Ropivacaine (Parenteral-Local)


VA CLASSIFICATION
Primary: CN204

Commonly used brand name(s): Naropin.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anesthetic (local){01}{02}

Indications

Accepted

Central neural blocks{01}{02}{09}{11}{16}{21}{31}{45}—Ropivacaine is indicated for epidural use for surgical anesthesia {12} {15} {17} {18} {23}.
—Ropivacaine is indicated for epidural use for the management of postoperative pain {19} {20}.
—Ropivacaine is indicated for epidural use for the management of pain during labor, for surgical anesthesia for cesarean section, and for the management of postoperative pain {22}.

Local infiltration—Ropivacaine is indicated for local infiltration for the management of postoperative pain {25}.

Peripheral nerve block{28}—Ropivacaine is indicated for peripheral nerve block for the management of postoperative pain, and for anesthesia for surgery {10} {13} {14}.

Acceptance not established
Ropivacaine has not been studied for obstetrical paracervical block anesthesia or retrobulbar block {01} {02}, and has received only limited study for subarachnoid block {29}.

Unaccepted
Ropivacaine should not be used for intravenous regional block (Bier block) due to a lack of clinical experience with ropivacaine for this indication and the risk of reaching toxic blood concentrations of ropivacaine {01} {02}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    S-enantiomer of a propyl-pipecoloxylidide; an amide-type local anesthetic {01} {02} {40}.
Molecular weight—
    274.41 {57}

pKa—
    8.07 {01} {02}

Mechanism of action/Effect:

Ropivacaine blocks the initiation and conduction of nerve impulses by decreasing neuronal membrane permeability to sodium ions {01} {02}. This reversibly stabilizes the membrane and inhibits depolarization, resulting in the failure of propagated action potentials and subsequent conduction blockade {01} {02} {44} {48} {51}. The conduction blockade results in sensory and motor blockade. There is less motor blockade with ropivacaine as compared with bupivacaine {38}.


Other actions/effects:

Ropivacaine may cause central nervous system (CNS) stimulation or depression, and cardiac depression {01} {02} {37}. These effects are usually dose-related, and result from administration of large doses or unintentional intravascular injection of ropivacaine {01} {02}.

In in vitro and animal tests, ropivacaine caused more cardiac depression than lidocaine, but less than bupivacaine {32} {46} {43}.

Absorption:

Complete systemic absorption {01} {02}. The rate of absorption is dependent on the vascularity of the site of administration, and the volume and concentration of ropivacaine administered {01} {02}.

Distribution:

Ropivacaine has biphasic distribution from the epidural space {01} {02}.

Protein binding:

Very high (94%), primarily to alpha 1-acid glycoprotein {01} {02}.

Biotransformation:

Extensive, hepatic, mainly by cytochrome P450 1A to 3-hydroxy ropivacaine and other metabolites {01} {02} {49}.

Half-life:


Distribution:


From epidural space—

Rapid distribution—14 minutes {01} {02}.

Slower distribution—4.2 hours {01} {02}.




Elimination:


Terminal elimination—

Epidural administration—4.2 hours {01} {02}.

Intravascular administration—1.8 hours {01} {02}.



Onset of action:

1 to 45 {60} minutes, depending on concentration and volume administered, and the site of administration {01} {02} {07} {09} {13} {14} {35}.

Time to peak effect:

Dependent on the concentration and volume administered, and the site of administration {01} {02} {35}.

Duration of action:

Dependent on the concentration and volume administered, and the site of administration {01} {02} {09} {14} {35}. Ropivacaine 20 to 40 mg administered epidurally as a 0.2% solution for the management of labor pain has a duration of action of 0.5 to 1.5 hours {01}.

The addition of epinephrine to ropivacaine does not alter the pharmacokinetic profile of ropivacaine when it is used for brachial plexus nerve block {33}, but increases the duration of action of intradermal injections of ropivacaine {47}.

