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  • CLASSES

    Amide Local Anesthetics

    DEA CLASS

    Rx

    DESCRIPTION

    Long-acting amide-type local anesthetic; rapid onset of action; analgesia persists longer than anesthesia; available with and without epinephrine.

    COMMON BRAND NAMES

    Marcaine, Sensorcaine, Sensorcaine MPF

    HOW SUPPLIED

    Bupivacaine Hydrochloride, Dextrose/Bupivacaine, Dextrose/Marcaine/Sensorcaine MPF Intrathecal Inj Sol: 0.75-8.25%
    Bupivacaine/Bupivacaine Hydrochloride/Marcaine/Sensorcaine MPF Retrobulbar Inj Sol: 0.75%
    Bupivacaine/Bupivacaine Hydrochloride/Marcaine/Sensorcaine/Sensorcaine MPF Epidural Inj Sol: 0.25%, 0.5%, 0.75%
    Bupivacaine/Bupivacaine Hydrochloride/Marcaine/Sensorcaine/Sensorcaine MPF Infiltration Inj Sol: 0.25%, 0.5%, 0.75%
    Bupivacaine/Bupivacaine Hydrochloride/Marcaine/Sensorcaine/Sensorcaine MPF Intracaudal Inj Sol: 0.25%, 0.5%
    Bupivacaine/Bupivacaine Hydrochloride/Marcaine/Sensorcaine/Sensorcaine MPF Intramuscular Inj Sol: 0.25%, 0.5%
    Marcaine Epidural Sol: 0.25%
    Marcaine Infiltration Sol: 0.25%
    Marcaine Intraspinal Inj Sol: 0.75-8.25%
    Sensorcaine MPF Subarachnoid Inj Sol: 0.75-8.25%

    DOSAGE & INDICATIONS

    For local anesthesia or regional 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.
    For caudal anesthesia.
    Epidural dosage
    Adults

    15 to 30 mL of 0.25% or 0.5% solution (37.5 to 150 mg).

    Children†

    1 to 3.7 mg/kg.

    For infiltration anesthesia including dental anesthesia.
    Regional dosage
    Adults

    Up to 175 mg bupivacaine 0.25% as a single dose. May repeat once every 3 hours, do not exceed 400 mg in 24 hours.

    For epidural anesthesia (other than caudal block).
    Epidural dosage
    Adults

    10 to 20 mL of 0.25%, 0.5%, 0.75% solution (25 to 150 mg). Bupivacaine 0.75% should not be used for obstetrical anesthesia or intermittent (catheter) epidural technique. For obstetrics only the 0.25% or 0.5% solution should be used. Incremental doses of 3 to 5 mL of the 0.5% solution not exceeding 50 to 100 mg are recommended.

    Children†

    1.25 mg/kg.

    For peripheral nerve block.
    Regional dosage
    Adults

    Initially, 5 mL (12.5 to 25 mg) of a 0.25% or 0.5% solution, up to a maximum of 400 mg daily. Single doses should not exceed 175 mg and may be repeated once every 3 hours.

    For sympathetic nerve block.
    Regional dosage
    Adults

    20 to 50 mL of a 0.25% solution (50 to 125 mg).

    For ophthalmic anesthesia (i.e., retrobulbar nerve block).
    Regional dosage
    Adults

    2 to 4 mL of a 0.75% solution (15 to 30 mg).

    For spinal anesthesia.
    NOTE: The following doses are guidelines only. Lower doses may be required in elderly or debilitated patients
    Obstetric anesthesia including caesarean section anesthesia.
    Intrathecal dosage (0.75% Marcaine Spinal or 0.75% Sensorcaine Spinal Injection in dextrose only)
    Adults

    Doses as low as 6 mg of bupivacaine have been used for spinal anesthesia during vaginal delivery. At recommended doses, spinal bupivacaine produces complete motor and sensory block.

    For anesthesia in lower extremity and perineal procedures.
    Intrathecal dosage (0.75% Marcaine Spinal or 0.75% Sensorcaine Spinal Injection in dextrose only)
    Adults

    1 mL (7.5 mg) of 0.75% bupivacaine in 8.25% dextrose. For lower abdominal procedures, such as abdominal hysterectomy, tubal ligation, and appendectomy use 1.6 mL (12 mg).

