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    Local Anesthetics in Combination with Vasoconstrictors
    Topical Local Anesthetics

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral combination of an amide local anesthetic and vasoconstrictor
    Used for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, and for obstetrical procedures
    Addition of epinephrine slows local anesthetic absorption and prolongs maintenance of an active tissue concentration

    COMMON BRAND NAMES

    Xylocaine MPF with Epinephrine, Xylocaine with Epinephrine

    HOW SUPPLIED

    Lidocaine Hydrochloride, Epinephrine/Lidocaine, Epinephrine Dental Inj Sol
    Lidocaine Hydrochloride, Epinephrine/Lidocaine, Epinephrine/Xylocaine MPF with Epinephrine Epidural Inj Sol
    Lidocaine Hydrochloride, Epinephrine/Lidocaine, Epinephrine/Xylocaine MPF with Epinephrine Intracaudal Inj Sol
    Lidocaine Hydrochloride, Epinephrine/Lidocaine, Epinephrine/Xylocaine MPF with Epinephrine/Xylocaine with Epinephrine Infiltration Inj Sol

    DOSAGE & INDICATIONS

    For local anesthesia, including infiltration anesthesia.
    Infiltration dosage (lidocaine 0.5% and epinephrine 1:200,000 or lidocaine 1% and epinephrine 1:100,000 or 1:200,000)
    Adults

    1 to 60 mL (lidocaine 5 to 300 mg) by percutaneous infiltration. Do not exceed lidocaine 7 mg/kg.

    For regional anesthesia, including caudal anesthesia, epidural anesthesia, or obstetric anesthesia such as paracervical block.
    For caudal block in obstetric anesthesia.
    Intracaudal dosage (lidocaine 1% and epinephrine 1:100,000 or 1:200,000)
    Adults

    2 to 3 mL (lidocaine 20 to 30 mg) intracaudally as a test dose, then 20 to 30 mL (lidocaine 200 to 300 mg) intracaudally. Max: lidocaine 500 mg/90 minutes for continuous caudal anesthesia. Do not exceed lidocaine 7 mg/kg.

    For caudal block in surgical anesthesia.
    Intracaudal dosage (lidocaine 1.5% and epinephrine 1:200,000)
    Adults

    2 to 3 mL (lidocaine 30 to 45 mg) intracaudally as a test dose, then 15 to 20 mL (lidocaine 225 to 300 mg) intracaudally. Max: lidocaine 500 mg/90 minutes for continuous caudal anesthesia. Do not exceed lidocaine 7 mg/kg.

    For thoracic epidural block.
    Epidural dosage (lidocaine 1% and epinephrine 1:200,000)
    Adults

    2 to 3 mL (lidocaine 20 to 30 mg) epidurally as a test dose, then 2 to 3 mL (lidocaine 20 to 30 mg) epidurally per dermatome up to 20 to 30 mL (lidocaine 200 to 300 mg). Max: lidocaine 500 mg/90 minutes for continuous epidural anesthesia. Do not exceed lidocaine 7 mg/kg.

    For lumbar epidural block for analgesia.
    Epidural dosage (lidocaine 1% and epinephrine 1:200,000)
    Adults

    2 to 3 mL (lidocaine 20 to 30 mg) epidurally as a test dose, then 2 to 3 mL (lidocaine 20 to 30 mg) epidurally per dermatome up to 25 to 30 mL (lidocaine 250 to 300 mg). Max: lidocaine 500 mg/90 minutes for continuous epidural anesthesia. Do not exceed lidocaine 7 mg/kg.

    For lumbar epidural block for anesthesia.
    Epidural dosage (lidocaine 1.5% or 2% and epinephrine 1:200,000)
    Adults

    2 to 3 mL (lidocaine 30 to 60 mg) epidurally as a test dose, then 2 to 3 mL (lidocaine 30 to 60 mg) epidurally per dermatome up to 10 to 20 mL (lidocaine 200 to 300 mg). Max: lidocaine 500 mg/90 minutes for continuous epidural anesthesia. Do not exceed lidocaine 7 mg/kg.

    For paracervical block in obstetric anesthesia.
    Perineural dosage (lidocaine 1% and epinephrine 1:100,000 or 1:200,000)
    Adults

    1 mL (lidocaine 10 mg) perineurally to each side. Max: lidocaine 200 mg/90 minutes. Do not exceed lidocaine 7 mg/kg.

    For nerve block anesthesia, including peripheral nerve block such as brachial plexus block, intercostal nerve block, paravertebral block, and pudendal nerve block.
    For brachial nerve block.
    Perineural dosage (lidocaine 1.5% and epinephrine 1:200,000)
    Adults

    15 to 20 mL (lidocaine 225 to 300 mg) perineurally. Do not exceed lidocaine 7 mg/kg.

    For intercostal nerve block.
    Perineural dosage (lidocaine 1% and epinephrine 1:100,000 or 1:200,000)
    Adults

    3 mL (lidocaine 30 mg) perineurally. Do not exceed lidocaine 7 mg/kg.

