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  • CLASSES

    Amide Local Anesthetics

    DEA CLASS

    Rx

    DESCRIPTION

    Long-acting, amide-type local anesthetic; structure and kinetics are similar to bupivacaine, however, ropivacaine appears to be less arrhythmogenic.

    COMMON BRAND NAMES

    Naropin, Ropivacaine

    HOW SUPPLIED

    Naropin/Ropivacaine/Ropivacaine Hydrochloride Monohydrate Epidural Inj Sol: 0.2%, 0.5%, 0.75%, 1%
    Naropin/Ropivacaine/Ropivacaine Hydrochloride Monohydrate Infiltration Inj Sol: 0.2%, 0.5%, 0.75%, 1%

    DOSAGE & INDICATIONS

    For local anesthesia, regional anesthesia, or surgical anesthesia.
    NOTE: Doses listed below are those considered necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration may occur. The dose for a major nerve block must be adjusted for the administration site and patient status.
    NOTE: Ropivacaine is not recommended for emergency situations, as a fast onset of surgical anesthesia is necessary. Ropivacaine should be administered in incremental doses.
    For minor nerve block anesthesia and infiltration anesthesia.
    Regional dosage for field block
    Adults

    1—40 ml of a 0.5% solution (5—200 mg) administered in incremental doses.

    For lumbar epidural anesthesia.
    Lumbar epidural dosage
    Adults

    15—30 ml of a 0.5% solution (75—150 mg), 15—25 ml of a 0.75% solution (113—188 mg), or 15—20 ml of a 1% solution (150—200 mg) administered in incremental doses. Long term (continuous) epidural infusion of ropivacaine was evaluated in 11 patients undergoing hip or knee surgery. Patients received an epidural infusion of ropivacaine 2 mg/ml at a rate of 6 ml/hour. The infusion rate was adjusted and ranged from 7—9 ml/ hour (14—18 mg) for up to 72 hours (range of 64—72 hours). The total amount of ropivacaine received during the study ranged between 690 and 1559 mg. Stable sensory block was achieved with minimal motor block.

    For caudal anesthesia†.
    Epidural dosage
    Children

    1 ml/kg (2.5 mg/kg) of 0.25% ropivacaine was similar to 0.25% bupivacaine (1 ml/kg or 2.5 mg/kg) in motor and sensory effects as well as quality and duration of postoperative pain relief.

    For peripheral nerve block, brachial plexus block.
    NOTE:  A higher frequency of adverse events from a local anesthetic may be associated with supraclavicular brachial plexus blocks. Administration of the local anesthetic for a major peripheral nerve block may lead to a high concentration of the drug in a highly vascularized area (see Administration).
    Regional dosage for major nerve block anesthesia
    Adults

    35—50 ml of a 0.5% solution (175—250 mg) or 10—40 ml of a 0.75% solution (75—300 mg) administered in incremental doses.

    For thoracic epidural anesthesia.
    Thoracic epidural dosage
    Adults

    5—15 ml of a 0.5% solution (25—75 mg) or 5—15 ml of a 0.75% solution (38—113 mg) administered in incremental doses.

    For obstetric anesthesia or Caesarean section anesthesia.
    Lumbar epidural infusion dosage
    Adults

    10—20 ml of a 0.2% solution (20—40 mg) initially, then 6—14 ml/hour of a 0.2% solution (12—28 mg/hour) as a continuous epidural infusion. Alternatively, 10—15 ml/hour of a 0.2% solution (20—30 mg/hour) administered in incremental doses.

    Lumbar epidural dosage
    Adults

    1—100 ml of a 0.2% solution (2—200 mg) or 1—40 ml of a 0.5% solution (5—200 mg) administered in incremental doses.

    Epidural dosage (Caesarean anesthesia)
    Adults

    20—30 ml of a 0.5% solution (100—150 mg) or 15—20 ml of a 0.75% solution (113—150 mg) in incremental doses.

    For postoperative treatment of severe pain.
    Lumbar epidural dosage
    Adults

    6—14 ml/hour of a 0.2% solution (12—28 mg/hour) as a continuous epidural infusion can provide analgesia with slight motor block. If regional anesthesia was not used intraoperatively, then an initial epidural block with 5—7 ml of a 0.2% solution epidurally may be given with a cumulative dose up to 770 mg over 24 hours (intraoperative block plus postoperative infusion). Continuous epidural infusions at rates up to 28 mg/hour for 72 hours (2016 mg plus surgical dose of approximately 100—150 mg as top-up) have been well tolerated. Administration of ropivacaine through this technique may reduce the need for opioids.

    Thoracic epidural dosage
    Adults

    6—14 ml/hour of a 0.2% solution (12—28 mg/hour) as a continuous epidural infusion for up to 72 hours.

    Regional dosage for minor nerve block
    Adults

    1—100 ml of a 0.2% solution (2—200 mg) or 1—40 ml of a 0.5% solution (5—200 mg) in incremental doses.

