Naropin Information
Naropin (Ropivacaine hcl) Description:
Naropin (Ropivacaine hcl) Injection contains ropivacaine HCl, which is a member of the amino amide class of local anesthetics. Naropin (Ropivacaine hcl) 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 a molecular formula of CHNO•HCl•HO, molecular weight of 328.89 and 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.Naropin (Ropivacaine hcl) Injection is preservative-free and is available in single dose containers in 2 (0.2%), 5 (0.5%), 7.5 (0.75%) and 10 mg/mL (1%) concentrations. The specific gravity of Naropin (Ropivacaine hcl) Injection solutions range from 1.002 to 1.005 at 25°C.
Naropin (Ropivacaine hcl) Pharmacokinetics:
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.
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 ). At a dose of greater than 300 mg, for local infiltration, the terminal half-life may be longer (>30 hours).
Ropivacaine was studied as a local anesthetic both for surgical anesthesia and for acute pain management (see ).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. There were 25 clinical studies performed in 900 patients to evaluate Naropin (Ropivacaine hcl) epidural injection for general surgery. Naropin (Ropivacaine hcl) was used in doses ranging from 75 to 250 mg. In doses of 100 to 200 mg, the median (1st-3rd quartile) onset time to achieve a T10 sensory block was 10 (5 to 13) minutes and the median (1st-3rd quartile) duration at the T10 level was 4 (3 to 5) hours (see ). Higher doses produced a more profound block with a greater duration of effect. A total of 12 studies were performed with epidural administration of Naropin (Ropivacaine hcl) for cesarean section. Eight of these studies involved 218 patients using the concentration of 5 mg/mL (0.5%) in doses up to 150 mg. Median onset measured at T6 ranged from 11 to 26 minutes. Median duration of sensory block at T6 ranged from 1.7 to 3.2 h, and duration of motor block ranged from 1.4 to 2.9 h. Naropin (Ropivacaine hcl) provided adequate muscle relaxation for surgery in all cases. In addition, 4 active controlled studies for cesarean section were performed in 264 patients at a concentration of 7.5 mg/mL (0.75%) in doses up to 187.5 mg. Median onset measured at T6 ranged from 4 to 15 minutes. Seventy-seven to 96% of Naropin (Ropivacaine hcl) -exposed patients reported no pain at delivery. Some patients received other anesthetic, analgesic, or sedative modalities during the course of the operative procedure. A total of 9 double-blind clinical studies, involving 240 patients were performed to evaluate Naropin (Ropivacaine hcl) for epidural block for management of labor pain. When administered in doses up to 278 mg as intermittent injections or as a continuous infusion, Naropin (Ropivacaine hcl) produced adequate pain relief.A prospective meta-analysis on 6 of these studies provided detailed evaluation of the delivered newborns and showed no difference in clinical outcomes compared to bupivacaine. There were significantly fewer instrumental deliveries in mothers receiving ropivacaine as compared to bupivacaine.
Naropin (Ropivacaine hcl) Indications And Usage:
Naropin (Ropivacaine hcl) is indicated for the production of local or regional anesthesia for surgery and for acute pain management.
Surgical Anesthesia: epidural block for surgery including cesarean section; major nerve block; local infiltrationAcute Pain Management: epidural continuous infusion or intermittent bolus, eg, postoperative or labor; local infiltration
Naropin (Ropivacaine hcl) Contraindications:
Naropin (Ropivacaine hcl) is contraindicated in patients with a known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide type.
Naropin (Ropivacaine hcl) Warnings:
In performing Naropin (Ropivacaine hcl) 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 Naropin (Ropivacaine hcl) 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. Naropin (Ropivacaine hcl) 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. Prior to receiving major blocks the general condition of the patient should be optimized and the patient should have an i.v. 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 ensuring the 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 , , and ). Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. Solutions of Naropin (Ropivacaine hcl) 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 ensure against an intravascular or subarachnoid injection. A well-known risk of epidural anesthesia may be an unintentional subarachnoid injection of local anesthetic. Two clinical studies have been performed to verify the safety of Naropin (Ropivacaine hcl) at a volume of 3 mL injected into the subarachnoid space since this dose represents an incremental epidural volume that could be unintentionally injected. The 15 and 22.5 mg doses injected resulted in sensory levels as high as T5 and T4, respectively. Anesthesia to pinprick started in the sacral dermatomes in 2 to 3 minutes, extended to the T10 level in 10 to 13 minutes and lasted for approximately 2 hours. The results of these two clinical studies showed that a 3 mL dose did not produce any serious adverse events when spinal anesthesia blockade was achieved. Naropin (Ropivacaine hcl) 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.