    For paravertebral nerve block.
    Perineural dosage (lidocaine 1% and epinephrine 1:100,000 or 1:200,000)
    Adults

    3 to 5 mL (lidocaine 30 to 50 mg) perineurally. Do not exceed lidocaine 7 mg/kg.

    For pudendal nerve block.
    Perineural dosage (lidocaine 1% and epinephrine 1:100,000 or 1:200,000)
    Adults

    10 mL (lidocaine 100 mg) perineurally to each side. Do not exceed lidocaine 7 mg/kg.

    For sympathetic nerve block, including cervical nerve block and lumbar sympathetic block.
    For cervical sympathetic nerve block.
    Perineural dosage (lidocaine 1% and epinephrine 1:100,000 or 1:200,000)
    Adults

    5 mL (lidocaine 50 mg) perineurally. Do not exceed lidocaine 7 mg/kg.

    For lumbar sympathetic nerve block.
    Perineural dosage (lidocaine 1% and epinephrine 1:100,000 or 1:200,000)
    Adults

    5 to 10 mL (lidocaine 50 to 100 mg) perineurally. Do not exceed lidocaine 7 mg/kg.

    For dental anesthesia, including local infiltration and mandibular nerve block and maxillary nerve block.
    Infiltration or Perineural dosage (lidocaine 2% and epinephrine 1:50,000 or 1:100,000)
    Adults

    1 to 5 mL (lidocaine 20 to 100 mg) by infiltration or block injection. Max: lidocaine 7 mg/kg. For most routine dental procedures, lidocaine 2% and epinephrine 1:100,000 is preferred; however, when greater depth and a more pronounced hemostasis are required, use lidocaine 2% and epinephrine 1:50,000.

    Children and Adolescents 10 to 17 years

    1 to 5 mL (lidocaine 20 to 100 mg) by infiltration or block injection. Max: lidocaine 7 mg/kg. For most routine dental procedures, lidocaine 2% and epinephrine 1:100,000 is preferred; however, when greater depth and a more pronounced hemostasis are required, use lidocaine 2% and epinephrine 1:50,000.

    Children 1 to 9 years

    0.9 to 5 mL (lidocaine 18 to 100 mg) by infiltration or nerve block. Usual dose: 0.9 to 1 mL (lidocaine 18 to 20 mg). Max: lidocaine 7 mg/kg. For most routine dental procedures, lidocaine 2% and epinephrine 1:100,000 is preferred; however, when greater depth and a more pronounced hemostasis are required, use lidocaine 2% and epinephrine 1:50,000.

    For the treatment of epistaxis†.
    Nasal dosage (lidocaine 1% or 2% and epinephrine 1:100,000)
    Adults

    Soak gauze or a cotton pledget and place in the affected nostril(s) for 10 to 15 minutes.[65040]

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Lidocaine 7 mg/kg up to a total dose of lidocaine 500 mg by infiltration, epidurally, intracaudally, or perineurally.

    Geriatric

    Lidocaine 7 mg/kg up to a total dose of lidocaine 500 mg by infiltration, epidurally, intracaudally, or perineurally.

    Adolescents

    Lidocaine 7 mg/kg up to a total dose of lidocaine 500 mg by infiltration, epidurally, intracaudally, or perineurally.

    Children

    Lidocaine 7 mg/kg by infiltration, epidurally, intracaudally, or perineurally.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; however, reduce the dose in patients with hepatic disease.

    Renal Impairment

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

    ADMINISTRATION

    Lidocaine; epinephrine is to be administered by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies that might arise from lidocaine exposure.
    Ensure oxygen, resuscitative equipment and medications, and personnel resources are immediately available for proper management of toxic reactions and related emergencies.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration, whenever the solution and container permit. Do not use if color is pinkish or darker than slightly yellow or if it contains a precipitate.
    Avoid rapid administration of a large volume; administer in incremental doses when feasible.
    Carefully monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness after each local anesthetic injection.
    If dilution is necessary, use 0.9% Sodium Chloride Injection to obtain the required final concentration.
    Storage: Discard any unused portion from a single-dose vial.

    Other Injectable Administration

    Epidural or Intracaudal Administration
    Do not use solutions containing preservatives for caudal or epidural anesthesia.
    Administer a test dose at least 5 minutes before injecting the total volume and monitor the effects before the full dose is given. Repeat the test dose if the patient is moved in a manner that may have displaced the catheter.
    Administer slowly in incremental doses with sufficient time between doses to detect toxicity. Perform frequent aspirations before and during the injection to avoid intravascular or intrathecal injection; negative aspiration does not guarantee intravascular or intrathecal injection has been avoided.
     
    Local Infiltration Administration
    Administer slowly in incremental doses with sufficient time between doses to detect toxicity. Perform frequent aspirations before and during the injection to avoid intravascular or intrathecal injection; negative aspiration does not guarantee intravascular or intrathecal injection has been avoided.
     
    Nerve Block Administration
    Administer slowly in incremental doses with sufficient time between doses to detect toxicity. Perform frequent aspirations before and during the injection to avoid intravascular or intrathecal injection; negative aspiration does not guarantee intravascular or intrathecal injection has been avoided.
    For paracervical block, allow 5 minutes before injection to other side.

