidural Administration Surgery 5 (0.5%) 5 to 15 25 to 75 10 to 20 n/a* Major Nerve Block † (e.g., brachial plexus block) 5 (0.5%) 35 to 50 175 to 250 15 to 30 5 to 8 Field Block (e.g., minor nerve blocks and infiltration) 5 (0.5%) 1 to 40 5 to 200 1 to 15 2 to 6 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 § Infiltration (e.g., minor nerve block) 2 (0.2%) 6 to 14 mL/h 12 to 28 mg/h n/a* n/a* 2 (0.2%) 1 to 100 2 to 200 1 to 5 2 to 6 5 (0.5%) 1 to 40 5 to 200 1 to 5 2 to 6 * = Not Applicable † = The dose for a major nerve block must be adjusted according to site of administration and patient status. Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used [see Warnings and Precautions ( 5.7 )]. ‡ = 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, i.e., 2016 mg plus surgical dose of approximately 100 to 150 mg as top-up. The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration occur. The figures reflect the expected average dose range needed. For other local anesthetic techniques standard current text books 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 Injection administered over 24 hours is well tolerated in adults when used for postoperative pain management: i.e., 2016 mg. Caution should be exercised when administering Ropivacaine Hydrochloride Injection for prolonged periods of time, e.g., >70 hours in debilitated patients. For treatment of postoperative pain, the following technique can be recommended: If regional anesthesia was not used intraoperatively, then an initial epidural block with 5 to 7 mL Ropivacaine Hydrochloride Injection is induced via an epidural catheter. Analgesia is maintained with an infusion of Ropivacaine Hydrochloride Injection, 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 Injection epidural infusions for up to 72 hours. 2.3 Other Administration Considerations 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 polypropylene ampule or vial stopper thoroughly with cotton or gauze that has been moistened with the recommended alcohol just prior to use. When a container is required to have a sterile outside, a Sterile-Pak should be chosen. Glass containers may, as an alternative, be autoclaved once. Stability has been demonstrated using a targeted F0 of 7 minutes at 121°C. The solubility of ropivacaine is limited at pH above 6. Thus, care must be taken as precipitation may occur if Ropivacaine Hydrochloride Injection is mixed with alkaline solutions. 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.
Warnings & Precautions
Delay in proper management of dose-related toxicity, under ventilation, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. ( 5.1 ) In performing Ropivacaine Hydrochloride blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardiac arrest. ( 5.2 ) Intra-articular infusions of local anesthetics may cause chondrolysis. Ropivacaine Hydrochloride is not approved for this use. ( 5.3 ). Signs of methemoglobinemia may occur. ( 5.4 ) 5.1 General Warnings and Precautions Prior to receiving major blocks the general condition of the patient should be optimized and the patient should have an IV line inserted. All necessary precautions should be taken to avoid intravascular injection. Local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate (without delay) availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnelresources needed for proper management of toxic reactions and related emergencies [see Adverse Reactions ( 6) and Overdosage ( 10.1 )]. 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. 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 Adverse Reactions ( 6 )]. 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 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 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. 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. 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. 5.2 Unintended Intravenous Injection 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 berequired 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/circulatory arrest and death when 0.75% bupivacaine (another member of the amino amide class of local anesthetics) was inadvertently rapidly injected intravenously. 5.3 Intra-Articular Infusions and Risk of Chondrolysis Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd monthafter 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. 5.4 Risk of Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue 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. 5.5 Central Nervous System Toxicity 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. 5.6 Epidural Anesthesia 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. During epidural administration, Ropivacaine Hydrochloride should be administered in incremental doses of 3 to 5 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 a 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 a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a 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 a 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 a heart rate increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring candetect a rise in systolic blood pressure. A test dose of a short-acting amide anesthetic such as lidocaine is recommended to detect an unintentional intrathecal administration. This will be manifested within a few minutes by signs of spinal block (e.g., 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 a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects. 5.7 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 ( 10 )]. The dose for a major nerve block must be adjusted according to the 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. 5.8 Use in Peripheral Nerve Block Major peripheral nerve blocks may result in the administration of a 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. 5.9 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 ( 2.2 )]. 5.10 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. 5.11 Hepatic Disease 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. 5.12 Cardiovascular Impairment 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. 5.13 Risk of Additive Effects 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. [See Drug Interactions 7.0 ] Patients treated with class III antiarrhythmic drugs (e.g., amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive. [See Drug Interactions 7.0 ] 5.14 Malignant Hyperthermia 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.