Elimination:
    Renal, 86%, primarily as metabolites {01} {02}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to other amide-type local anesthetics may be allergic to ropivacaine also {01} {02}.

Carcinogenicity/Tumorigenicity

Studies have not been done to determine the carcinogenic and tumorigenic potential of ropivacaine {01} {02}.

Mutagenicity

Weak mutagenic activity was seen in the mouse lymphoma test. No mutagenicity was observed in in vivo testing {01} {02}.

Pregnancy/Reproduction
Fertility—
Adequate and well-controlled studies have not been done in humans {01} {02}.

Ropivacaine did not reduce the fertility of two generations of rats given ropivacaine {01} {02}.

Pregnancy—
Ropivacaine crosses the placenta {01} {02} {04}. Adequate and well-controlled studies have not been done in pregnant women {01} {02}.

Teratogenic effects were not observed in studies of rabbits and rats given 2.5 and 5 times the maximum recommended human dose, respectively {01}.

FDA Pregnancy Category B {01} {02}.


Labor and delivery—

Use of epidural ropivacaine during labor may prolong the second stage of labor by interfering with motor function or suppressing the reflex urge to bear down {01} {06}.

Use of ropivacaine for obstetrical analgesia can result in fetal and/or maternal hypotension, fetal bradycardia or tachycardia, and fetal distress {01} {02} {06} {07}.

Cardiovascular collapse has occurred in pregnant women given local anesthetics similar to ropivacaine during labor and delivery, possibly due to inadvertent intravascular injection of the local anesthetic {40} {50} {56}. Resuscitation of these obstetric patients sometimes has been more difficult than resuscitation of nonpregnant patients {39} {52} {55}. For resuscitation of near-term pregnant patients, standard cardiopulmonary resuscitation must be modified to include leftward uterine displacement {58}. Advanced cardiac life support guidelines should be consulted for other modifications of resuscitation procedures during pregnancy {58}. The effectiveness of resuscitation efforts in pregnant women receiving ropivacaine has not been established. In vitro and animal testing suggest that resuscitation of pregnant patients inadvertently given intravascular injections of ropivacaine may not be more difficult than resuscitation of nonpregnant patients {53} {54}.

Postpartum —
Neonates may experience cardiovascular or neurologic effects, fever, jaundice, respiratory distress, tachypnea, or vomiting {01} {02} {03} {06}.

When compared with bupivacaine for the management of pain during labor and for epidural use for surgical anesthesia for cesarean section, there was no difference in neonatal outcomes {03} {04} {05} {06} {07}.

Breast-feeding

It is not known whether ropivacaine is distributed into breast milk {01} {02}. However, problems in humans have not been documented {01} {02}.

Pediatrics

No information is available on the relationship of age to the effects of ropivacaine in pediatric patients up to 12 years of age {01}. Safety and efficacy have not been established {01} {02}.


Geriatrics


Although geriatric patients were included in some published trials of ropivacaine, there has been no analysis of the relationship of age to the effects of ropivacaine in geriatric patients {09} {23}. It is known, however, that the risk of bradycardia and hypotension in patients receiving epidural anesthesia with ropivacaine increases in an age-dependent manner {60}. Based on experience with similar local anesthetics, systemic toxicity may be more likely to occur in geriatric patients; geriatric patients should be monitored closely {01} {02}. In addition, geriatric patients are more likely to have age-related renal function impairment, which may require adjustment in the dosing interval of ropivacaine.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anesthetics, local, other    (toxic effects of ropivacaine are additive to those of other local anesthetics {01} {02})


Fluvoxamine or
Imipramine or
Theophylline or
Verapamil    (inhibition of cytochrome P450 1A enzymes can lead to toxic blood concentrations of ropivacaine {01} {02})

    (although an interaction has not yet been established with other cytochrome P450 1A substrates, other cytochrome P450 1A substrates may also interact with ropivacaine {59})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Allergy to any amide-type local anesthetic{01}{02}
Risk-benefit should be considered when the following medical problems exist
» Cardiovascular function impairment    (may be exacerbated by cardiac depressant actions of ropivacaine {01} {02}; patients with cardiovascular function impairment may not be able to compensate for the cardiovascular effects of ropivacaine {01} {02})