    For ophthalmic anesthesia†, specifically, peribulbar anesthesia and retrobulbar anesthesia.
    NOTE: Although the package labeling advises against this use of ropivacaine (see Contraindications/Precautions), ropivacaine has been studied for retrobulbar and peribulbar nerve block.
    Retrobulbar and Peribulbar dosage
    Adults

    Ropivacaine 0.2% was compared with lidocaine 1% in patients receiving peribulbar/retrobulbar anesthetic blocks. It was found that ropivacaine provided analgesia comparable to lidocaine for ocular surgical analgesia. Supplementary anesthesia was similar in both groups. Ropivacaine produced significantly less motor blockade at the end of treatment compared with lidocaine. Two hours after surgery, significantly more ropivacaine patients had impaired eye movements that required patching than with the lidocaine group.

    †Indicates off-label use

    MAXIMUM DOSAGE

    The dose of local anesthetics differs with the anesthetic procedure; the area to be anesthetized; the vascularity of the tissues; the number of neuronal segments to be blocked; the intensity of the block; the degree of muscle relaxation required; the duration of anesthesia desired; individual tolerance; and the physical condition of the patient.

    Adults

    The maximum dosage is dependent on route of administration and indication for therapy.

    Elderly

    The maximum dosage is dependent on route of administration and indication for therapy.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established; 2.5 mg/kg using a 0.25% solution has been used for caudal anesthesia.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Ropivacaine is extensively metabolized by the liver. Lower doses of ropivacaine may be required in patients with hepatic dysfunction due to prolonged effects and systemic accumulation. Specific dosage guidelines are not available.

    Renal Impairment

    The clearance of ropivacaine may be reduced. However specific guidelines for dosage adjustments in renal impairment are not available.

    ADMINISTRATION

    Injectable Administration

    Consult specialized references for specific procedures and administration techniques.
    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. Delay in proper management of dose-related toxicity, underventilation from any cause, or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death.
    Carefully and constantly monitor cardiovascular and respiratory vital signs and the patient's state of consciousness after each injection and during continuous infusion. Resuscitative equipment and drugs used in the management of adverse reactions should be immediately available while administering local anesthetics.
    Administer by infiltration or peripheral block techniques. Avoid intravascular administration or subarachnoid injection. Aspirate for blood or cerebrospinal fluid before EACH injection. A negative aspiration does not ensure against an intravascular or subarachnoid injection but is a measure to help reduce the risk. Before receipt of a major block, determine the correct dose for your patient (see Dosage), take all necessary precautions to avoid intravascular administration, establish an intravenous line, and optimize the patient's general condition status.
    Ropivacaine solubility is limited at pH above 6. Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer solutions that are discolored or that have particulate matter.

    Other Injectable Administration

    Peripheral block
    Inject slowly and with frequent aspirations to prevent intravascular injection.
     
    Epidural administration
    This route of administration should only be used by specially trained healthcare professionals. Specialized references should be consulted for specific procedures and administration techniques.
    May be given as intermittent bolus, continuous infusion, or as patient-controlled epidural analgesia.
    Placement of the epidural catheter and administration should be at a site near the dermatomes covering the field of pain to decrease dose requirements and increase specificity.
    A test dose of 3—5 ml of a short acting amide anesthetic (e.g., lidocaine with epinephrine) is recommended to detect unintentional intrathecal administration. This will be manifested within a few minutes by signs of subarachnoid block (e.g., decreased sensation of the buttocks, paresis of the legs or absence of knee jerk reflex).
     
    Epidural injection:
    Injections containing preservatives should not be used for epidural injections.
    Discard any partially used injections that do not contain preservatives.
    After ensuring proper placement of the needle or catheter, inject appropriate dose in 3—5 ml increments into the epidural space. Inject doses slowly with frequent aspirations. Time should be taken in between doses to evaluate for toxic manifestations of inadvertent intravascular or intrathecal injection.
     
    Epidural infusion:
    A controlled-infusion device must be used. For highly concentrated injections, an implantable controlled-microinfusion device is used. Patients should be monitored for several days following implantation of the device.
    Injections containing preservatives should not be used for epidural infusion.
    Discard any partially used injections that do not contain preservatives.
    Preservative-free NS injection is recommended for dilution.
     
    Implantable controlled epidural infusion device:
    Filling of the infusion device reservoir should only be done by fully trained and qualified healthcare professionals. Strict aseptic technique must be used. Withdraw dose from the ampule through a 5-µm (or smaller pore diameter) microfilter to avoid contamination with glass or other particles. Remove filter needle and replace with a clean needle prior to injecting dosage into the reservoir. Ensure proper placement of the needle when filling the reservoir to avoid accidental overdosage.
    To avoid exacerbation of severe pain and/or reflux of CSF into the reservoir, depletion of the reservoir should be avoided.