    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

    175 mg bupivacaine as a single dose without epinephrine or a total dose of 400 mg/24 hours. Doses should not be repeated any more frequently than every 3 hours. In obstetrics, 3—4 mL incremental doses of a 0.5% solution, not to exceed 50—100 mg at any dosing interval. For dental procedures, no more than 90 mg per procedure is recommended.

    Children

    Maximum dosage information is not available.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Specialized references should be consulted for specific procedures and administration techniques.
    Resuscitative equipment and drugs used in the management of adverse reactions should be immediately available while administering local anesthetics.
    Bupivacaine is administered by infiltration, peripheral, sympathetic, or spinal block techniques.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Other Injectable Administration

    Dental, peripheral, or sympathetic block:
    Inject slowly and with frequent aspirations to prevent intravascular injection.

    Other Administration Route(s)

    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.
    Resuscitative equipment and drugs used in the management of adverse reactions should be immediately available while administering local anesthetics.
    May be given as a caudal block, epidural intermittent bolus, continuous infusion or as patient controlled epidural analgesia.
    Placement of 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 2 mL or 20% of the total dose (whichever is less) or 3 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 or caudal 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. 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:
    Injections containing preservatives should not be used for epidural infusion. Discard any partially used injections that do not contain preservatives.
    Preservative-free 0.9% Sodium Chloride injection is recommended for dilution.
    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.
    Implantable 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-micrometer (or smaller pore diameter) microfilter to avoid contamination with glass or other particles. After withdrawing medication from the ampule, replace filter needle with a clean needle prior to injecting 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 cerebral spinal fluid (CSF) into the reservoir, depletion of the reservoir should be avoided.
     
    Spinal Administration (Marcaine Spinal or Sensorcaine Spinal in dextrose only)
    This route should only be used by specially trained healthcare professionals. Specialized references should be consulted for specific procedures and administration techniques.
    Resuscitative equipment and drugs used in the management of adverse reactions should be immediately available while administering spinal anesthesia.
    Use bupivacaine hydrochloride in dextrose injection. Injections containing preservatives should not be used. Prior to using, the outside of ampules should be sterilized, preferably by autoclaving.
    Do not autoclave ampules more than once since the formulation contains dextrose, caramelization may occur under prolonged heating and, in some instances, prolonged storage.
    Do not use solution if it is discolored or a precipitate is present.
    Discard any partially used injections that do not contain preservatives.
     
    Spinal block:
    Spinal anesthesia may be induced in the right or left lateral recumbent position or the sitting position. Since this is a hyperbaric solution, the anesthetic will tend to move in the direction in which the table is tilted.
    Administer via 22 or 25 gauge spinal needles. Monitor blood pressure during administration.
    After the desired level of anesthesia is obtained and the anesthetic has become fixed, the patient may be positioned appropriately.

    STORAGE

    Marcaine:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sensorcaine:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sensorcaine MPF :
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Local anesthetics such as bupivacaine should only be administered by a clinician trained in the diagnosis and management of drug-related toxicity and other acute emergencies that might arise from the administration of a regional anesthetic block. The immediate availability of oxygen, cardiopulmonary resuscitative equipment and drugs, and the appropriate support personnel for the management of toxic reactions or emergencies must be ensured. Any delay in appropriate management may lead to the development of acidosis, cardiac arrest, and possibly death.

    Intraarterial administration, intrathecal administration, intravenous administration

    Intravenous administration, intraarterial administration, or intrathecal administration of bupivacaine should be avoided. Unintended intravenous or intraarterial administration may result in cardiac arrest and may require prolonged resuscitation. To avoid intravascular administration of bupivacaine during local anesthetic procedures, aspiration should be performed before the local anesthetic is injected and after repositioning of the needle. During epidural administration, a test dose should be administered initially and the patient should be monitored for CNS and cardiovascular toxicity, as well as signs of inadvertent intrathecal administration. Syringe aspiration should also 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.

