Ropivacaine

Ropivacaine
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]

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Overview

Ropivacaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of cesarean section - local anesthetic lumbar epidural block, epidural anesthesia - surgical procedure, labor pain, local anesthetic nerve block - surgical procedure, postoperative pain. Common adverse reactions include cardiovascular: fetal bradycardia (12.1% ), hypotension (32% to 37% ), dermatologic: pruritus (5.1% ), gastrointestinal: nausea (24.8% .), vomiting (11.6% ), musculoskeletal: backache (4% to 40% ), neurologic: headache (5.1% ), paresthesia (5.6% ), other: fever (9.2% ).

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Cesarean section

• Local anesthetic lumbar epidural block

• 20 to 30 mL of 0.5% solution (100 to 150 mg) OR 15 to 20 mL of 0.75% solution (113 to 150 mg)

Epidural anesthesia

• Surgical procedure

• 15 to 30 mL (75 to 150 mg) of 0.5% solution

Labor pain

• Lumbar Epidural 10 to 20 mL (20 to 40 mg) of 0.2% solution
• Continuous lumbar Epidural infusion, 6 to 14 mL/hr (12 to 28 mg/hr) of 0.2% solution
• Incremental lumbar Epidural injections (top-up), 10 to 15 mL/hr (20 to 30 mg/hr) of 0.2% solution
• Surgical procedure: Field block 1 to 40 mL of 0.5% solution (5 to 200 mg)
• Surgical procedure: Major nerve block 35 to 50 mL of 0.5% solution (175 to 250 mg) OR 10 to 40 mL of 0.75% solution (75 to 300 mg)

Postoperative pain

• Lumbar or thoracic EpiduraL continuous infusion

• 6 to 14 mL/hr (12 to 28 mg/hr) of a 0.2% (2 mg/mL) solution

• Local Infiltration

• 1 to 100 mL (2 to 200 mg) of a 0.2% (2 mg/mL) solution OR 1 to 40 mL (5 to 200 mg) of a 0.5% (5 mg/mL) solution

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

• Pain
• Peribulbar infiltration of local anesthetic
• Spinal anesthesia - Surgical procedure

Non–Guideline-Supported Use

• There is limited information regarding Off-Label Non–Guideline-Supported Use of Ropivacaine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

• Safety and efficacy in pediatric patients has not been established

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Ropivacaine in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Ropivacaine in pediatric patients.

Contraindications

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

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 which might 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 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 withclass III antiarrhythmic drugs (eg, amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.

Adverse Reactions

Clinical Trials Experience

• 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.

Incidence ≥5%

• For the indications of epidural administration in surgery, cesarean section, post-operative 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 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 mg/mL (0.5%) were treated with Naropin.

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

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.

This image is provided by the National Library of Medicine.

• 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.

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

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 (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).

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.

Postmarketing Experience

There is limited information regarding Ropivacaine Postmarketing Experience in the drug label.

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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): B

• Reproduction toxicity studies have been performed in pregnant New Zealand white rabbits and Sprague-Dawley rats. During gestation days 6 to 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 to 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.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ropivacaine in women who are pregnant.

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.

Geriatic 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).

Gender

There is no FDA guidance on the use of Ropivacaine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Ropivacaine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Ropivacaine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Ropivacaine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Ropivacaine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Ropivacaine in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Ropivacaine Administration in the drug label.

Monitoring

There is limited information regarding Ropivacaine Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Ropivacaine and IV administrations.

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 adverse reactions, Warnings, and Precautions).

Management of local anesthetic emergencies

• 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.

Pharmacology

Mechanism of Action

• Ropivacaine is a member of the amino amide class of local anesthetics and is supplied as the pure S-(-)-enantiomer. Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows

1. Pain,
2. Temperature
3. Touch,
4. Proprioception,
5. Skeletal muscle tone.

Structure

• 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.

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 C17H26N2O•HCl•H2O, molecular weight of 328.89 and the following structural formula:

This image is provided by the National Library of Medicine.

• 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 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.