Contraindications
Ropivacaine Hydrochloride is contraindicated in patients with a known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide type. History of hypersensitivity to local anesthetics of the amide type. ( 4 )
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. Because clinical trials are conducted under widely conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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 2 and Table 3 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 2 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 3 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 7.5 mg/mL total N=297 10 mg/mL total N=207 5 mg/mL total N=236 7.5 mg/mL total N=174 N (%) N (%) N (%) N (%) N (%) hypotension 99 (38.7) 146 (49.2) 113 (54.6) 91 (38.6) 89 (51.1) nausea 34 (13.3) 68 (22.9) 41 (17.4) 36 (20.7) bradycardia 29 (11.3) 58 (19.5) 40 (19.3) 32 (13.6) 25 (14.4) back pain 18 (7) 23 (7.7) 34 (16.4) 21 (8.9) 23 (13.2) vomiting 18 (7) 33 (11.1) 23 (11.1) 19 (8.1) 14 (8) headache 12 (4.7) 20 (6.7) 16 (7.7) 13 (5.5) 9 (5.2) fever 8 (3.1) 5 (1.7) 18 (8.7) 11 (4.7) chills 6 (2.3) 7 (2.4) 6 (2.9) 4 (1.7) 3 (1.7) urinary retention 5 (2) 8 (2.7) 10 (4.8) 10 (4.2) paresthesia 5 (2) 10 (3.4) 5 (2.4) 7 (3) pruritus 14 (4.7) 3 (1.4) 7 (4) Using data from the same studies, the number (%) of patients experiencing hypotension is displayed by patient age, drug and concentration in Table 5. In Table 6, the adverse events for 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 7.5 mg/mL 10 mg/mL 5 mg/mL 7.5 mg/mL N (%) N (%) N (%) N (%) N (%) < 65 68 (32.2) 99 (43.2) 87 (51.5) 64 (33.5) 73 (48.3) ≥ 65 31 (68.9) 47 (69.1) 26 (68.4) 27 (60) 16 (69.6) Table 6 Most Common Adverse Events by Gender (Epidural Administration) Total N: Females = 405, Males = 355 Adverse Reaction Female Male N (%) N (%) hypotension 220 (54.3) 138 (38.9) nausea 119 (29.4) 23 (6.5) bradycardia 65 (16) 56 (15.8) vomiting 59 (14.6) 8 (2.3) back pain 41 (10.1) 23 (6.5) headache 33 (8.1) 17 (4.8) chills 18 (4.4) 5 (1.4) fever 16 (4) 3 (0.8) pruritus 16 (4) 1 (0.3) pain 12 (3) 4 (1.1) urinary retention 11 (2.7) 7 (2) dizziness 9 (2.2) 4 (1.1) hypoesthesia 8 (2) 2 (0.6) paresthesia 8 (2) 10 (2.8) Systemic Reactions The most commonly encountered acute adverse experiences that demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose-related and due to high plasma levels that may result from overdosage, rapid absorption from the injection site, diminished tolerance or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea ("Total or High Spinal"). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Factors influencing plasma protein binding, such as acidosis, systemic diseases that alter protein production or competition with other drugs for protein binding sites, may diminish individual tolerance. Epidural administration of 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 lowerextremities, 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 ( 2.1 )]. 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 and Precautions ( 5.2 ) and Overdosage ( 10 )]. Allergic Reactions Allergic type reactions are rare and may occur as a result of sensitivity to the local anesthetic [see Warnings and Precautions ( 5.1 )]. 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. Most common adverse reactions (incidence ≥ 5%) are hypotension, nausea, vomiting, bradycardia, fever, pain, postoperative complications, anemia, paresthesia, headache, pruritus, and back pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Anthea Pharma Private Limited at 1-8xx-xxx-xxxx or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [see Warnings and Precautions ( 5.4 )]: Examples of Drugs Associated with Methemoglobinemia Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 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 CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine Hydrochloride, can interact with Ropivacaine Hydrochloride leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 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. Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (e.g., amiodarone) have not been performed, but caution is advised [see Warnings and Precautions ( 5.13 )]. Agents structurally related to amide-type local anesthetics: Concurrent use may cause additive effects. ( 7 )
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