    Head and neck anesthesia

    Patients receiving bupivacaine for local head and neck anesthesia including retrobulbar, stellate ganglion, and dental blocks, are at increased risk of CNS toxicity similar to the systemic toxicity seen with unintentional intravascular injections of large doses. These reactions may be due to potential intraarterial injection of the local anesthetic such as bupivacaine with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their ventilatory and circulatory systems monitored closely. Recommended doses should not be exceeded in these patients.

    Ocular surgery

    When local anesthetics, like bupivacaine, are used for retrobulbar block during ocular surgery, lack of corneal sensation should not be relied upon to determine whether or not the patient is ready for surgery. Lack of corneal sensation usually precedes clinically acceptable external ocular muscle akinesia.

    AV block, cardiac disease, cardiogenic shock, dehydration, hemorrhagic shock, hypotension, hypovolemia, myasthenia gravis, shock

    Local anesthetics , such as bupivacaine, should be used with caution in patients with hypotension, hypovolemia or dehydration, myasthenia gravis, shock (e.g., cardiogenic shock or hemorrhagic shock), or cardiac disease. Patients with impaired cardiac function, particularly AV block, may be less able to compensate for functional changes associated with prolonged AV conduction (i.e., PR or QT prolongation) caused by local anesthetics.

    Anticoagulant therapy, coagulopathy, epidural anesthesia, hypertension, infection, neurological disease, sepsis, thrombocytopenia

    Spinal and epidural anesthesia and nerve block injections of bupivacaine 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.

    Bleeding, cardiac arrhythmias, children, geriatric, headache, infants, neonates, spinal anesthesia

    Bupivacaine solutions should not be used in neonates, infants, and children < 12 years old. The solution for spinal anesthesia should not be used in children or adolescents under the age of 18 years. Spinal anesthesia is contraindicated in patients with severe bleeding, severe hypotension, shock, cardiac arrhythmias, infection at the injection site, and sepsis. Patients with the following conditions should receive spinal anesthesia with caution: pre-existing CNS disorders such as poliomyelitis, pernicious anemia, paralysis from nerve injuries or syphilis; infants, children < 16 years, or geriatric patients; hematologic disorders predisposing to coagulopathy (e.g., thrombocytopenia); anticoagulant therapy; chronic backache; preoperative headache; hypotension; hypertension; arthritis or spinal deformity; technical problems (persistent paresthesias, persistent bloody tap); psychotic or uncooperative patients. Consult standard textbooks for specific techniques and precautions for spinal anesthetic procedures. Elderly patients, especially those receiving treatment for hypertension, may be at increased risk for the hypotensive effects of bupivacaine. In addition, elderly patients may require decreased doses of bupivacaine as compared to younger patients due to pharmacokinetic differences.
     

    Amide local anesthetic hypersensitivity, paraben hypersensitivity

    Bupivacaine is contraindicated in patients with known amide local anesthetic hypersensitivity. Multi-dose vials of bupivacaine contain methylparaben as a preservative and thus, should not be used in patients with paraben hypersensitivity. Allergic-type reactions including anaphylactic symptoms (e.g., urticaria, pruritus, erythema, laryngeal edema, tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and severe hypotension) may occur.

    Heart failure, hepatic disease

    Due to extensive liver metabolism of bupivacaine, dosage adjustments may be needed in patients 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 bupivacaine. Patients with hepatic disease may be more susceptible to the potential toxicities of bupivacaine. Dosage adjustments or extension of the dosing interval may be required.

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

    Bupivacaine is classified in FDA pregnancy risk category C. ONLY the 0.25% and 0.5% concentrations are indicated for obstetrical anesthesia. The 0.75% solution of bupivacaine HCL is contraindicated for obstetric anesthesia; cardiac arrest with difficult resuscitation or death has occurred during use of 0.75% bupivacaine concentration for epidural anesthesia during obstetric delivery, despite apparently adequate preparation and appropriate management. Cardiac arrest occurred after convulsions resulting from systemic toxicity, presumably after unintentional intravascular injection. Most cases of cardiac arrest occurred after use of the 0.75% concentration; reserve the 0.75% concentration for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary. Obstetrical paracervical nerve block with bupivacaine is contraindicated; its use 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. Bupivacaine is about 95% bound to plasma proteins, resulting in a low fetal to maternal ratio (0.2—0.4). Epidural bupivacaine has been used safely in labor and delivery when the maximum recommended dosages are not exceeded and strict adherence to manufacturer guidelines are followed. 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 and can result in 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, although this has not been reported with bupivacaine.