    STORAGE

    Xylocaine MPF with Epinephrine:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Xylocaine with Epinephrine:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Store below 77 degrees F
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Requires a specialized care setting, requires an experienced clinician

    Lidocaine; epinephrine use requires an experienced clinician who is well versed in the diagnosis and management of dose-related toxicity and other acute emergencies that might arise from lidocaine exposure. Lidocaine; epinephrine use also requires a specialized care setting; use lidocaine; epinephrine only if the following are immediately available: oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies. Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death.  

    Epidural administration, intraarterial administration, intrathecal administration, intravenous administration

    Avoid intravenous administration, intraarterial administration, or intrathecal administration of lidocaine; epinephrine. Unintended intravascular or intrathecal injection may be associated with systemic toxicities, including central nervous system or cardiorespiratory depression. Aspirate for blood or cerebrospinal fluid (when applicable) before injecting lidocaine; epinephrine, both before the initial injection and with all subsequent doses, to avoid inadvertent intravascular or intrathecal administration. The absence of blood or cerebrospinal fluid does not ensure against intravascular or intrathecal injection. Administer an initial test dose before epidural administration. Monitor the patient for central nervous system and cardiovascular toxicity, as well as signs of inadvertent intravascular administration (e.g., increased heart rate, transient rise in systolic blood pressure) or intrathecal administration (e.g., decreased sensation of the buttocks, paresis of the legs, absent knee jerk) for an appropriate amount of time before the full dose is given. When using a continuous catheter technique, give test doses initially and before any reinforcing doses.

    Head and neck anesthesia

    Small doses of lidocaine; epinephrine used for local head and neck anesthesia (e.g., retrobulbar and dental blocks) may produce systemic toxicity similar to that seen with unintentional intravascular injections of larger doses. These reactions may be due to intraarterial injection of the local anesthetic with retrograde flow to the cerebral circulation or, during retrobulbar blocks, puncture of the optic nerve dural sheath with subsequent drug diffusion into the subdural space. Monitor circulation and respiration constantly; resuscitative medications and equipment and appropriate supportive personnel should be immediately available.

    AV block, cardiac disease, hypertension, hypotension, peripheral vascular disease, shock

    Give lidocaine; epinephrine in reduced doses in patients with impaired cardiovascular function (e.g., hypotension, AV block, shock); these patients are less able to compensate for functional changes associated with lidocaine; epinephrine-related prolongation of AV conduction. Use local anesthetics with vasoconstrictor agents during dental practice in patients with ischemic cardiac disease only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, take extreme care to avoid intravascular injection and use the minimum possible amount of vasoconstrictor. Use lidocaine; epinephrine with caution and in restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease or hypertension and/or hypertension-related vascular disease, may exhibit exaggerated vasoconstrictor response.

    Amide local anesthetic hypersensitivity, paraben hypersensitivity, sulfite hypersensitivity

    Lidocaine; epinephrine is contraindicated in patients with amide local anesthetic hypersensitivity or hypersensitivity to other formulation ingredients. Do not use multidose vials in patients with paraben hypersensitivity as they contain methylparaben as a preservative. Lidocaine; epinephrine contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. Sulfite hypersensitivity is seen more frequently in persons with asthma. The overall prevalence of sulfite hypersensitivity in the general population is unknown and probably low.

    Hepatic disease

    Use lidocaine; epinephrine with caution and reduce the dose in patients with hepatic disease, since amide-type local anesthetics are metabolized by the liver. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations.

    Continuous intraarticular infusion administration

    Continuous intraarticular infusion administration of local anesthetics, including lidocaine, after arthroscopic and other surgical procedures is an unapproved use, and there have been postmarketing reports of chondrolysis in patients receiving such infusions. Patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures, and some required arthroplasty or shoulder replacement.

    Malignant hyperthermia

    Many drugs used during anesthesia are considered triggering agents for familial malignant hyperthermia. Although it is unknown whether amide-type local anesthetics trigger this reaction, a standard protocol for management should be available when lidocaine; epinephrine is administered. Early unexplained tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspected trigger(s), and prompt institution of treatment (e.g., oxygen, supportive measures, dantrolene).

    Children, electrolyte imbalance, infants, neonates, seizure disorder

    Neonates and infants may be at increased risk for lidocaine toxicity due to decreased protein binding, increased volume of distribution, decreased metabolism, and prolonged half-life.[54603] [65897] Because of these pharmacokinetic differences, systemic toxicity can be more unpredictable, with cardiac toxicity presenting concomitantly with (instead of preceding) central nervous system toxicity.[65897] Reduce the local anesthetic infusion rate in children at risk for seizures (e.g., preexisting seizure disorder, electrolyte imbalance); such patients are at increased risk of seizures with lower drug plasma concentrations.[54620]

    Critical illness, geriatric

    Use reduced doses of lidocaine; epinephrine in geriatric patients or patients with critical illness.