» Hepatic function impairment or
Renal function impairment    (increased risk of toxicity due to reduced clearance {01} {02})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Cardiovascular status and
» Respiratory status and
» State of consciousness (unless ropivacaine is administered under general anesthesia{61} )    (should be monitored after each local anesthetic injection to detect CNS and/or cardiovascular toxicity {01} {02})


Fetal heart rate    (should be monitored during obstetric use to detect fetal bradycardia and fetal distress {01} {02})




Side/Adverse Effects

Note: Side/adverse effects generally are dose-related and may result from high plasma concentrations of ropivacaine caused by inadvertent intravascular administration, excessive dosage, or rapid absorption from the injection site {01} {02}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hypotension{01}{02}{03}{04}{05}{06}{07}{09}{12}{17}{18}{19}{20}{21}{22}{23}{30}{31}{41} (dizziness)
    
nausea{01}{02}{05}{06}{07}{09}{10}{12}{18}{19}{20}{22}{23}{30}{41} —may indicate neurotoxicity

Incidence less frequent
    
Back pain{01}{02}{05}{06}{07}{09}{12}{18}{21}{22}{41}
    
bradycardia{01}{02}{06}{09}{17}{19}{21}{23}{41} (dizziness)
    
fever{01}
    
headache{01}{02}{05}{12}{21}{22}{41} —may indicate neurotoxicity
    
pain{01}{02}{06}{41}
    
paresthesia{01}{02}{06}{23}{41} (burning or prickling sensation)
    
vomiting{01}{02}{07}{10}{12}{19}{20}{30} —may indicate neurotoxicity

Incidence rare
    
Anxiety{01}{02} —may indicate neurotoxicity
    
blurred vision{01}{42} —may indicate neurotoxicity
    
chills{01}{02}{22} —may indicate neurotoxicity
    
dizziness{01} —may indicate neurotoxicity
    
drowsiness{01}{02} —may indicate neurotoxicity
    
incoherent speech{01}{02} —may indicate neurotoxicity
    
metallic taste{01}{02} —may indicate neurotoxicity
    
numbness and tingling of mouth or lips{01}{02}{42} —may indicate neurotoxicity
    
pruritus{01}{02}{10} (itching)
    
restlessness{01}{02} —may indicate neurotoxicity
    
tremors{01}{02}{41} (trembling)—may indicate neurotoxicity
    
twitching{01}{02}{10}{42} —may indicate neurotoxicity
    
urinary retention{01}{02}{07}{09}{18}{20}{22}{41} (difficulty urinating)



Note: All symptoms of neurotoxicity may progress to tonic-clonic seizures {58}.




Overdose
For specific information on the agents used in the management of ropivacaine overdose, see:    • Anesthetics, Barbiturate (Systemic) monograph;
   • Benzodiazepines (Systemic) monograph;
   • Ephedrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph;
   • Epinephrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph; and/or
   • Neuromuscular Blocking Agents (Systemic) monograph.

For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Apnea{01}{02}{26}{42} (bluish lips or skin)
    
circulatory depression{01}{02}{26} (dizziness)
    
seizures{01}{02}{26}{42}


Treatment of overdose


Specific treatment:
Ropivacaine should be discontinued {01} {02}.


For circulatory depression—
Administration of intravenous fluids and a vasopressor may be needed {01} {02} {26}.

For maternal hypotension during obstetrical use of ropivacaine, it is recommended that the patient be placed on her left side, if possible, to correct aortocaval compression by the gravid uterus {01} {02}. The effectiveness of resuscitation efforts in pregnant women receiving ropivacaine has not been established. Delivery of the fetus may improve the response of the obstetric patient to cardiopulmonary resuscitation {01} {02} {58}.