    Breast-feeding

    According to the manufacturer, caution should be exercised when local anesthetics are administered to a woman who is breast-feeding. Bupivacaine is minimally excreted into breast milk. Due to poor oral absorption of local anesthetics, the potential for adverse effects in the nursing infant is low. In general, use of such agents during surgery or other procedures allows breast-feeding of the healthy term infant to be permissible as soon as the mother is awake and alert. In one study of 27 pregnant women undergoing cesarean delivery, administration of epidural anesthesia with 0.5% bupivacaine and 2% lidocaine during delivery had no effect on the infants who were breast-fed. In one comparison study of epidural anesthesia with bupivacaine to a general anesthesia regimen, the time to first breast-feed was significantly shorter (107 vs 228 minutes) with bupivacaine than with general anesthesia. 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 bupivacaine 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

    Bupivacaine 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 intra-articular postoperative infusions or for use with infusion devices such as elastomeric pumps.

    Requires a specialized care setting, requires an experienced clinician

    Parenteral administration of local anesthetics such as bupivacaine requires an experienced clinician, trained in the diagnosis and management of drug-related toxicity and other acute emergencies that might arise from the administration of an anesthetic nerve block. Administration requires a specialized care setting; immediate availability of oxygen, resuscitative medications and equipment, and appropriate supportive personnel must be ensured prior to injection. Any delay in appropriate management may lead to the development of acidosis, cardiac arrest, and possibly death.

    Malignant hyperthermia

    Use bupivacaine with caution in patients with a genetic predisposition to malignant hyperthermia. Although it is unknown whether amide-type local anesthetics trigger this reaction, it is recommended that a standard protocol for management be available when bupivacaine is administered.

    Electrolyte imbalance, seizure disorder, seizures

    Patients at risk for seizures (e.g., those with electrolyte imbalance) or those with a  pre-existing seizure disorder may be at an increased risk of convulsions; such patients should receive bupivacaine at a reduced infusion rate.

    Renal disease, renal impairment

    Use bupivacaine with caution in patients with renal disease. Bupivacaine is substantially excreted by the kidney and risk of toxicity may be greater in patients with renal impairment.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 0.1-0.1
    apnea / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    muscle paralysis / Delayed / Incidence not known
    AV block / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    arachnoiditis / Early / Incidence not known
    cranial nerve palsies / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    chondrolysis / Delayed / Incidence not known
    malignant hyperthermia / Rapid / Incidence not known

    Moderate

    hypoventilation / Rapid / Incidence not known
    blurred vision / Early / Incidence not known
    palpitations / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    erythema / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    urinary incontinence / Early / Incidence not known
    meningitis / Delayed / Incidence not known
    fecal incontinence / Early / Incidence not known
    urinary retention / Early / Incidence not known
    fetal acidosis / Delayed / Incidence not known
    fetal bradycardia / Delayed / Incidence not known
    decreased uterine contractility / Early / Incidence not known

