Naropin Drug Information

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 NAROPIN is an amide local anesthetic indicated in adults for the production of local or regional anesthesia for surgery and for acute pain management. Surgical Anesthesi a: 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

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 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 NAROPIN (concentrations ranged from 0.125% to 1% for NAROPIN 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 NAROPIN-treated patients in these studies. The majority of patients receiving concentrations higher than 5 mg/mL (0.5%) were treated with NAROPIN. 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) NAROPIN total N=1661 Bupivacaine total N=1433 Adverse Reaction N % N % Hypotension 536 408 Nausea 283 207 Vomiting 117 88 Bradycardia 96 73 Headache 84 68 Paresthesia 82 57 Back pain 73 75 Pain 71 71 Pruritus 63 40 Fever 61 37 Dizziness 42 23 Rigors (Chills) 42 24 Postoperative complications 41 44 Hypoesthesia 27 24 Urinary retention 23 20 Progression of labor poor/failed 23 22 Anxiety 21 11 Breast disorder, breast-feeding 21 12 Rhinitis 18 13 Table 3 Adverse Events Reported in ≥1% of Fetuses or Neonates of Mothers Who Received Regional Anesthesia (Cesarean Section and Labor Studies) Adverse Reaction NAROPIN total N = 639 Bupivacaine total N = 573 N % N % Fetal bradycardia 77 68 Neonatal jaundice 49 47 Neonatal complication-NOS 42 38 Apgar score low 18 14 Neonatal respiratory disorder 17 18 Neonatal tachypnea 14 15 Neonatal fever 13 14 Fetal tachycardia 13 12 Fetal distress 11 10 Neonatal infection 10 8 Neonatal hypoglycemia 8 16 Incidence <1% The following adverse events were reported during the NAROPIN 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 NAROPIN and bupivacaine.

Table 4 is based on data from trials in the U.S. and other countries where NAROPIN was administered as an epidural anesthetic for surgery. Table 4 Common Events (Epidural Administration) Adverse Reaction NAROPIN 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 99 146 113 91 89 nausea 34 68 41 36 bradycardia 29 58 40 32 25 back pain 18 23 34 21 23 vomiting 18 33 23 19 14 headache 12 20 16 13 9 fever 8 5 18 11 chills 6 7 6 4 3 urinary retention 5 8 10 10 paresthesia 5 10 5 7 pruritus 14 3 7 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 are broken down by gender. Table 5 Effects of Age on Hypotension (Epidural Administration) Total N: NAROPIN = 760, Bupivacaine = 410 NAROPIN Bupivacaine AGE 5 mg/mL 7.5 mg/mL 10 mg/mL 5 mg/mL 7.5 mg/mL N (%) N (%) N (%) N (%) N (%) < 65 68 99 87 64 73 ≥ 65 31 47 26 27 16 Table 6 Most Common Adverse Events by Gender (Epidural Administration) Total N: Females = 405, Males = 355 Female Male Adverse Reaction N (%) N (%) hypotension 220 138 nausea 119 23 bradycardia 65 56 vomiting 59 8 back pain 41 23 headache 33 17 chills 18 5 fever 16 3 pruritus 16 1 pain 12 4 urinary retention 11 7 dizziness 9 4 hypoesthesia 8 2 paresthesia 8 10 Most common adverse reactions (incidence ≥ 5%) are hypotension, nausea, vomiting, bradycardia, fever, pain, postoperative complications, anemia, paresthesia, headache, pruritus, and back pain.

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 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 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.

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 NAROPIN 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. 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 . Allergic Reactions Allergic type reactions are rare and may occur as a result of sensitivity to the local anesthetic . 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.

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 : 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 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. 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 NAROPIN, can interact with NAROPIN 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 . Agents structurally related to amide-type local anesthetics: Concurrent use may cause additive effects.

Pregnancy Risk Summary There are no available human data on use of Naropin (ropivacaine) Injection in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone, and cardiac function (see Clinical Considerations ). No teratogenicity was observed at doses up to 0.3 times the maximum recommended human dose of 770 mg/24 hours for epidural use, and equal to the MRHD of 250 mg for nerve block use, based on body surface area (BSA) comparisons and a 60 kg human weight (see Animal data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U. S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Labor or Delivery Local anesthetics, including ropivacaine, rapidly cross the placenta, and when used for epidural block can cause varying degrees of maternal, fetal, and neonatal toxicity . The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function.

Maternal Adverse reactions Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. 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 be accomplished.

Elevating the patient's legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Data Animal data No malformations were reported in embryo-fetal development toxicity studies conducted in pregnant New Zealand white rabbits and Sprague-Dawley rats.

During gestation days 6 to 18, rabbits received daily subcutaneous doses of ropivacaine at 1.3, 4.2, or 13 mg/kg/day (equivalent to 0.03, 0.10, and 0.33 times the maximum recommended human dose (MRHD) of 770 mg/24 hours, respectively, and 0.10, 0.32, and 1.0 times the MRHD of 250 mg for nerve block use, respectively based on body surface area (BSA) comparisons and a 60 kg human weight). Rats received daily subcutaneous doses of 5.3, 11, and 26 mg/kg/day (equivalent to 0.07, 0.14, and 0.33 times the MRHD for epidural use, respectively, and 0.21, 0.43, and 1.0 times the MRHD for nerve block use, respectively, based on BSA comparisons) during GD 6 to 15. No treatment-related effects on late fetal development, parturition, litter size, lactation, neonatal viability, or growth of the offspring were reported in a prenatal and postnatal reproductive and development toxicity study; however functional endpoints were not evaluated. Female rats were dosed daily subcutaneously from GD 15 to Lactation Day 20 at doses of 5.3, 11,and 26 mg/kg/day (equivalent to 0.07, 0.1, and 0.3 times the MRHD for epidural use, respectively, and 0.21, 0.43, and 1.0 times the MRHD for nerve block use, respectively), with maternal toxicity exhibited at the high dose. No adverse effects in physical developmental milestones or in behavioral tests were reported in a 2-generational reproduction study, in which rats received daily subcutaneous doses of 6.3, 12, and 23 mg/kg/day (equivalent to 0.08, 0.15, and 0.29 times the MRHD for epidural use, respectively, and 0.24, 0.45, and 0.88 times the MRHD for nerve block use, respectively, based on BSA comparisons) for 9 weeks before mating and during mating for males, and for 2 weeks before mating and during mating, pregnancy, and lactation, up to day 42 post coitus for females.

Significant pup loss was observed in the high dose group during the first 3 days postpartum, from a few hours up to 3 days after delivery compared to the control group, which was considered secondary to impaired maternal care due to maternal toxicity. No differences were observed in litter parameters, or fertility, mean gestation time, or number of live births were observed between the control (saline) and treatment groups .

Pediatric Use The safety and efficacy of NAROPIN in pediatric patients have not been established.

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.

Treatment 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.