    G6PD deficiency, methemoglobinemia, pulmonary disease

    Closely monitor patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise (cardiac disease or pulmonary disease), infants younger than 6 months, and those with concurrent exposure to oxidizing agents or their metabolites for signs and symptoms of methemoglobinemia. Methemoglobinemia is characterized by cyanotic skin discoloration and abnormal coloration of the blood, presenting immediately or within hours of local anesthetic exposure. Discontinue lidocaine and any other oxidizing agents immediately and initiate supportive care (e.g., oxygen, hydration) if necessary to avoid serious central nervous system and cardiovascular effects. Severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

    Epidural anesthesia, labor, obstetric delivery, paracervical nerve block, pregnancy, pudendal nerve block, spinal anesthesia

    There are no adequate and well-controlled studies with lidocaine in pregnancy. Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus. Local anesthetics rapidly cross the placenta and when used for epidural anesthesia, caudal anesthesia, paracervical nerve block, or pudendal nerve block can cause varying degrees of maternal, fetal, and neonatal toxicity. The potential for toxicity depends upon the procedure performed, the type and amount of drug used, and the administration technique. Adverse reactions in the mother, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Paracervical block anesthesia has been associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. However, spinal anesthesia and epidural anesthesia have also been reported to prolong the second stage of labor by removing the reflex urge to bear down, or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetics during labor and obstetric delivery may be followed by diminished muscle strength and tone for the first 1 or 2 days of life. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20% to 30% of patients receiving paracervical nerve block anesthesia with amide-type local anesthetics and may be associated with fetal acidosis. Monitor fetal heart rate during paracervical anesthesia. Weigh the possible advantages against risks when considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported after intended paracervical or pudendal block or both. Affected infants present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum concentrations, and often manifest seizures within 6 hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. Case reports of maternal convulsions and cardiovascular collapse after use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. Do not exceed the recommended maximum dose of each drug. Injection should be made slowly and with frequent aspiration, and allow a 5-minute interval between sides. When lidocaine is used for dental anesthesia, no fetal harm has been observed; it is generally the dental anesthetic of choice during pregnancy, and guidelines suggest the second trimester is the best time for dental procedures if necessary. When needed, the use of local or topical dental anesthetics at 13 through 21 weeks of pregnancy or later is likely safe and does not raise incidences of adverse pregnancy outcomes or other adverse effects. Prolonged experience with epinephrine use during human pregnancy does not identify a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, there are risks to the mother and fetus associated with epinephrine use during labor and obstetric delivery. In animal studies, subcutaneous epinephrine resulted in adverse developmental effects (e.g., gastroschisis, embryonic lethality, delayed skeletal ossification) when given during organogenesis at doses approximately 2 times the maximum recommended parenteral daily dose. Avoid epinephrine use during the second stage of labor at dosages sufficient to reduce uterine contractions; it may cause a prolonged period of uterine atony with hemorrhage. Avoid epinephrine use if the maternal blood pressure exceeds 130/80 mmHg.[56575] [60589]

    Breast-feeding

    Use lidocaine; epinephrine with caution in a breast-feeding woman. Lidocaine is excreted in breast milk with a milk to plasma ratio of 0.4. Previous American Academy of Pediatric recommendations considered lidocaine as usually compatible with breast-feeding. When it is used for dental or short-term, limited local anesthesia, the healthy term infant can generally safely nurse as soon as the mother is awake and alert. There is no information regarding the presence of epinephrine in human milk or the effects of epinephrine on the breast-fed infant or on milk production. However, due to its poor oral bioavailability and short half-life, epinephrine exposure is expected to be very low in the breast-fed infant.[56575]

    ADVERSE REACTIONS

    Severe

    respiratory arrest / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    AV block / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    neonatal depression / Rapid / Incidence not known
    chondrolysis / Delayed / Incidence not known
    malignant hyperthermia / Rapid / Incidence not known
    methemoglobinemia / Early / Incidence not known

    Moderate

    respiratory depression / Rapid / Incidence not known
    fecal incontinence / Early / Incidence not known
    euphoria / Early / Incidence not known
    confusion / Early / Incidence not known
    loss of consciousness / Rapid / Incidence not known
    blurred vision / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    palpitations / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    edema / Delayed / Incidence not known
    fetal bradycardia / Delayed / Incidence not known
    fetal acidosis / Delayed / Incidence not known
    decreased uterine contractility / Early / Incidence not known