Naropin (Ropivacaine hcl) 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 Naropin (Ropivacaine hcl) at concentrations up to 1% in clinical trials. Each patient was counted once for each type of adverse event.
The following adverse events were reported during the Naropin (Ropivacaine hcl) clinical program in more than one patient (N=3988), occurred at an overall incidence of
Using data from the same studies, the number (%) of patients experiencing hypotension is displayed by patient age, drug and concentration in Table 5. In Table 6, the adverse events for Naropin (Ropivacaine hcl) are broken down by gender.
Naropin (Ropivacaine hcl) 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 , , and ).
Naropin (Ropivacaine hcl) Management Of Local Anesthetic Emergencies:
Therapy with Naropin (Ropivacaine hcl) should be discontinued at the first sign of toxicity. No specific information is available for the treatment of toxicity with Naropin (Ropivacaine hcl) ; therefore, treatment should be symptomatic and supportive. The first consideration is prevention, best accomplished by incremental injection of Naropin (Ropivacaine hcl) , careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic and during continuous infusion. At the first sign of change in mental status, oxygen should be administered. The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Circulation should be assisted as necessary. This may prevent convulsions if they have not already occurred. If necessary, use drugs to control convulsions. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome. The mean dosages of ropivacaine producing seizures, after intravenous infusion in dogs, nonpregnant and pregnant sheep were 4.9, 6.1 and 5.9 mg/kg, respectively. These doses were associated with peak arterial total plasma concentrations of 11.4, 4.3 and 5 mcg/mL, respectively. In human volunteers given intravenous Naropin (Ropivacaine hcl) , the mean (min-max) maximum tolerated total and free arterial plasma concentrations were 4.3 (3.4 to 5.3) and 0.6 (0.3 to 0.9) mcg/mL respectively, at which time moderate CNS symptoms (muscle twitching) were noted. Clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen, which may avoid cardiac arrest. If difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated, endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels should be accomplished. Resuscitation of obstetrical patients may take longer than resuscitation of non-pregnant patients and closed-chest cardiac compression may be ineffective. Rapid delivery of the fetus may improve the response to resuscitative efforts.
Naropin (Ropivacaine hcl) 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. 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. 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.
The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration occur. The figures reflect the expected average dose range needed. For other local anesthetic techniques standard current textbooks should be consulted. When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. Experience to date indicates that a cumulative dose of up to 770 mg Naropin (Ropivacaine hcl) administered over 24 hours is well tolerated in adults when used for postoperative pain management: ie, 2016 mg. Caution should be exercised when administering Naropin (Ropivacaine hcl) 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 Naropin (Ropivacaine hcl) is induced via an epidural catheter. Analgesia is maintained with an infusion of Naropin (Ropivacaine hcl) , 2 mg/mL (0.2%). Clinical studies have demonstrated that infusion rates of 6 to 14 mL (12 to 28 mg) per hour provide adequate analgesia with nonprogressive motor block. With this technique a significant reduction in the need for opioids was demonstrated. Clinical experience supports the use of Naropin (Ropivacaine hcl) epidural infusions for up to 72 hours.
Naropin (Ropivacaine hcl) How Supplied:
The solubility of ropivacaine is limited at pH above 6. Thus, care must be taken as precipitation may occur if Naropin (Ropivacaine hcl) 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 required to have a sterile outside, a Sterile-Pak should be chosen. Glass containers may, as an alternative, be autoclaved once. Stability has been demonstrated using a targeted F of 7 minutes at 121°C. Solutions should be stored at 20º to 25°C (68º to 77°F) [see USP Controlled Room Temperature]. Vial stoppers do not contain natural rubber latex. 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. Naropin (Ropivacaine hcl) is a trademark of APP Pharmaceuticals, LLC.
Distributed by: Novation, the supply company of VHA and UHC, and NOVAPLUS are trademarks of Novation, LLC.
451113/Issued: April 2009
Naropin (Ropivacaine hcl)