    STORAGE

    Naropin:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Ropivacaine:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    AV block, cardiac arrhythmias, cardiac disease, dehydration, hypotension, hypovolemia, myasthenia gravis, QT prolongation, shock

    Ropivacaine should be used with caution in patients with cardiovascular disease since these patients may not be able to compensate for the cardiac depressant effects of ropivacaine. Local anesthetics should be used with caution in patients with hypotension, hypovolemia or dehydration, myasthenia gravis, shock, or cardiac disease. Patients with cardiac arrhythmias, particularly AV block, may be less able to compensate for functional changes associated with prolonged A-V conduction (i.e., PR or QT prolongation) caused by local anesthetics.

    Intraarterial administration, intrathecal administration, intravenous administration, spinal anesthesia

    Do not use ropivacaine for the production of retrobulbar block or spinal anesthesia (subarachnoid block) due to insufficient data to support such use. Further, intravenous regional anesthesia (Bier block) should not be performed using ropivacaine due to the lack of clinical experience and the risk of attaining toxic blood concentrations of ropivacaine. While performing ropivacaine blocks, avoid intravenous administration. Avoidance of intravascular or subarachnoid injection is essential. Aspirate for blood or cerebrospinal fluid before EACH injection of ropivacaine. Syringe aspiration should be performed before and during each supplemental injection in continuous catheter techniques. Clinicians should be aware that the absence of blood return does not guarantee that intravascular injection has been avoided. Ropivacaine should be administered in incremental doses with close monitoring between doses for signs of intravascular administration. As ropivacaine should not be injected rapidly in large doses, it is not recommended in emergency situations where fast onset of surgical anesthesia is necessary. Unintended intravenous administration, intraarterial administration, or intrathecal administration may result in convulsions, cardiac arrhythmia, and/or cardiac arrest. Cardiac arrest during the use of ropivacaine for epidural anesthesia or peripheral nerve blockade has been reported rarely; most events occurred after unintentional intravascular administration in older patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. If cardiac arrest occurs, prolonged resuscitative efforts may be required to improve the probability of a successful outcome. The potential for successful resuscitation has not been studied in humans. Do not administer ropivacaine intravenously, intrathecally, or intraarterially.

    Anticoagulant therapy, coagulopathy, infection, neurological disease, sepsis, thrombocytopenia

    During epidural administration, a test dose of a local anesthetic with a fast onset (i.e., lidocaine) should be administered initially and the patient should be monitored for CNS and cardiovascular toxicity, as well as signs of inadvertent intrathecal administration. Epidural, spinal, and nerve block injections of ropivacaine are contraindicated in patients with the following: infection or inflammation at the injection site, bacteremia, platelet abnormalities, thrombocytopenia < 100,000/mm3, increased bleeding time, uncontrolled coagulopathy, or anticoagulant therapy. Lumbar and caudal anesthesia should be used with extreme caution in patients with neurological disease, spinal deformities, sepsis, or severe hypertension.

    Head and neck anesthesia

    During head and neck anesthesia, small doses of local anesthetics may produce adverse reactions similar to the systemic toxicity seen with unintentional intravascular injections of larger doses. Patients receiving these blocks should have their ventilatory and circulatory systems monitored closely. Recommended ropivacaine doses should not be exceeded in these patients.

    Geriatric

    Debilitated, acutely ill, and geriatric patients should be given reduced doses of ropivacaine commensurate with their age and physical condition.

    Children

    Safety and efficacy of ropivacaine have not been established in children.

    Amide local anesthetic hypersensitivity

    Ropivacaine is contraindicated in patients with a known amide local anesthetic hypersensitivity. Patients allergic to other types of amide-type local anesthetics may be allergic to ropivacaine.

    Heart failure, hepatic disease

    Due to extensive liver metabolism of ropivacaine by cytochrome P450 (CYP) isoenzymes 1A2, dosage adjustments may be needed inpatients with hepatic disease. In addition, any condition that affects liver blood flow, such as congestive heart failure, may result in increased toxicity due to decreased clearance of ropivacaine. Repeated doses of ropivacaine may cause a significant increase in blood levels with each successive dose. A decrease dosage and/or increase in the interval between doses may be necessary. Due to the extensive liver metabolism of ropivacaine by hepatic microsomal isoenzymes, drugs that affect these enzymes may interact with ropivacaine (see Drug Interactions).