    Mild

    headache / Early / 3.0-3.0
    back pain / Delayed / 3.0-3.0
    shivering / Rapid / 2.0-2.0
    nausea / Early / 0-1.0
    anxiety / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    tremor / Early / Incidence not known
    dizziness / Early / Incidence not known
    vomiting / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Acebutolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Acetaminophen: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Chlorpheniramine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Codeine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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; Dextromethorphan: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Diphenhydramine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Hydrocodone: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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; Pamabrom; Pyrilamine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Pentazocine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Acetaminophen; Propoxyphene: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Aclidinium; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Acrivastine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Adapalene; Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Albiglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Albuterol: (Moderate) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Aldesleukin, IL-2: (Moderate) Concomitant use of systemic lidocaine and aldesleukin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; aldesleukin inhibits CYP3A4.
    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.
    Aliskiren: (Moderate) Antihypertensives, including aliskiren, antagonize the vasopressor effects of parenteral epinephrine.
    Aliskiren; Amlodipine: (Moderate) Antihypertensives, including aliskiren, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including aliskiren, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including aliskiren, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Aliskiren; Valsartan: (Moderate) Antihypertensives, including aliskiren, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Alogliptin; Pioglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Alpha-blockers: (Moderate) Alpha-blockers antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by an alpha-blocker, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Alpha-glucosidase Inhibitors: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Ambrisentan: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
    Amiloride: (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Coadministration of lidocaine with oxidizing agents, such as aminosalicylic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Amiodarone: (Major) Concomitant administration of lidocaine with amiodarone has been reported to cause sinus bradycardia and seizure. Amiodarone and its main metabolite, N-monodesethylamiodarone (DEA), appear to inhibit the metabolism of lidocaine by competitively inhibiting CYP3A4. Furthermore, DEA inhibits lidocaine metabolism in a concentration-dependent manner. Also, the metabolism of amiodarone to DEA appears to be competitively inhibited by lidocaine. Close correlations between amiodarone N-monodesethylase activities and the amounts of CYP3A4 and the rates of lidocaine N-monodesethylation have been observed from analyses of in vitro data. Inhibition of lidocaine metabolism is supported by in vivo data from 6 adults. The mean systemic concentration of lidocaine over 300 minutes after receipt of lidocaine hydrochloride 1 mg/kg intravenously before amiodarone treatment is 111.7 +/- 23.2 mcg/minute/mL. In contrast, the mean systemic concentration of lidocaine over 300 minutes after cumulative amiodarone doses of 3 g and 13 g is 135.3 +/- 34.6 and 131.7 +/- 25.5 mcg/minute/mL, respectively. As expected, the systemic exposure of the lidocaine metabolite, monoethylglycinexylidide, decreases from 19.2 +/- 6.5 to 15.8 +/- 8.3 mcg/minute/mL after 3 g of amiodarone. In addition, the systemic clearance of lidocaine decreases from 7.86 +/- 1.83 to 6.31 +/- 2.21 mL/minute/kg body weight. As compared with values before amiodarone administration, the lidocaine elimination half-life and the distribution volume at steady state remain relatively unchanged. Due to the long half-life of amiodarone, clinicians should use caution when administering lidocaine to patients who are receiving or who have recently discontinued amiodarone. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Amitriptyline: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Amlodipine: (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Amlodipine; Atorvastatin: (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Amlodipine; Benazepril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Amlodipine; Celecoxib: (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Amlodipine; Olmesartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Amlodipine; Valsartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Amobarbital: (Major) Amobarbital increases cardiac irritability via myocardial sensitization to catecholamines and can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine.
    Amoxapine: (Major) Concomitant use of amoxapine with sympathomimetics should be avoided whenever possible; use with caution when concurrent use cannot be avoided. One drug information reference suggests that cyclic antidepressants potentiate the pharmacologic effects of direct-acting sympathomimetics, such as epinephrine, however, the data are not consistent.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4.
    Amphetamines: (Moderate) Amphetamines may potentiate the pressor effects of epinephrine.
    Amprenavir: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    Amyl Nitrite: (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Anagrelide: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including lidocaine, could lead to increases in the serum concentrations of lidocaine and, thus, adverse effects. Patients receiving anagrelide and lidocaine concomitantly should be monitored for increased toxicity of lidocaine.
    Angiotensin II receptor antagonists: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Angiotensin-converting enzyme inhibitors: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Apalutamide: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with apalutamide is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Aprepitant, Fosaprepitant: (Major) Use caution if lidocaine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in lidocaine-related adverse effects, including QT prolongation and torsade de pointes (TdP), for several days after administration of a multi-day aprepitant regimen. This interaction is not expected with topical preparations of lidocaine. Lidocaine 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 systemic lidocaine. 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.
    Arformoterol: (Moderate) Caution and close observation should be used when arformoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Articaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias. (Moderate) Use articaine and lidocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Asciminib: (Moderate) Monitor for lidocaine toxicity if coadministration with asciminib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and asciminib is a weak CYP3A inhibitor.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    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) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    Atazanavir; Cobicistat: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Atenolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Atenolol; Chlorthalidone: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Atomoxetine: (Major) Due to the potential for additive increases in blood pressure and heart rate, atomoxetine should be used cautiously with vasopressors such as epinephrine. Consider monitoring the patient's blood pressure and heart rate at baseline and regularly if vasopressors are coadministered with atomoxetine.
