Ropivacaine HCL
DRUG DESCRIPTION
NaropinĀ® 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.
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 C17H26N2Oā¢HClā¢H2O, molecular weight of 328.89 and the following structural formula:
At 25Ā° 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 Injection is preservative-free and is available in single dose containers in 2.0 (0.2%), 5.0 (0.5%), 7.5 (0.75%) and 10.0 mg/mL (1.0%) concentrations. The specific gravity of Naropin Injection solutions range from 1.002 to 1.005 at 25Ā°C.
INDICATIONS
Naropin is indicated for the production of local or regional anesthesia for surgery and for acute pain management.
Surgical Anesthesia: epidural block for surgery including cesarean section; major nerve block; local infiltration
Acute Pain Management: epidural continuous infusion or intermittent bolus, eg, postoperative or labor; local infiltration
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 (3-5 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 that are discolored or that contain particulate matter should not be administered.
Table 7: Dosage Recommendations Conc. Volume mL Dose mg Onset min Duration hours
mg/mL (%)
SURGICAL ANESTHESIA
Lumbar Epidural 5.0 (0.5%) 15-30 75-150 15-30 2-4
Administration 7.5 (0.75%) 15-25 113-188 10-20 3-5
Surgery 10.0 (1.0%) 15-20 150-200 10-20 4-6
Lumbar Epidural 5.0 (0.5%) 20-30 100-150 15-25 2-4
Administration 7.5 (0.75%) 15-20 113-150 10-20 3-5
Cesarean Section
Thoracic Epidural 5.0 (0.5%) 5-15 25-75 10-20 n/a*
Administration 7.5 (0.75%) 5-15 38-113 10-20 n/a*
Surgery
Major Nerve Blockā 5.0 (0.5%) 35-50 175-250 15-30 5-8
(eg, brachial plexus block) 7.5 (0.75%) 10-40 75-300 10-25 6-10
Field Block (eg, minor nerve blocks and infiltration) 5.0 (0.5%) 1-40 5-200 1-15 2-6
LABOR PAIN MANAGEMENT
Lumbar Epidural Administration
Initial Dose 2.0 (0.2%) 10-20 20-40 10-15 0.5-1.5
Continuous infusionā” 2.0 (0.2%) 6-14 mL/h 12-28 mg/h n/a* n/a*
Incremental injections (top-up)ā” 2.0 (0.2%) 10-15 mL/h 20-30mg/h n/a* n/a*
POSTOPERATIVE PAINMANAGEMENT
Lumbar Epidural Administration
Continuous infusionĀ§ 2.0 (0.2%) 6-14 mL/h 12-28 mg/h n/a* n/a*
Thoracic Epidural Administration 2.0 (0.2%) 6-14mL/h 12-28 mg/h n/a* n/a*
Continuous infusionĀ§
Infiltration 2.0 (0.2%) 1-100 2-200 1-5 2-6
(eg, minor nerve block) 5.0 (0.5%) 1-40 5-200 1-5 2-6
*= Not Applicable
ā = The dose for a major nerve block must be adjusted according to site of administration and patient status. Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used (See PRECAUTIONS).
ā”= 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.
Ā§ = Cumulative doses up to 770 mg of Naropin over 24 hours (intraoperative block plus postoperative infusion); Continuous epidural infusion at rates up to 28 mg per hour for 72 hours have been well tolerated in adults, ie, 2016 mg plus surgical dose of approximately 100-150 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 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 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 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 5-7 mL Naropin is induced via an epidural catheter. Analgesia is maintained with an infusion of Naropin, 2 mg/mL (0.2%). Clinical studies have demonstrated that infusion rates of 6-14 mL (12-28 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 epidural infusions for up to 72 hours.
