Naropin ® Injection contains ropivacaine HCl which is a member of the amino amide class of local anesthetics. Naropin 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.

Naropin 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 Injection solutions range from 1.002 to 1.005 at 25°C.

Mechanism of Action

* Continuous 72 hour epidural infusion after an epidural block with 5 or 10 mg/mL.

Epidural anesthesia with Naropin 5 mg/mL, (0.5%) was used intraoperatively for each of these procedures prior to initiation of postoperative Naropin. The incidence and intensity of the motor block were dependent on the dose rate of Naropin and the site of injection. Cumulative doses of up to 770 mg of ropivacaine were administered over 24 hours (intraoperative block plus postoperative continuous infusion). The overall quality of pain relief, as judged by the patients, in the ropivacaine groups was rated as good or excellent (73% to 100%). The frequency of motor block was greatest at 4 hours and decreased during the infusion period in all groups. At least 80% of patients in the upper and lower abdominal studies and 42% in the orthopedic studies had no motor block at the end of the 21-hour infusion period. Sensory block was also dose rate-dependent and a decrease in spread was observed during the infusion period.

Naropin is indicated for the production of local or regional anesthesia for surgery and for acute pain management.

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

In performing Naropin 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 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 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 IV line inserted. All necessary precautions should be taken to avoid intravascular injection. Local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate (without delay) availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies (see also ADVERSE REACTIONS, PRECAUTIONS and MANAGEMENT OF LOCAL ANESTHETIC EMERGENCIES). Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. Solutions of Naropin should not be used for the production of obstetrical paracervical block anesthesia, retrobulbar block, or spinal anesthesia (subarachnoid block) due to insufficient data to support such use. Intravenous regional anesthesia (bier block) should not be performed due to a lack of clinical experience and the risk of attaining toxic blood levels of ropivacaine.

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2 nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

It is essential that aspiration for blood, or cerebrospinal fluid (where applicable), be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection.

A well-known risk of epidural anesthesia may be an unintentional subarachnoid injection of local anesthetic. Two clinical studies have been performed to verify the safety of Naropin at a volume of 3 mL injected into the subarachnoid space since this dose represents an incremental epidural volume that could be unintentionally injected. The 15 and 22.5 mg doses injected resulted in sensory levels as high as T5 and T4, respectively. Anesthesia to pinprick started in the sacral dermatomes in 2 to 3 minutes, extended to the T10 level in 10 to 13 minutes and lasted for approximately 2 hours. The results of these two clinical studies showed that a 3 mL dose did not produce any serious adverse events when spinal anesthesia blockade was achieved.

Naropin should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive.

Patients treated with class III antiarrhythmic drugs (e.g., amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.

Methemoglobinemia

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Naropin and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

General

Carcinogenesis, Mutagenesis, Impairment of Fertility

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Application Site Reactions - injection site pain

Epidural administration of Naropin has, in some cases, as with other local anesthetics, been associated with transient increases in temperature to >38.5°C. This occurred more frequently at doses of Naropin > 16 mg/h.

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).

Therapy with Naropin should be discontinued at the first sign of toxicity. No specific information is available for the treatment of toxicity with Naropin; therefore, treatment should be symptomatic and supportive. The first consideration is prevention, best accomplished by incremental injection of Naropin, 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, 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.

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.

Naropin® Single Dose Vials

The solubility of ropivacaine is limited at pH above 6. Thus, care must be taken as precipitation may occur if Naropin is mixed with alkaline solutions.