    Atracurium: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Avacopan: (Moderate) Monitor for lidocaine toxicity if coadministration with avacopan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
    Azelastine; Fluticasone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Azilsartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Azilsartan; Chlorthalidone: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Beclomethasone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension. (Moderate) Concomitant use of systemic lidocaine and phenobarbital may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenobarbital induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as phenobarbital, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    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.
    Belumosudil: (Moderate) Monitor for lidocaine toxicity if coadministration with belumosudil is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and belumosudil is a weak CYP3A inhibitor.
    Benazepril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Bendroflumethiazide; Nadolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Benzalkonium Chloride; Benzocaine: (Moderate) Use lidocaine and benzocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Benzhydrocodone; Acetaminophen: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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.
    Benzocaine: (Moderate) Use lidocaine and benzocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Benzocaine; Butamben; Tetracaine: (Moderate) Use lidocaine and benzocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Benzoyl Peroxide; Clindamycin: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Benzoyl Peroxide; Erythromycin: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Benzoyl Peroxide; Sulfur: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Berotralstat: (Moderate) Monitor for lidocaine toxicity if coadministration with berotralstat is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
    Beta-adrenergic blockers: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers.
    Beta-blockers: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Betamethasone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Betaxolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Bethanechol: (Moderate) Bethanechol offsets the effects of sympathomimetics at sites where sympathomimetic and cholinergic receptors have opposite effects.
    Bexarotene: (Moderate) Concomitant use of systemic lidocaine and bexarotene may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; bexarotene induces CYP3A4.
    Bicalutamide: (Moderate) Monitor for lidocaine toxicity if coadministration with bicalutamide is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
    Bisoprolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Boceprevir: (Major) Close clinical monitoring is advised when administering systemic lidocaine with boceprevir due to an increased potential for serious and/or life-threatening lidocaine-related adverse events. If lidocaine 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 lidocaine. Lidocaine is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated lidocaine plasma concentrations.
    Bosentan: (Major) Avoid use of sympathomimetic agents with bosentan. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including bosentan. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications. (Moderate) Bosentan is an inducer of CYP3A4 enzymes, and may decrease plasma concentrations of drugs metabolized by these enzymes. Caution is recommended when administering bosentan to patients receiving lidocaine as lidocaine is a CYP3A4 substrate.
    Bretylium: (Moderate) Monitor blood pressure and heart rate closely when sympathomimetics are administered with bretylium. The pressor and arrhythmogenic effects of catecholamines are enhanced by bretylium.
    Brimonidine; Timolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Bromocriptine: (Moderate) One case report documented worsening headache, hypertension, premature ventricular complexes, and ventricular tachycardia in a post-partum patient receiving bromocriptine for lactation suppression who was subsequently prescribed acetaminophen; dichloralphenazone; isometheptene for a headache. A second case involved a post-partum patient receiving bromocriptine who was later prescribed phenylpropanolamine; guaifenesin and subsequently developed hypertension, tachycardia, seizures, and cerebral vasospasm. Also, ergot alkaloids, which are chemically related to bromocriptine, should not be administered with other vasoconstrictors. Therefore, until more data become available, concurrent use of bromocriptine and some sympathomimetics such as vasopressors (e.g., norepinephrine, dopamine, phenylephrine), cocaine, epinephrine, phenylpropanolamine, ephedra, ma huang, ephedrine, pseudoephedrine, amphetamines, and phentermine should be approached with caution.
    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: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (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; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Budesonide: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Budesonide; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects. (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects. (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Bumetanide: (Moderate) Loop diuretics may antagonize the pressor effects and potentiate the arrhythmogenic and hypokalemic effects of epinephrine.
    Bupivacaine Liposomal: (Major) Avoid use of other local anesthetics for 96 hours after liposomal bupivacaine administration. Liposomal bupivacaine administration may follow lidocaine administration after a delay of 20 minutes or more. Use lidocaine and other formulations of bupivacaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine: (Major) Avoid use of other local anesthetics for 96 hours after liposomal bupivacaine administration. Liposomal bupivacaine administration may follow lidocaine administration after a delay of 20 minutes or more. Use lidocaine and other formulations of bupivacaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Epinephrine: (Major) Avoid use of other local anesthetics for 96 hours after liposomal bupivacaine administration. Liposomal bupivacaine administration may follow lidocaine administration after a delay of 20 minutes or more. Use lidocaine and other formulations of bupivacaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Bupivacaine; Lidocaine: (Major) Avoid use of other local anesthetics for 96 hours after liposomal bupivacaine administration. Liposomal bupivacaine administration may follow lidocaine administration after a delay of 20 minutes or more. Use lidocaine and other formulations of bupivacaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Meloxicam: (Major) Avoid use of other local anesthetics for 96 hours after liposomal bupivacaine administration. Liposomal bupivacaine administration may follow lidocaine administration after a delay of 20 minutes or more. Use lidocaine and other formulations of bupivacaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Butalbital; Acetaminophen: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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.
    Butyrophenone: (Major) Use of epinephrine to treat droperidol or haloperidol -induced hypotension can result in a paradoxical lowering of blood pressure due to droperidol's alpha-blocking effects. Avoid using epinephrine concurrently with droperidol and haloperidol.
    Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Caffeine; Sodium Benzoate: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Calamine; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics 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. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Concomitant use of systemic lidocaine and famotidine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; famotidine inhibits CYP1A2.
    Calcium-channel blockers: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
    Canagliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Canagliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Candesartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Cannabidiol: (Moderate) Monitor for lidocaine toxicity if coadministration with cannabidiol is necessary as concurrent use may increase lidocaine exposure. Consider a dose reduction of lidocaine as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Lidocaine is a CYP1A2 substrate and cannabidiol is a weak CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
    Capmatinib: (Moderate) Monitor for an increase in lidocaine-related adverse reactions if coadministration with capmatinib is necessary. Monitor lidocaine concentrations if clinically indicated and lidocaine is being given intravenously. Lidocaine is a CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Concomitant use may increase lidocaine exposure.
    Capreomycin: (Moderate) Partial neuromuscular blockade has been reported with capreomycin after the administration of large intravenous doses or rapid intravenous infusion. Lidocaine could potentiate the neuromuscular blocking effect of capreomycin by impairing transmission of impulses at the motor nerve terminals. If these drugs are used in combination, monitor patients for increased adverse effects.
    Captopril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Carbamazepine: (Moderate) Concomitant use of systemic lidocaine and carbamazepine may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; carbamazepine induces both hepatic isoenzymes.
    Carbetapentane; Chlorpheniramine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Carbetapentane; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Carbidopa; Levodopa; Entacapone: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    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: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (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; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Carteolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Carvedilol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Ceritinib: (Moderate) Monitor for lidocaine toxicity if coadministration with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor; lidocaine is metabolized by CYP3A4 and CYP1A2. Concomitant treatment CYP3A4 inhibitors has the potential to increase lidocaine plasma levels by decreasing lidocaine clearance and prolonging the elimination half-life.
    Cetirizine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Chloramphenicol: (Moderate) Concomitant use of systemic lidocaine and chloramphenicol may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; chloramphenicol inhibits CYP3A4.
    Chlordiazepoxide; Amitriptyline: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Chloroprocaine: (Moderate) Use lidocaine and chloroprocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Chloroquine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as chloroquine, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Chlorothiazide: (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Chloroxylenol; Hydrocortisone; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics 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. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Chlorpheniramine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine.
    Chlorpheniramine; Codeine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (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; Dextromethorphan: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (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: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (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: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (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) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (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) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (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: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (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; Ibuprofen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine.
    Chlorpheniramine; Phenylephrine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine.
    Chlorpheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine.
    Chlorpromazine: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Chlorthalidone: (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Chlorthalidone; Clonidine: (Moderate) Clonidine may potentiate the pressor effects of epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Ciclesonide: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Cimetidine: (Moderate) Concomitant use of systemic lidocaine and cimetidine may increase lidocaine plasma concentrations. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP1A2 and CYP3A4 substrate; cimetidine inhibits both of these isoenzymes. Concomitant use of lidocaine with a weak CYP1A2 and CYP3A4 inhibitor has reportedly increased lidocaine plasma concentrations by 24% to 75%.
    Ciprofloxacin: (Moderate) Concomitant use of systemic lidocaine and ciprofloxacin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; ciprofloxacin inhibits both of these isoenzymes. In a study of healthy volunteers (n = 9), concomitant use of lidocaine (1.5mg/kg IV) and ciprofloxacin (500 mg twice daily) resulted in an increase of lidocaine Cmax and AUC by 12% and 26%, respectively.
    Cisatracurium: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    Citalopram: (Moderate) Concomitant use of systemic lidocaine and citalopram may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; citalopram is a weak CYP1A2 inhibitor.
    Clarithromycin: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4.
    Class IA Antiarrhythmics: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Class IB Antiarrhythmics: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Class IC Antiarrhythmics: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Clomipramine: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Clonidine: (Moderate) Clonidine may potentiate the pressor effects of epinephrine.
    Clozapine: (Moderate) Clozapine may induce significant alpha-adrenergic blockade during clozapine overdose, leading to profound hypotension. Epinephrine should generally not be used to treat clozapine-induced hypotension due to the unopposed beta-activity, which potentially could worsen the hypotension.
    Cobicistat: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Cocaine: (Major) Avoid concomitant use of additional vasoconstrictor agents with cocaine. If unavoidable, prolonged vital sign and ECG monitoring may be required. Myocardial ischemia, myocardial infarction, and ventricular arrhythmias have been reported after concomitant administration of topical intranasal cocaine and vasoconstrictor agents during nasal and sinus surgery. The risk for nervousness, irritability, convulsions, and other cardiac arrhythmias may increase during coadministration.
    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; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (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) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure. (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) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure. (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.
    Colchicine: (Minor) The response to sympathomimetics may be enhanced by colchicine.