    Eclampsia, fetal distress, fetal prematurity, labor, obstetric delivery, paracervical nerve block, pregnancy, pudendal nerve block

    Ropivacaine is classified as FDA pregnancy risk category B. Well-controlled studies have not been performed in pregnant women; however, no teratogenicity was seen in animal studies. Ropivacaine 0.5% in total doses up to 150 mg may be used for Caesarian section. Inadvertent intravascular injections of the concentrated solution of the related anesthetic bupivacaine have been associated with maternal cardiac arrest and death. Obstetrical paracervical nerve block with ropivacaine is not recommended. Use of some other local anesthetics by this technique has resulted in fetal bradycardia and death. Placental transfer of local anesthetics is dependent upon the degree of plasma protein binding, ionization, and lipid solubility of each agent. Fetal to maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding since only free, unbound drug is available for placental transfer. Ropivacaine rapidly crosses the placenta, and when used for obstetric delivery, can cause maternal, fetal, or neonatal toxicity. The incidence and severity of toxicity depend upon the procedure performed, the type and amount of drug used, and drug administration technique. Appropriate patient positioning during obstetric delivery may decrease maternal hypotension that can result from regional anesthesia-induced vasodilation. Injection of the local anesthetic should be performed with the patient in the left lateral decubitus position to displace the gravid uterus, thereby minimizing aortocaval compression. Epidural, spinal, or pudendal nerve block may alter the forces of parturition. The use of obstetrical anesthesia may alter the duration of various phases of labor and increase the need for forceps assistance. Paracervical nerve block may be associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation, and use in early pregnancy (i.e., anesthesia for elective abortion) may result in rapid systemic absorption with maternal seizures or cardiovascular collapse. Epidural anesthesia may prolong the second stage of labor by removing the reflex urge to bear down or by interfering with motor function. Local anesthetics should be used with extreme caution in patients with pregnancies complicated by fetal prematurity, eclampsia, fetal distress, or maternal or fetal sepsis. Electronic fetal monitoring for signs of fetal distress is highly recommended. The newborn may experience diminished muscle strength and tone for the first day or two of life after use of regional anesthetics during labor and delivery.

    Breast-feeding

    According to the manufacturer, the rate and extent of ropivacaine excretion into breast milk is unknown, and caution should be exercised if the drug is administered to a breast-feeding woman. Studies in animals indicate that the estimated daily dose to a nursing rat pup would be about 4% of the dose given to the mother. With a similar assumption in humans, ropivacaine exposure in the nursing infant would be much less than that of the mother during her pregnancy. In addition, due to poor absorption of local anesthetics through the GI tract, the potential for adverse effects in the nursing infant is low. Local anesthetics such as lidocaine and bupivacaine are minimally excreted into breast milk; however, the potential for adverse effects in the nursing infant is low due to poor oral absorption. A prospective cohort study comparing women who received no analgesia (n = 63) to women who received continuous epidural fentanyl and either bupivacaine 0.05 to 0.1% (n = 39) or ropivacaine (n = 13) during labor and delivery found no differences between the groups in breast-feeding effectiveness or infant neurobehavioral status at 8—12 hours postpartum. Although ropivacaine has not been evaluated by the American Academy of Pediatrics (AAP), the AAP considers lidocaine to be usually compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternal drug exposure, healthcare providers are encouraged to report the adverse effect to the FDA.

    Continuous intraarticular infusion administration

    Ropivacaine is not approved for continuous intraarticular infusion administration. Infusion of local anesthetics into a joint space may have caused chondrolysis (see Adverse Reactions). Local anesthetics are not indicated for continuous intraarticular postoperative infusions or for use with infusion devices such as elastomeric pumps.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 5.0-20.0
    oliguria / Early / 1.0-5.0
    ventricular tachycardia / Early / 1.0-5.0
    seizures / Delayed / 0-1.0
    myocardial infarction / Delayed / 0-1.0
    atrial fibrillation / Early / 0-1.0
    bronchospasm / Rapid / 0-1.0
    thrombosis / Delayed / 0-1.0
    pulmonary embolism / Delayed / 0-1.0
    muscle paralysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    coma / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    visual impairment / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    AV block / Early / Incidence not known
    chondrolysis / Delayed / Incidence not known
    malignant hyperthermia / Rapid / Incidence not known

    Moderate

    hypotension / Rapid / 32.0-54.0
    fetal bradycardia / Delayed / 12.1-12.1
    jaundice / Delayed / 7.7-7.7
    anemia / Delayed / 6.0-6.0
    urinary retention / Early / 1.0-5.0
    hypertension / Early / 1.0-5.0
    chest pain (unspecified) / Early / 1.0-5.0
    sinus tachycardia / Rapid / 1.0-5.0
    dyspnea / Early / 1.0-5.0
    hypokalemia / Delayed / 1.0-5.0
    tachypnea / Early / 2.0-2.0
    fetal distress / Delayed / 1.7-1.7
    hypoglycemia / Early / 1.3-1.3
    fecal incontinence / Early / 0-1.0
    urinary incontinence / Early / 0-1.0
    blurred vision / Early / 0-1.0
    confusion / Early / 0-1.0
    orthostatic hypotension / Delayed / 0-1.0
    phlebitis / Rapid / 0-1.0
    hypomagnesemia / Delayed / 0-1.0
    meningitis / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    erythema / Early / Incidence not known
    dyskinesia / Delayed / Incidence not known
    hypotonia / Delayed / Incidence not known
    respiratory depression / Rapid / Incidence not known
    hallucinations / Early / Incidence not known
    depression / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    paresis / Delayed / Incidence not known
    angina / Early / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    palpitations / Early / Incidence not known
    fetal acidosis / Delayed / Incidence not known
    decreased uterine contractility / Early / Incidence not known