For seizures—
Protect the patient and administer oxygen immediately {58}. If seizures do not respond to respiratory support, administration of a benzodiazepine or ultrashort-acting barbiturate is recommended {01} {02} {26}. A neuromuscular blocking agent may also be used to decrease the muscular manifestations of persistent seizures if positive-pressure ventilation can be immediately provided {01} {02} {58}. Hypoxia, hypercapnea, and acidosis can develop quickly following the onset of seizures {01} {02}.




Monitoring:
Blood pressure, heart rate, neurologic status, and respiratory status should be monitored continuously {01} {02}.



Supportive care:
Support of respiratory function may be needed. It may be necessary to secure and maintain a patent airway, administer oxygen, and institute assisted or controlled ventilation {01} {02}. In some patients, endotracheal intubation may be required {01} {02}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ropivacaine (Parenteral-Local) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Allergy to amide-type local anesthetics {01} {02}

Pregnancy—Ropivacaine crosses the placenta; use of ropivacaine during labor may prolong the second stage of labor; fetal and/or maternal hypotension, fetal bradycardia or tachycardia, or fetal distress may occur when ropivacaine is used for obstetrical analgesia; cardiovascular or neurologic effects, fever, jaundice, respiratory distress, tachypnea, or vomiting may occur in newborns whose mothers are given ropivacaine during labor and delivery {01} {02}





Use in the elderly—Increased sensitivity to the effects of ropivacaine {01} {02}
Other medical problems, especially cardiovascular or hepatic function impairment {01} {02}

Proper use of this medication
Proper dosing

Precautions after receiving this medication
Caution that injury may occur undetected while numbness persists in the affected area; using care to prevent injury


Side/adverse effects
Signs of potential side effects, especially hypotension, nausea, back pain, bradycardia, fever, headache, pain, paresthesia, vomiting, anxiety, blurred vision, chills, dizziness, drowsiness, incoherent speech, metallic taste, numbness and tingling of the mouth or lips, pruritus, restlessness, tremors, twitching, and urinary retention


General Dosing Information
Ropivacaine should be used only by persons trained in the management of local anesthetic toxicity {01} {02} and airway management {61}. Equipment and drugs for resuscitation as well as suction and supplemental oxygen should be immediately available {01} {02}.

Large doses of ropivacaine should not be injected rapidly {01} {02}. Incremental injections are recommended {01} {02}.

Patients should be closely monitored after each injection of ropivacaine {01} {02}. Anxiety, blurred vision, chills, dizziness, drowsiness, headache, incoherent speech, metallic taste, nausea, numbness and tingling of the mouth or lips, restlessness, tremors, twitching, and vomiting may be early signs of neurotoxicity {01} {02}.

Extreme caution is recommended when ropivacaine is administered in the head and neck region because systemic toxicity may occur even with therapeutic doses {01} {02}. The extensive vasculature in this area may lead to rapid absorption, resulting in systemic toxicity {01} {02}.

When ropivacaine is used epidurally, use of a test dose of a short-acting local anesthetic solution containing epinephrine is recommended prior to induction of complete block {01} {02}. However, an intravascular or subarachnoid injection is possible even when the test dose is negative {01} {02}.

When using ropivacaine in or near the spinal canal, aspiration to check for blood or cerebrospinal fluid (CSF) should be done prior to injection of ropivacaine {01} {02}. However, failure to obtain blood or CSF on aspiration does not guarantee that intravascular or subarachnoid injection will not occur {01} {02}.

Ropivacaine causes dose-dependent motor block. Use of the lowest concentration and dose necessary for postoperative analgesia is recommended to achieve an acceptable balance between sensory and motor block {18} {30} {31} {34} {36}.

There is an increased risk of accumulation of ropivacaine, with resultant systemic toxicity or local neuronal injury, when it is used for prolonged block {01} {02}. Ropivacaine has been used for up to 24 hours in clinical trials {01} {02}. A cumulative dose of 770 mg in 24 hours for postoperative pain management is well tolerated by most adults {01} {02}.