HOW SUPPLIED
NaropinĀ® Polyamp DuoFitā¢ Sterile Pak:
Boxes of 5 polypropylene ampules fitting both Luer-lock and Luer-slip (tapered) syringes
2.0 mg/mL (0.2%) 10 mL NDC 0186-0859-47
Product No. 0186-0859-44
2.0 mg/mL (0.2%) 20 mL NDC 0186-0859-57
Product No. 0186-0859-54
5.0 mg/mL (0.5%) 20 mL NDC 0186-0863-57
Product No. 0186-0863-54
7.5 mg/mL (0.75%) 20 mL NDC 0186-0867-57
Product No. 0186-0867-54
10.0 mg/mL (1.0%) 10 mL NDC 0186-0868-47
Product No. 0186-0868-44
10.0 mg/mL (1.0%) 20 mL NDC 0186-0868-57
Product No. 0186-0868-54
NaropinĀ® Single Dose Vials:
5.0 mg/mL (0.5%) 30 mL NDC 0186-0863-61
NaropinĀ®Single Dose Infusion Bottles:
2.0 mg/mL (0.2%) 100 mL NDC 0186-0859-81
2.0 mg/mL (0.2%) 200 mL NDC 0186-0859-91
NaropinĀ®Sterile-Pak Single Dose Vials:
Boxes of 5
5.0 mg/mL (0.5%) 30 mL NDC 0186-0863-61
Product No: 0186-0863-69
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.
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 F0 of 7 minutes at 121Ā°C.
Solutions should be stored at controlled room temperature 20-25Ā°C (68-77Ā°F) [see USP].
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.
SIDE EFFECTS
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 1.0% in clinical trials. Each patient was counted once for each type of adverse event.
Incidence? 5%
For the indications of epidural administration in surgery, cesarean section, postoperative pain management, peripheral nerve block, and local infiltration, the following treatment-emergent adverse events were reported with an incidence of ? 5% in all clinical studies (N=3988): hypotension (37.0%), nausea (24.8%), vomiting (11.6%), bradycardia (9.3%), fever (9.2%), pain (8.0%), postoperative complications (7.1%), anemia (6.1%), paresthesia (5.6%), headache (5.1%), pruritus (5.1%), and back pain (5.0%).
Incidence 1-5%
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 1.0% for Naropin and 0.25% to 0.75% for bupivacaine) in the U.S. and other countries involving 3,094 patients. Table 3A and 3B list adverse events (number and percentage) that occurred in at least 1% of Naropin-treated patients in these studies. The majority of patients receiving concentrations higher than 5.0 mg/mL (0.5%) were treated with Naropin.
Table 3A: Adverse Events Reported in ? 1% of Adult Patients Receiving Regional or Local Anesthesia (Surgery, Labor, Cesarean Section, Post-Operative Pain Management, Peripheral Nerve Block and Local Infiltration)Adverse Reaction Naropin total
N=1661 Bupivacaine total
N=1433
N (%) N (%)
Hypotension 536 (32.3) 408 (28.5)
Nausea 283 (17.0) 207 (14.4)
Vomiting 117 (7.0) 88 (6.1)
Bradycardia 96 (5.8) 73 (5.1)
Headache 84 (5.1) 68 (4.7)
Paresthesia 82 (4.9) 57 (4.0)
Back pain 73 (4.4) 75 (5.2)
Pain 71 (4.3) 71 (5.0)
Pruritus 63 (3.8) 40 (2.8)
Fever 61 (3.7) 37 (2.6)
Dizziness 42 (2.5) 23 (1.6)
Rigors (Chills) 42 (2.5) 24 (1.7)
Postoperative complications 41 (2.5) 44 (3.1)
Hypoesthesia 27 (1.6) 24 (1.7)
Urinary retention 23 (1.4) 20 (1.4)
Progression of labor poor/failed 23 (1.4) 22 (1.5)
Anxiety 21 (1.3) 11 (0.8)
Breast disorder, breast-feeding 21 (1.3) 12 (0.8)
Rhinitis 18 (1.1) 13 (0.9)
Table 3B: Adverse Events Reported in ? 1% of Fetuses or Neonates of Mothers Who Received Regional Anesthesia (Cesarean Section and Labor Studies)Adverse Reaction Naropin 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 (2.0) 14 (2.4)
Fetal tachycardia 13 (2.0) 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 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, nonspecific 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 (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 (7.0) 23 (7.7) 34 (16.4) 21 (8.9) 23 (13.2)
vomiting 18 (7.0) 33 (11.1) 23 (11.1) 19 (8.1) 14 (8.0)
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 (2.0) 8 (2.7) 10 (4.8) 10 (4.2)
paresthesia 5 (2.0) 10 (3.4) 5 (2.4) 7 (3.0)
pruritus 14 (4.7) 3 (1.4) 7 (4.0)
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 = 410AGE Naropin 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 (60.0) 16 (69.6)
Table 6: Most Common Adverse Events by Gender (Epidural Administration) Total N: Females = 405, Males = 355Adverse Reaction Female Male
N (%) N (%)
hypotension 220 (54.3) 138 (38.9)
nausea 119 (29.4) 23 (6.5)
bradycardia 65 (16.0) 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 (4.0) 3 (0.8)
pruritus 16 (4.0) 1 (0.3)
pain 12 (3.0) 4 (1.1)
urinary retention 11 (2.7) 7 (2.0)
dizziness 9 (2.2) 4 (1.1)
hypoesthesia 8 (2.0) 2 (0.6)