    Mild

    nausea / Early / 13.0-25.0
    back pain / Delayed / 4.0-17.0
    vomiting / Early / 7.0-12.0
    fever / Early / 2.0-9.0
    headache / Early / 4.0-8.0
    paresthesias / Delayed / 2.0-6.0
    pruritus / Rapid / 1.0-5.0
    chills / Rapid / 2.0-3.0
    dizziness / Early / 2.5-2.5
    hypoesthesia / Delayed / 1.6-1.6
    infection / Delayed / 1.6-1.6
    anxiety / Delayed / 1.3-1.3
    rhinitis / Early / 1.1-1.1
    tenesmus / Delayed / 0-1.0
    urticaria / Rapid / 0-1.0
    hypothermia / Delayed / 0-1.0
    tremor / Early / 0-1.0
    drowsiness / Early / 0-1.0
    asthenia / Delayed / 0-1.0
    malaise / Early / 0-1.0
    tinnitus / Delayed / 0-1.0
    syncope / Early / 0-1.0
    injection site reaction / Rapid / 0-1.0
    myalgia / Early / 0-1.0
    cough / Delayed / 0-1.0
    weakness / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    sneezing / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    agitation / Early / Incidence not known
    emotional lability / Early / Incidence not known
    restlessness / Early / Incidence not known
    nightmares / Early / Incidence not known
    insomnia / Early / Incidence not known
    vertigo / Early / Incidence not known
    diplopia / Early / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Codeine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Hydrocodone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Oxycodone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Propoxyphene: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Alfentanil: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Ambenonium Chloride: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine.
    Aprepitant, Fosaprepitant: (Major) Use caution if ropivacaine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in ropivacaine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Ropivacaine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ropivacaine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Oxycodone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Atazanavir: (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate.
    Atazanavir; Cobicistat: (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate. (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate.
    Atenolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Atenolol; Chlorthalidone: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Atracurium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Atropine; Edrophonium: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine.
    Belladonna; Opium: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bendroflumethiazide; Nadolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Benzonatate: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Beta-adrenergic blockers: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Betaxolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Bisoprolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering ropivacaine with boceprevir due to an increased potential for ropivacaine-related adverse events. If ropivacaine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ropivacaine. Ropivacaine is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated ropivacaine plasma concentrations.
    Brimonidine; Timolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Carteolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Carvedilol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chloroprocaine: (Major) Caution is advised if a local anesthetic is used concurrently with other local anesthetics. The toxic effects of the drugs are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage.
    Chlorpheniramine; Codeine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlorpheniramine; Hydrocodone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Cimetidine: (Major) Known inhibitors of cytochrome P450 1A2, such as cimetidine, may increase the systemic levels of ropivacaine and increase the risk of toxicity when given concurrently.
    Ciprofloxacin: (Moderate) Ropivacaine is metabolized to a 3-OH metabolite primarily by CYP1A2 and to a lesser extent to the pipecoloxylidide (PPX) metabolite by CYP3A4. In a double-blind study, ciprofloxacin reduced the mean plasma clearance of ropivacaine by 31% by inhibiting CYP1A2 and increased the formation of PPX by redirecting metabolism to CYP3A4.
    Cisatracurium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Cobicistat: (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate.
    Codeine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Codeine; Guaifenesin: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Codeine; Phenylephrine; Promethazine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Codeine; Promethazine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Darunavir: (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate.
    Darunavir; Cobicistat: (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate. (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Donepezil: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine.
    Donepezil; Memantine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine.
    Dorzolamide; Timolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Doxacurium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Edrophonium: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine.
    Elbasvir; Grazoprevir: (Moderate) Administering ropivacaine with elbasvir; grazoprevir may result in elevated ropivacaine plasma concentrations. Ropivacaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Esmolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Ester local anesthetics: (Major) Caution is advised if a local anesthetic is used concurrently with other local anesthetics. The toxic effects of the drugs are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage.
    Fentanyl: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Fluvoxamine: (Major) Ropivacaine is metabolized primarily by cytochrome P450 (CYP) isoenzyme 1A2. Agents that are known inhibitors of CYP1A2, such as fluvoxamine, may result in increased systemic levels of ropivacaine when given concurrently, resulting in toxicity. In vivo, the plasma clearance of ropivacaine was reduced by 70% and the half-life doubled during concurrent administration of fluvoxamine.
    Galantamine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine.