Pharmacodynamics

• Studies in humans have demonstrated that, unlike most other local anesthetics, the presence of epinephrine has no major effect on either the time of onset or the duration of action of ropivacaine. Likewise, addition of epinephrine to ropivacaine has no effect on limiting systemic absorption of ropivacaine.
• Systemic absorption of local anesthetics can produce effects on the central nervous and cardiovascular systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance have been reported. Toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure.
• Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. Apparent central stimulation is usually manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression and coma, progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage.
• In 2 clinical pharmacology studies (total n=24) ropivacaine and bupivacaine were infused (10 mg/min) in human volunteers until the appearance of CNS symptoms, eg, visual or hearing disturbances, perioral numbness, tingling and others. Similar symptoms were seen with both drugs. In 1 study, the mean ± SD maximum tolerated intravenous dose of ropivacaine infused (124 ± 38 mg) was significantly higher than that of bupivacaine (99 ± 30 mg) while in the other study the doses were not different (115 ± 29 mg of ropivacaine and 103 ± 30 mg of bupivacaine). In the latter study, the number of subjects reporting each symptom was similar for both drugs with the exception of muscle twitching which was reported by more subjects with bupivacaine than ropivacaine at comparable intravenous doses. At the end of the infusion, ropivacaine in both studies caused significantly less depression of cardiac conductivity (less QRS widening) than bupivacaine. Ropivacaine and bupivacaine caused evidence of depression of cardiac contractility, but there were no changes in cardiac output.
• 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. However, no pharmacokinetic differences were observed between elderly and younger patients.
• In non-clinical pharmacology studies comparing ropivacaine and bupivacaine in several animal species, the cardiac toxicity of ropivacaine was less than that of bupivacaine, although both were considerably more toxic than lidocaine. Arrhythmogenic and cardio-depressant effects were seen in animals at significantly higher doses of ropivacaine than bupivacaine. The incidence of successful resuscitation was not significantly different between the ropivacaine and bupivacaine groups.

Pharmacokinetics

Absorption

• 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.

This image is provided by the National Library of Medicine.

• 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 Precautions). At a dose of greater than 300 mg, for local infiltration, the terminal half-life may be longer (>30 hours).

Distribution

• After intravascular infusion, ropivacaine has a steady state volume of distribution of 41 ± 7 liters. Ropivacaine is 94% protein bound, mainly to α1-acid glycoprotein. An increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of α1-acid glycoprotein. Variations in unbound, ie, pharmacologically active, concentrations have been less than in total plasma concentration. Ropivacaine readily crosses the placenta and equilibrium in regard to unbound concentration will be rapidly reached (see PRECAUTIONS, Labor and Delivery).

Metabolism

• Ropivacaine is extensively metabolized in the liver, predominantly by aromatic hydroxylation mediated by cytochrome P4501A to 3-hydroxy ropivacaine. After a single IV dose approximately 37% of the total dose is excreted in the urine as both free and conjugated 3-hydroxy ropivacaine. Low concentrations of 3-hydroxy ropivacaine have been found in the plasma. Urinary excretion of the 4-hydroxy ropivacaine, and both the 3-hydroxy N-de-alkylated (3-OH-PPX) and 4-hydroxy N-de-alkylated (4-OH-PPX) metabolites account for less than 3% of the dose. An additional metabolite, 2-hydroxy-methyl-ropivacaine, has been identified but not quantified in the urine. The N-de-alkylated metabolite of ropivacaine (PPX) and 3-OH-ropivacaine are the major metabolites excreted in the urine during epidural infusion. Total PPX concentration in the plasma was about half as that of total ropivacaine; however, mean unbound concentrations of PPX were about 7 to 9 times higher than that of unbound ropivacaine following continuous epidural infusion up to 72 hours. Unbound PPX, 3-hydroxy and 4-hydroxy ropivacaine, have a pharmacological activity in animal models less than that of ropivacaine. There is no evidence of in vivo racemization in urine of ropivacaine.

Elimination

• The kidney is the main excretory organ for most local anesthetic metabolites. In total, 86% of the ropivacaine dose is excreted in the urine after intravenous administration of which only 1% relates to unchanged drug. After intravenous administration ropivacaine has a mean ± SD total plasma clearance of 387 ± 107 mL/min, an unbound plasma clearance of 7.2 ± 1.6 L/min, and a renal clearance of 1 mL/min. The mean ± SD terminal half-life is 1.8 ± 0.7 h after intravascular administration and 4.2 ± 1 h after epidural administration (see Absorption).

Nonclinical Toxicology

There is limited information regarding Ropivacaine Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Ropivacaine Clinical Studies in the drug label.

How Supplied

This image is provided by the National Library of Medicine.

• 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 121°C.

• Solutions should be stored at 20º to 25°C (68º to 77°F) [see USP Controlled Room Temperature].
• 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 is a trademark of APP Pharmaceuticals, LLC.

Distributed by:

Novation, the supply company of VHA and UHC, and NOVAPLUS are trademarks of Novation, LLC.

451114/Issued: March 2009

Storage

There is limited information regarding Ropivacaine Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Ropivacaine Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Ropivacaine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Ropivacaine Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Ropivacaine Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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