paresthesia 8 (2.0) 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 Naropin has, in some cases, as with other local anesthetics, been associated with transient increases in temperature to > 38.5Ā°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 2-3 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 2-3 minutes and extended to the T10 level in 10-13 minutes and lasted for approximately 2 hours. Other neurological effects following unintentional subarachnoid administration during epidural anesthesia may include persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities, and loss of sphincter control; all of which may have slow, incomplete or no recovery. Headache, septic meningitis, meningismus, slowing of labor, increased incidence of forceps delivery, or cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid have been reported (see DOSAGE AND ADMINISTRATION discussion of Lumbar Epidural Block). A high spinal is characterized by paralysis of the arms, loss of consciousness, respiratory paralysis and bradycardia.
Cardiovascular System Reactions
High doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and possibly cardiac arrest. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE sections.)
Allergic Reactions
Allergic type reactions are rare and may occur as a result of sensitivity to the local anesthetic (see WARNINGS). These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid symptomatology (including severe hypotension). Cross-sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitively established.
DRUG INTERACTIONS
Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (eg, amiodarone) have not been performed, but caution is advised (see WARNINGS).
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.
WARNINGS
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 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 that may arise from the block to be employed, and then only after ensuring 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.
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 2-3 minutes, extended to the T10 level in 10-13 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 (eg, amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.
PRECAUTIONS
General
The safe and effective use of local anesthetics depends on proper dosage, correct technique, adequate precautions and readiness for emergencies.
Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use. (See WARNINGS and ADVERSE REACTIONS.) The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse events. Injections should be made slowly and incrementally, with frequent aspirations before and during the injection to avoid intravascular injection. When a continuous catheter technique is used, syringe aspirations should also be performed before and during each supplemental injection. During the administration of epidural anesthesia, it is recommended that a test dose of a local anesthetic with a fast onset be administered initially and that the patient be monitored for central nervous system and cardiovascular toxicity, as well as for signs of unintended intrathecal 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 Naropin to achieve greater motor blockade or increased duration of sensory blockade may result in cardiovascular depression, particularly in the event of inadvertent intravascular injection. Tolerance to elevated blood levels varies with the physical condition of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical condition. Local anesthetics should also be used with caution in patients with hypotension, hypovolemia or heart block.
Careful and constant monitoring of cardiovascular and respiratory vital signs (adequacy of ventilation) and the patient's state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, light-headedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. Because amide-type local anesthetics such as ropivacaine are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs.
Many drugs used during the conduct of anesthesia are considered potential triggering agents for malignant hyperthermia (MH). Amide-type local anesthetics are not known to trigger this reaction. However, since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for MH management should be available.
Epidural Anesthesia
During epidural administration, Naropin 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 can detect 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 (eg, 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.
Use in Brachial Plexus Block
Ropivacine 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 OVERDOSE.)
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.
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.
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.)
Use in Ophthalmic Surgery
The use of Naropin in retrobulbar blocks for ophthalmic surgery has not been studied. Until appropriate experience is gained, the use of Naropin for such surgery is not recommended.