Parenteral Dosage Forms

ROPIVACAINE HYDROCHLORIDE INJECTION

Note: The recommended adult and adolescent doses are intended as a guide for use in the average adult {01} {02}. The actual dose must be individualized based on the physical status of the patient and the expected rate of systemic absorption from the injection site {01} {02}. The lowest dose (volume and concentration) that produces the desired result should be used {01} {02}.


Usual adult and adolescent dose
Central neural blocks


Lumbar epidural:


Anesthesia, surgical—


• 75 to 150 mg of 0.5% (5 mg per mL) solution, administered in incremental doses.{62}


• 113 to 188 mg of 0.75% (7.5 mg per mL) solution, administered in incremental doses.{62}


• 150 to 200 mg of 1% (10 mg per mL) solution, administered in incremental doses.{62}



Anesthesia, surgical, cesarean section—
100 to 150 mg of 0.5% (5 mg per mL) solution, administered in incremental doses {01} {02}.



Pain, obstetrical—
20 to 40 mg of 0.2% (2 mg per mL) solution initially, then 12 to 28 mg per hour as a continuous infusion or 20 to 30 mg per hour, administered in incremental doses {01} {02}.



Pain, postoperative—
Continuous infusion, 12 to 20 mg of 0.2% (2 mg per mL) solution per hour {01} {02}{62}.




Thoracic epidural:


Anesthesia, surgical—
25 to 75 mg of 0.5% (5 mg per mL) solution, administered in incremental doses {01} {02}{62}.



Pain, postoperative—
Continuous infusion, 8 to 16 mg of 0.2% (2 mg per mL) solutionper hour {01} {02}{62}.



Local infiltration


Pain, postoperative:
2 to 200 mg of 0.2% (2 mg per mL) solution or 5 to 200 mg of 0.5% (5 mg per mL) solution, administered in incremental doses {01} {02}.{62}


Peripheral nerve block


Anesthesia, surgical:
Field block—5 to 200 mg of 0.5% (5 mg per mL) solution {62}, administered in incremental doses {01} {02}.

Major nerve block—175 to 250 mgof 0.5% (5 mg per mL) solution {62} , administered in incremental doses {01} {02}.



Usual pediatric dose
Children up to 12 years of age—Safety and efficacy have not been established {01} {02}.

Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


0.2% (2 mg per mL) (Rx) [Naropin{01}]


0.5% (5 mg per mL) (Rx) [Naropin{01}]


0.75% (7.5 mg per mL) (Rx) [Naropin{01}]


1% (10 mg per mL) (Rx) [Naropin{01}]

Canada—


0.2% (2 mg per mL) (Rx) [Naropin{02}]


0.5% (5 mg per mL) (Rx) [Naropin{02}]


0.75% (7.5 mg per mL) (Rx) [Naropin{02}]


1% (10 mg per mL) (Rx) [Naropin{02}]

Packaging and storage:
Store between 20 and 25 ºC (68 and 77 ºF) {01}.

Stability:
Ropivacaine contains no preservatives {01} {02}. Ropivacaine should be used promptly after opening, and any remaining solution should be discarded {01} {02}. Bottles used for continuous infusion should not be left in place for more than 24 hours {01} {02}.

Incompatibilities:
Ropivacaine is incompatible with alkaline solutions {01} {02}.



Revised: 01/10/2001



References
  1. Naropin package insert (Astra USA—US), Rev 11/98, Rec 5/99.
  1. Naropin package insert (Astra Pharma Inc—Canada), Rev 12/96, Rec 2/97.
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  1. Panel comment, 5/97.
  1. Panel comment, 5/97.
  1. Manufacturer comment, 6/97.
  1. Panel comment, 5/97.
  1. Product Information: Naropin™, ropivacaine HCL. Astra, Westborough, MA (PI revised 1/1999) reviewed 1/2001.
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