    Mild

    chills / Rapid / Incidence not known
    vomiting / Early / Incidence not known
    drowsiness / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    nausea / Early / Incidence not known
    restlessness / Early / Incidence not known
    tremor / Early / Incidence not known
    miosis / Early / Incidence not known
    metallic taste / Early / Incidence not known
    headache / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    weakness / Early / Incidence not known
    sneezing / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    syncope / Early / Incidence not known
    fever / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    shivering / Rapid / Incidence not known
    back pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Acetaminophen; Butalbital: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Acetaminophen; Butalbital; Caffeine: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    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. (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Amitriptyline: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    Amitriptyline; Chlordiazepoxide: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    Amobarbital: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Amprenavir: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if bupivacaine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in bupivacaine-related adverse effects for several days after administration of a multi-day aprepitant regimen. In vitro, bupivacaine 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 bupivacaine. 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: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    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. (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    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) Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of local anesthetics and an increased potential for QT prolongation or other adverse effects.
    Atazanavir; Cobicistat: (Moderate) Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of local anesthetics and an increased potential for QT prolongation or other adverse effects. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
    Atenolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Atenolol; Chlorthalidone: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Barbiturates: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug. (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    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. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Benzonatate: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Betaxolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Bisoprolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering bupivacaine with boceprevir due to an increased potential for bupivacaine-related adverse events. If bupivacaine 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 bupivacaine. Bupivacaine is metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated bupivacaine plasma concentrations.
    Brimonidine; Timolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    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.
    Butabarbital: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Caffeine; Ergotamine: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Carbamazepine: (Minor) Bupivacaine is metabolized by CYP3A4. Carbamazepine induces these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    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. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Carvedilol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    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.
    Cholinesterase inhibitors: (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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Ciprofloxacin: (Moderate) Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration as plasma concentrations of bupivacaine may be elevated when administered concurrently with ciprofloxacin. Ciprofloxacin is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
    Cisatracurium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Clomipramine: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    Cobicistat: (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine 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.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bupivacaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bupivacaine. Treatment with bupivacaine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Darunavir: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Darunavir; Cobicistat: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Delavirdine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as delavirdine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Desipramine: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    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.
    Dihydroergotamine: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Diltiazem: (Moderate) Diltiazem may inhibit the CYP3A4-mediated metabolism of bupivacaine. Use caution when administering these drugs concomitantly.
    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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Dorzolamide; Timolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Doxacurium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Doxepin: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Elbasvir; Grazoprevir: (Moderate) Administering bupivacaine with elbasvir; grazoprevir may result in elevated bupivacaine plasma concentrations. Bupivacaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Enflurane: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Ergoloid Mesylates: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Ergonovine: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Ergot alkaloids: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Ergotamine: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Esmolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    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.
    Etomidate: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    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.
    Fluconazole: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Fluoxetine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Fluoxetine; Olanzapine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Fluvoxamine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluvoxamine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Fosamprenavir: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Fospropofol: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    General anesthetics: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    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.
    Halothane: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    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.
    Hydantoins: (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Propranolol has been shown to significantly decrease the clearance of the amide local anesthetics (e.g., lidocaine, bupivacaine, and mepivacaine). Lidocaine and bupivacaine toxicity have been reported after coadministration with propranolol. The mechanism of the interaction between propranolol and lidocaine is thought to be due to propranolol-induced decreased hepatic blood flow causing decreased elimination of lidocaine. Local anesthetics may also cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents or rapid-onset vasodilators, such as nitrates. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    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 bupivacaine, a CYP3A substrate, as bupivacaine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imatinib: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as imatinib, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Imipramine: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    Indinavir: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with bupivacaine may result in increased serum concentrations of bupivacaine. Bupivacaine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    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.