Carcinogenesis,Mutagenesis,Impairment of Fertility
Long term studies in animals of most local anesthetics, including ropivacaine, to evaluate the carcinogenic potential have not been conducted.
Weak mutagenic activity was seen in the mouse lymphoma test. Mutagenicity was not noted in the other assays, demonstrating that the weak signs of in vitro activity in the mouse lymphoma test were not manifest under diverse in vivo conditions. Studies performed with ropivacaine in rats did not demonstrate an effect on fertility or general reproductive performance over 2 generations.
Pregnancy Category B
Reproduction toxicity studies have been performed in pregnant New Zealand white rabbits and Sprague-Dawley rats. During gestation days 6-18, rabbits received 1.3, 4.2, or 13 mg/kg/day subcutaneously. In rats, subcutaneous doses of 5.3, 11 and 26 mg/kg/day were administered during gestation days 6-15. No teratogenic effects were observed in rats and rabbits at the highest doses tested. The highest doses of 13 mg/kg/day (rabbits) and 26 mg/kg/day (rats) are approximately 1/3 of the maximum recommended human dose (epidural, 770 mg/24 hours) based on a mg/m2 basis. In 2 prenatal and postnatal studies, the female rats were dosed daily from day 15 of gestation to day 20 postpartum. The doses were 5.3, 11 and 26 mg/kg/day subcutaneously. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring. In another study with rats, the males were dosed daily for 9 weeks before mating and during mating. The females were dosed daily for 2 weeks before mating and then during the mating, pregnancy, and lactation, up to day 42 post coitus. At 23 mg/kg/day, an increased loss of pups was observed during the first 3 days postpartum. The effect was considered secondary to impaired maternal care due to maternal toxicity.
There are no adequate or well-controlled studies in pregnant women of the effects of Naropin on the developing fetus. Naropin should only be used during pregnancy if the benefits outweigh the risk.
Teratogenicity studies in rats and rabbits did not show evidence of any adverse effects on organogenesis or early fetal development in rats (26 mg/kg sc) or rabbits (13 mg/kg). The doses used were approximately equal to total daily dose based on body surface area. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring in 2 perinatal and postnatal studies in rats, at dose levels equivalent to the maximum recommended human dose based on body surface area. In another study at 23 mg/kg, an increased pup loss was seen during the first 3 days postpartum, which was considered secondary to impaired maternal care due to maternal toxicity.
Labor and 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 (see CLINICAL PHARMACOLOGY and Pharmacokinetics). 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 hypotension has resulted from regional anesthesia with Naropin for obstetrical pain relief. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient's legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural anesthesia has been reported to prolong the second stage of labor by removing the patient's reflex urge to bear down or by interfering with motor function. Spontaneous vertex delivery occurred more frequently in patients receiving Naropin than in those receiving bupivacaine.
Nursing Mothers
Some local anesthetic drugs are excreted in human milk and caution should be exercised when they are administered to a nursing woman. The excretion of ropivacaine or its metabolites in human milk has not been studied. Based on the milk/plasma concentration ratio in rats, the estimated daily dose to a pup will be about 4% of the dose given to the mother. Assuming that the milk/plasma concentration in humans is of the same order, the total Naropin dose to which the baby is exposed by breast-feeding is far lower than by exposure in utero in pregnant women at term (see PRECAUTIONS).
Pediatric Use
The safety and efficacy of Naropin in pediatric patients have not been established.
Geriatric Use
Of the 2,978 subjects that were administered Naropin Injection in 71 controlled and uncontrolled clinical studies, 803 patients (27%) were 65 years of age or older, which includes 127 patients (4%) 75 years of age and over. Naropin Injection was found to be safe and effective in the patients in these studies. Clinical data in one published article indicate that differences in various pharmacodynamic measures were observed with increasing age. In one study, the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (MAP) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age.
This drug and its metabolites are known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased hepatic, renal, or cardiac function, as well as concomitant disease. Therefore, care should be taken in dose selection, starting at the low end of the dosage range, and it may be useful to monitor renal function. (See Pharmacokinetics, Elimination.)