    Guaifenesin; Hydrocodone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Homatropine; Hydrocodone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Hyaluronidase: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Hydrocodone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydrocodone; Ibuprofen: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydrocodone; Phenylephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydrocodone; Pseudoephedrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydromorphone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Ibuprofen; Oxycodone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with ropivacaine, a CYP3A substrate, as ropivacaine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Isocarboxazid: (Severe) Patients receiving local anesthetics may have an increased risk of hypotension. Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. Use of epinephrine added to etidocaine with monoamine oxidase inhibitors (MAOIs) or drugs with MAOI activity (e.g., furazolidone, linezolid, or procarbazine) is not recommended. When local anesthetics containing sympathomimetic vasoconstrictors are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs and agents with MAOI activity can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine. Phenelzine, tranylcypromine, and transdermal selegiline are contraindicated for use for at least 10 days prior to elective surgery.
    Ivacaftor: (Minor) Use caution when administering ivacaftor and ropivacaine concurrently. Ivacaftor is an inhibitor of CYP3A; ropivacaine is partially metabolized by CYP3A. Co-administration may increase ropivacaine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ketoconazole: (Moderate) Concurrent administration of ketoconazole and ropivacaine may result in elevated ropivacaine serum concentration; thereby increasing the risk for drug toxicity. The metabolism of ropivacaine to 3-hydroxyropivacaine is dependent on CYP1A2, and the metabolism of ropivacaine to (S)-2',6'-pipecoloxylidide is dependent on CYP3A4. Ropivacaine is metabolized to a lesser extent by cytochrome CYP3A4. Without the presence of an enzyme inducer or inhibitor, the fraction of a ropivacaine dose that is converted to (S)-2',6'-pipecoloxylidide is 0.01 +/- 0.02 whereas 0.39 +/- 0.05 is converted to 3-hydroxyropivacaine. In the presence of the CYP3A4 inhibitor, ketoconazole, the disposition of ketoconazole was all 3-hydroxyropivacaine (0.47 +/- 0.07). Concurrent administration of ketoconazole (100 mg twice daily for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in vivo ropivacaine plasma clearance. Plasma ropivacaine concentrations increased slightly.
    Labetalol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Levobetaxolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Levobunolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Levomethadyl: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Levorphanol: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of ropivacaine by increasing its clearance; if used together, monitor therapeutic response and adjust the ropivacaine dosage as needed to attain appropriate anesthesia. Ropivacaine is partially metabolized by CYP3A4. Lumacaftor is a strong CYP3A inducer. (Minor) Use caution when administering ivacaftor and ropivacaine concurrently. Ivacaftor is an inhibitor of CYP3A; ropivacaine is partially metabolized by CYP3A. Co-administration may increase ropivacaine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of ropivacaine by increasing its clearance; if used together, monitor therapeutic response and adjust the ropivacaine dosage as needed to attain appropriate anesthesia. Ropivacaine is partially metabolized by CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as local anesthetics. Caution should be exercised when using these agents concurrently.
    Meperidine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meperidine; Promethazine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methadone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Metoprolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Minocycline: (Moderate) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as local anesthetics. Caution should be exercised when using these agents concurrently.
    Mitotane: (Moderate) Use caution if mitotane and ropivacaine are used concomitantly, and monitor for decreased efficacy of ropivacaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. Ropivacaine is a CYP3A4 substrate, although inhibition of this enzyme does not lead to clinically relevant changes in ropivacaine clearance; coadministration may theoretically result in decreased plasma concentrations of ropivacaine.
    Mivacurium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Monoamine oxidase inhibitors: (Severe) Patients receiving local anesthetics may have an increased risk of hypotension. Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. Use of epinephrine added to etidocaine with monoamine oxidase inhibitors (MAOIs) or drugs with MAOI activity (e.g., furazolidone, linezolid, or procarbazine) is not recommended. When local anesthetics containing sympathomimetic vasoconstrictors are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs and agents with MAOI activity can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine. Phenelzine, tranylcypromine, and transdermal selegiline are contraindicated for use for at least 10 days prior to elective surgery.
    Morphine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Morphine; Naltrexone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Nadolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Nebivolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Nebivolol; Valsartan: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Neostigmine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine.
    Neuromuscular blockers: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as ropivacaine. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration.
    Oxycodone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Oxymorphone: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Pancuronium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and ropivacaine, a CYP3A4 substrate, may cause an increase in systemic concentrations of ropivacaine. Use caution when administering these drugs concomitantly.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects, such as hypotension, bradycardia or GI effects, associated with increased exposure to ropivacaine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 inhibitor and ropivacaine is metabolized to a 3-OH metabolite primarily by CYP1A2 and to a lesser extent to the pipecoloxylidide (PPX) metabolite by CYP3A4.
    Penbutolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Phenelzine: (Severe) Patients receiving local anesthetics may have an increased risk of hypotension. Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. Use of epinephrine added to etidocaine with monoamine oxidase inhibitors (MAOIs) or drugs with MAOI activity (e.g., furazolidone, linezolid, or procarbazine) is not recommended. When local anesthetics containing sympathomimetic vasoconstrictors are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs and agents with MAOI activity can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine. Phenelzine, tranylcypromine, and transdermal selegiline are contraindicated for use for at least 10 days prior to elective surgery.
    Physostigmine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine.
    Pindolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Procaine: (Major) Caution is advised if a local anesthetic is used concurrently with other local anesthetics. The toxic effects of the drugs are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage.
    Procarbazine: (Major) Patients taking procarbazine should not be given local anesthetics containing sympathomimetic vasoconstrictors; coadministration may invoke a severe hypertensive reaction. Procarbazine should be discontinued for at least 10 days prior to elective surgery.
    Propoxyphene: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Propranolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Rapacuronium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Remifentanil: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Rituximab; Hyaluronidase: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Rocuronium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Rofecoxib: (Major) Ropivacaine is metabolized primarily by cytochrome P450 isoenzyme 1A2. Interactions are possible with other drug known to be inhibitors of CYP1A2, such as rofecoxib.
    Selegiline: (Severe) Patients receiving local anesthetics may have an increased risk of hypotension. Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. Use of epinephrine added to etidocaine with monoamine oxidase inhibitors (MAOIs) or drugs with MAOI activity (e.g., furazolidone, linezolid, or procarbazine) is not recommended. When local anesthetics containing sympathomimetic vasoconstrictors are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs and agents with MAOI activity can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine. Phenelzine, tranylcypromine, and transdermal selegiline are contraindicated for use for at least 10 days prior to elective surgery.
    Simeprevir: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of ropivacaine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of ropivacaine, such as hypotension, CNS toxicity, and respiratory depression.
    Succinylcholine: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Sufentanil: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tacrine: (Major) Known inhibitors of cytochrome P450 CYP1A2, such as tacrine, may increase the systemic plasma concentrations of ropivacaine and increase the risk of toxicity when given concurrently. Also, local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering ropivacaine with telaprevir due to an increased potential for ropivacaine-related adverse events. If ropivacaine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ropivacaine. Ropivacaine is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated ropivacaine plasma concentrations.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ropivacaine is necessary, as the systemic exposure of ropivacaine may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of ropivacaine; consider increasing the dose of ropivacaine if necessary. Ropivacaine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Tetracaine: (Major) Caution is advised if a local anesthetic is used concurrently with other local anesthetics. The toxic effects of the drugs are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage.
    Theophylline, Aminophylline: (Minor) Agents that are also metabolized by cytochrome P450 1A2, such as aminophylline, may decrease the metabolism of ropivacaine through competitive inhibition. (Minor) Agents that are also metabolized by cytochrome P450 1A2, such as theophylline, may decrease the metabolism of ropivacaine through competitive inhibition.
    Thiabendazole: (Moderate) Thiabendazole is a potent CYP1A2 inhibitor. Ropivacaine is metabolized to a 3-OH metabolite primarily by CYP1A2 and to a lesser extent to the pipecoloxylidide (PPX) metabolite by CYP3A4. Other significant CYP1A2 inhibitors can reduce the mean plasma clearance of ropivacaine by inhibiting CYP1A2 and increase the formation of PPX by redirecting metabolism to CYP3A4. Use caution and monitor closely during times of coadministration.
    Timolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Tranylcypromine: (Severe) Patients receiving local anesthetics may have an increased risk of hypotension. Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. Use of epinephrine added to etidocaine with monoamine oxidase inhibitors (MAOIs) or drugs with MAOI activity (e.g., furazolidone, linezolid, or procarbazine) is not recommended. When local anesthetics containing sympathomimetic vasoconstrictors are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs and agents with MAOI activity can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine. Phenelzine, tranylcypromine, and transdermal selegiline are contraindicated for use for at least 10 days prior to elective surgery.
    Tubocurarine: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Vancomycin: (Moderate) The concurrent administration of vancomycin and anesthetics has been associated with erythema, histamine-like flushing, and anaphylactoid reactions.
    Vecuronium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Zileuton: (Major) Concomitant use of ropivacaine and zileuton may result in increased systemic concentrations of ropivacaine and subsequent toxicity. Ropivacaine is metabolized primarily by CYP1A2. Zileuton is a competitive inhibitor of CYP1A2.