    Isoflurane: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Isoniazid, INH: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as isoniazid, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as isoniazid, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Isoniazid, INH; Rifampin: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as isoniazid, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Itraconazole: (Moderate) Itraconazole causes a modest increase in bupivacaine serum concentrations. It is unclear if this increase is due to CYP3A4 inhibition by itraconazole or if other mechanisms are involved.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and bupivacaine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as bupivacaine, can increase bupivacaine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ketamine: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Ketoconazole: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as ketoconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Labetalol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of bupivacaine; monitor for potential reduction in efficacy. Bupivacaine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of bupivacaine; monitor for potential reduction in efficacy. Bupivacaine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    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.
    Lopinavir; Ritonavir: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and bupivacaine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as bupivacaine, can increase bupivacaine exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Mephobarbital: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    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.
    Methohexital: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Methylergonovine: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Methysergide: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Metoprolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    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 bupivacaine are used concomitantly, and monitor for decreased efficacy of bupivacaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and bupivacaine is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of bupivacaine.
    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. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Nebivolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Nebivolol; Valsartan: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Nefazodone: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as nefazodone, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Nelfinavir: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Neuromuscular blockers: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Nevirapine: (Minor) Bupivacaine is metabolized by CYP3A4. Nevirapine induces these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Nilotinib: (Moderate) Nilotinib is a time-dependent inhibitor of CYP3A4, and cautious use of nilotinib with a CYP3A4 substrate such as bupivacaine is recommended. For example, single-dose coadministration of nilotinib with midazolam, a CYP3A4 substrate, increased midazolam exposure by 30%.
    Nortriptyline: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    Ombitasvir; Paritaprevir; Ritonavir: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Oritavancin: (Minor) Bupivacaine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of bupivacaine may be reduced if these drugs are administered concurrently.
    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 bupivacaine, a CYP3A4 substrate, may cause an increase in systemic concentrations of bupivacaine. Use caution when administering these drugs concomitantly.
    Penbutolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Pentobarbital: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Pergolide: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Perphenazine; Amitriptyline: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    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.
    Phenobarbital: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Pindolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Posaconazole: (Moderate) Posaconazole and bupivacaine should be coadministered with caution due to an increased potential for bupivacaine-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of bupivacaine. These drugs used in combination may result in elevated bupivacaine plasma concentrations, causing an increased risk for bupivacaine related adverse events.
    Povidone-Iodine: (Moderate) Bupivacaine liposomal should not come into contact with topical antiseptics (e.g., povidone-iodine). If a topical antiseptic is applied to the surgical site, allow the site to dry completely before administering bupivacaine liposomal.
    Primidone: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    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.
    Propofol: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    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: (Major) Propranolol has been shown to significantly decrease the clearance of the amide local anesthetics (e.g., lidocaine, bupivacaine, and mepivacaine). Lidocaine and bupivacaine toxicity have been reported after coadministration with propranolol. The mechanism of the interaction between propranolol and lidocaine is thought to be due to propranolol-induced decreased hepatic blood flow causing decreased elimination of lidocaine. Local anesthetics may also cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents or rapid-onset vasodilators, such as nitrates. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Protriptyline: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    Pyridostigmine: (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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    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.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib, a moderate CYP3A4 inhibitor, with bupivacaine, a CYP3A4 substrate, is necessary, as the systemic exposure of bupivacaine may be increased resulting in an increase in bupivacaine-related adverse reactions.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib, a moderate CYP3A4 inhibitor, with bupivacaine, a CYP3A4 substrate, is necessary, as the systemic exposure of bupivacaine may be increased resulting in an increase in bupivacaine-related adverse reactions.
    Rifamycins: (Minor) Bupivacaine is metabolized by CYP3A4. Rifapentine, rifabutin, and rifampin induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Ritonavir: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    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.
    Rivastigmine: (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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Rocuronium: (Moderate) Local anesthetics can prolong and enhance the effects of neuromuscular blockers. Monitoring of neuromuscular function is recommended.
    Secobarbital: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    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.
    Sevoflurane: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of bupivacaine, which is a CYP3A4 substrate. Monitor patients for adverse effects of bupivacaine, such as CNS or 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: (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. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering bupivacaine with telaprevir due to an increased potential for bupivacaine-related adverse events. If bupivacaine 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 bupivacaine. Bupivacaine is metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated bupivacaine plasma concentrations.
    Telithromycin: (Moderate) Telithromycin is an inhibitor of and bupivacaine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased concentrations of bupivicaine.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and bupivacaine is necessary, as the systemic exposure of bupivacaine may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of bupivacaine; consider increasing the dose of bupivacaine if necessary. Bupivacaine 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.
    Thiopental: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Timolol: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Tipranavir: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Trandolapril; Verapamil: (Moderate) Verapamil may inhibit the CYP3A4-mediated metabolism of and bupivacaine. Use caution when administering these drugs concomitantly.
    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.
    Tricyclic antidepressants: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    Trimipramine: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    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.
    Verapamil: (Moderate) Verapamil may inhibit the CYP3A4-mediated metabolism of and bupivacaine. Use caution when administering these drugs concomitantly.
    Voriconazole: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as voriconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.

    PREGNANCY AND LACTATION

    Pregnancy

    Bupivacaine is classified in FDA pregnancy risk category C. ONLY the 0.25% and 0.5% concentrations are indicated for obstetrical anesthesia. The 0.75% solution of bupivacaine HCL is contraindicated for obstetric anesthesia; cardiac arrest with difficult resuscitation or death has occurred during use of 0.75% bupivacaine concentration for epidural anesthesia during obstetric delivery, despite apparently adequate preparation and appropriate management. Cardiac arrest occurred after convulsions resulting from systemic toxicity, presumably after unintentional intravascular injection. Most cases of cardiac arrest occurred after use of the 0.75% concentration; reserve the 0.75% concentration for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary. Obstetrical paracervical nerve block with bupivacaine is contraindicated; its use 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. Bupivacaine is about 95% bound to plasma proteins, resulting in a low fetal to maternal ratio (0.2—0.4). Epidural bupivacaine has been used safely in labor and delivery when the maximum recommended dosages are not exceeded and strict adherence to manufacturer guidelines are followed. 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 and can result in 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, although this has not been reported with bupivacaine.

    MECHANISM OF ACTION

    Like all local anesthetics, bupivacaine 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 effects 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. Direct nerve membrane penetration is necessary for effective anesthesia, which is achieved by injecting the local anesthetic solution subcutaneously, intradermally, or submucosally around the nerve trunks or ganglia supplying the area to be anesthetized. Bupivacaine's effect on motor function varies with concentration. Specifically, when used for epidural, caudal, or peripheral nerve block, the 0.25% solution results in incomplete motor block, the 0.5% solution results in moderate muscle relaxation only, and the 0.75% solution provides complete muscle relaxation.
     
    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 vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Local anesthetics can produce central nervous system stimulation, depression, or both following systemic absorption. 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.

    PHARMACOKINETICS

    Bupivacaine is administered parenterally. It is distributed to all tissues, with a high concentration in well-perfused organs such as the liver, lung, heart, and brain. Metabolism is primarily in the liver via conjugation. Some is N-dealkylated to form pipecolylxylidine, which is the major metabolite. Formation of pipecolylxylidine appears to be mediated by the CYP3A subfamily. A cDNA expressed form of human CYP3A4 catalyzed the biotransformation of bupivacaine into pipecolylxylidine (turnover number of 931 +/- 15 pmol/minute/nmol of CYP3A4). The isoenzymes CYP2C19 and CYP2D6 metabolized bupivacaine into pipecolylxylidine slightly. The turnover numbers were 71.2 +/- 3.3 pmol/minute/nmol of CYP2C19 and 103 +/- 4.1 pmol/minute/nmol of CYP2D6. Pipecoloxylidine is hydroxylated and then forms glucuronide conjugates. In 2 healthy adults, almost half of a pipecolylxylidine dose is excreted unchanged in the urine after pipecolylxylidine administration, but only about 5% of a dose was eliminated in the urine as pipecolylxylidine. Thus, formation of pipecolylxylidine by N-dealkylation of bupivacaine does not appear to account for a large percentage of the drug's metabolism, and the clinical significance of concurrent use of CYP3A4 inhibitors and bupivacaine is unknown. Bupivacaine is excreted renally; approximately 6% is excreted as unchanged drug. Its half-life is 3.5 +/- 2 hours in adults.
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP2C19, CYP2D6

    Other Route(s)

    Epidural and Regional Route
     
    Absorption depends on the dose, concentration, route of administration, tissue vascularity, and degree of vasodilation surrounding the area of injection. The use of preparations containing a vasoconstrictor will counteract the vasodilation produced by bupivacaine. This will slow the rate of absorption, prolong the duration of action, and maintain hemostasis. Bupivacaine's onset of action is rapid (1 to 10 minutes), and it is significantly longer lasting than other commonly used local anesthetics (3 to 9 hours). After epidural or caudal injection or peripheral nerve block, peak blood concentrations are achieved in 30 to 45 minutes.