    PREGNANCY AND LACTATION

    Pregnancy

    Ropivacaine is classified as FDA pregnancy risk category B. Well-controlled studies have not been performed in pregnant women; however, no teratogenicity was seen in animal studies. Ropivacaine 0.5% in total doses up to 150 mg may be used for Caesarian section. Inadvertent intravascular injections of the concentrated solution of the related anesthetic bupivacaine have been associated with maternal cardiac arrest and death. Obstetrical paracervical nerve block with ropivacaine is not recommended. Use of some other local anesthetics by this technique has resulted in fetal bradycardia and death. Placental transfer of local anesthetics is dependent upon the degree of plasma protein binding, ionization, and lipid solubility of each agent. Fetal to maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding since only free, unbound drug is available for placental transfer. Ropivacaine rapidly crosses the placenta, and when used for obstetric delivery, can cause maternal, fetal, or neonatal toxicity. The incidence and severity of toxicity depend upon the procedure performed, the type and amount of drug used, and drug administration technique. Appropriate patient positioning during obstetric delivery may decrease maternal hypotension that can result from regional anesthesia-induced vasodilation. Injection of the local anesthetic should be performed with the patient in the left lateral decubitus position to displace the gravid uterus, thereby minimizing aortocaval compression. Epidural, spinal, or pudendal nerve block may alter the forces of parturition. The use of obstetrical anesthesia may alter the duration of various phases of labor and increase the need for forceps assistance. Paracervical nerve block may be associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation, and use in early pregnancy (i.e., anesthesia for elective abortion) may result in rapid systemic absorption with maternal seizures or cardiovascular collapse. Epidural anesthesia may prolong the second stage of labor by removing the reflex urge to bear down or by interfering with motor function. Local anesthetics should be used with extreme caution in patients with pregnancies complicated by fetal prematurity, eclampsia, fetal distress, or maternal or fetal sepsis. Electronic fetal monitoring for signs of fetal distress is highly recommended. The newborn may experience diminished muscle strength and tone for the first day or two of life after use of regional anesthetics during labor and delivery.

    MECHANISM OF ACTION

    Mechanism of Action: Ropivacaine works by interfering with sodium entry into nerve cell membranes. Like all local anesthetics, ropivacaine causes a reversible nerve-conduction blockade by decreasing nerve membrane permeability to sodium. This decreases the rate of membrane depolarization, thereby increasing the threshold for electrical excitability. The blockade affects all nerve fibers in the following sequence: autonomic, sensory, and motor, with effects diminishing in reverse order. Loss of nerve function clinically is as follows: pain, temperature, touch, proprioception, and skeletal muscle tone.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 AV block, ventricular arrhythmia, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilatation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. CNS stimulation is usually manifested as restlessness, tremors, and shivering progressing to convulsions, followed by depression and coma, progressing ultimately to respiratory arrest. However, local anesthetics have a primary depressant effect on the medulla and higher centers. The depressed stage may occur without the prior excitatory stage. Animal studies demonstrated that the cardiac toxicity of ropivacaine is less than bupivacaine, although both agents were more toxic than lidocaine. Ropivacaine caused significantly less depression of cardiac contractility (less QRS widening) than bupivacaine. Both caused evidence of depression of cardiac contractility, but there were no changes in cardiac output. In human studies, similar CNS symptoms were seen with both ropivacaine and bupivacaine.

    PHARMACOKINETICS

    Ropivacaine is given parenterally either as an epidural infusion or a regional nerve block. (NOTE: INTRAVENOUS ADMINISTRATION IS TO BE AVOIDED.) Absorption 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. Unlike other local anesthetics, epinephrine has no major effect on either the time of onset or the duration of action of ropivacaine. Therefore, the addition of epinephrine has no effect on limiting systemic absorption.
     
    Ropivacaine is distributed to all tissues and highly protein bound to alpha-1 acid glycoprotein. It is extensively metabolized by the liver and is excreted renally with 1% of the dose excreted unchanged.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP1A2, CYP3A4
    The metabolism of ropivacaine to 3-hydroxyropivacaine is dependent on CYP1A2, and the metabolism of ropivacaine to (S)-2',6'-pipecoloxylidide is dependent on CYP3A4. CYP3A4 is involved to a lesser extent, and inhibition of this enzyme does not lead to clinically relevant changes in ropivacaine clearance.

    Other Route(s)

    Epidural route
    After epidural injection, ropivacaine shows a biphasic absorption, with an initial rapid phase half-life (mean of 14 +/- 7 minutes) and a slower phase (4.2 +/- 0.9 minutes). After administration of ropivacaine the onset of action occurs at 10—25 minutes with a duration of 2—4 hours. The terminal half life of ropivacaine is 4.2 +/- 1.0 hours after epidural administration. The terminal half-life is longer after epidural administration than after intravenous administration because of this slow absorption.
     
    Nerve block 
    After administration of ropivacaine the onset of action occurs at 15—30 minutes for major nerve block with a duration of 5—8 hours.
     
    Field block 
    After administration of ropivacaine the onset of action occurs at 1—15 minutes for field block with a duration of 2—6 hours.
     
    Intravascular route
    The terminal half life of ropivacaine is 1.8 +/- 0.7 hours after intravascular administration.