    Colesevelam: (Moderate) Colesevelam may decrease the absorption of lidocaine. To minimize potential for interactions, consider administering lidocaine at least 1 hour before or at least 4 hours after colesevelam.
    Colistin: (Moderate) Lidocaine can potentiate the neuromuscular blocking effect of colistimethate sodium by impairing transmission of impulses at the motor nerve terminals. If these drugs are used in combination, monitor patients for increased adverse effects. Neuromuscular blockade may be associated with colistimethate sodium, and is more likely to occur in patients with renal dysfunction.
    COMT inhibitors: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
    Conivaptan: (Moderate) Monitor for lidocaine toxicity if coadministration with conivaptan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Corticosteroids: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Cortisone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Crizotinib: (Moderate) Monitor for lidocaine-related adverse reactions and toxicities if coadministration with crizotinib is necessary. Lidocaine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Cyclophosphamide: (Moderate) Coadministration of lidocaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Cyclosporine: (Moderate) Concomitant use of systemic lidocaine and cyclosporine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; cyclosporine inhibits CYP3A4.
    Dabrafenib: (Moderate) Concomitant use of systemic lidocaine and dabrafenib may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; dabrafenib induces CYP3A4.
    Dalfopristin; Quinupristin: (Moderate) Coadministration of lidocaine with dalfopristin; quinupristin may result in elevated lidocaine plasma concentrations. If these drugs are used together, closely monitor for signs of lidocaine-related adverse events. Lidocaine is a substrate of CYP3A; dalfopristin; quinupristin is a weak CYP3A inhibitor.
    Danazol: (Moderate) Danazol is a CYP3A4 inhibitor and may decrease the hepatic metabolism of lidocaine. Patients receiving lidocaine should be closely monitored for toxicity if danazol is added to therapy.
    Dapagliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Dapagliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Dapagliflozin; Saxagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Dapsone: (Moderate) Coadministration of dapsone with lidocaine may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
    Daratumumab; 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.
    Darunavir: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity.
    Darunavir; Cobicistat: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    Deferasirox: (Major) Concomitant use of systemic lidocaine and deferasirox may alter lidocaine plasma concentrations; avoid concurrent use. If use together is necessary, monitor patients closely for lidocaine toxicity and therapeutic efficacy. Lidocaine is a CYP3A4 and CYP1A2 substrate; deferasirox inhibits CYP1A2 and induces CYP3A4.
    Deflazacort: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as lidocaine, should be expected with concurrent use of delavirdine.
    Desflurane: (Moderate) Monitor patients who are concomitantly receiving epinephrine and desflurane for the development of arrhythmias. Halogenated anesthetics, such as desflurane, sensitize the myocardium and may potentiate the arrhythmogenic effects of epinephrine. If occur, such arrhythmias may respond to beta-blocker administration.
    Desipramine: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Desloratadine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Desmopressin: (Minor) The antidiuretic response to desmopressin may be reduced in patients receiving high doses of epinephrine concomitantly. Caution should be used when coadministering these agents.
    Dexamethasone: (Moderate) Concomitant use of systemic lidocaine and dexamethasone may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; dexamethasone induces CYP3A4. (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Dexbrompheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Dextromethorphan; Quinidine: (Major) Avoid concurrent use of quinidine with other antiarrhythmics with Class I activities, such as lidocaine. Concurrent use may result in additive or antagonistic cardiac effects and additive toxicity. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Dibucaine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics 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. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and epinephrine together with caution. Metabolic acidosis is associated with the use of dichlorphenamide and has been reported with the long-term use epinephrine. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diethylpropion: (Major) Diethylpropion has vasopressor effects. Coadministration with other vasopressors may have the potential for serious cardiac adverse effects such as hypertensive crisis and cardiac arrhythmias.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (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) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Diltiazem: (Moderate) Concomitant use of systemic lidocaine and diltiazem may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; diltiazem inhibits CYP3A4.
    Dinoprostone, Prostaglandin E2: (Major) Oxytocics have inherent vasopressor properties; hypertensive episodes have been reported in laboring women during induction with oxytoxin. Because epinephrine is a vasopressor, concomitant use may result in severe, prolonged hypertension. In addition, epinephrine, secondary to beta2-receptor agonism, can interfere with the oxytocic action of drugs such as dinoprostone or oxytocin.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Diphenhydramine: (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine. (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.
    Diphenhydramine; Ibuprofen: (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Diphenhydramine; Naproxen: (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Diphenhydramine; Phenylephrine: (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Disopyramide: (Major) The effects of concomitant administration of disopyramide with other antiarrhythmics could potentially be synergistic or antagonistic, and adverse cardiac effects could potentially be additive. Class IA antiarrhythmic agents are associated with proarrhythmias (e.g., torsades de pointes) resulting from QTc prolongation. Coadministration of disopyramide with other Class IA antiarrhythmics should be reserved for patients with life-threatening arrhythmias who are unresponsive to single-agent antiarrhythmic therapy. Lidocaine has occasionally been used concurrently with disopyramide; however, additive electrophysiologic effects may occur. Since disopyramide and lidocaine are both sodium-channel-acting agents, it is somewhat irrational to use these drugs together; isolated cases of intraventricular conduction abnormalities have been reported with this drug combination. Patients receiving more than one antiarrhythmic drug must be carefully monitored. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Disulfiram: (Moderate) Concomitant use of systemic lidocaine and disulfiram may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; disulfiram inhibits CYP1A2.
    Dobutamine: (Moderate) Dobutamine may potentiate the pressor effects of epinephrine.
    Dofetilide: (Contraindicated) Concurrent exposure of systemic lidocaine with dofetilide could increase the risk of dofetilide-induced proarrhythmias. Before switching from lidocaine to dofetilide therapy, lidocaine generally should be withheld for at least three half-lives prior to initiating dofetilide. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Dopamine: (Moderate) Monitor blood pressure during concomitant use of dopamine and other vasopressors, such as epinephrine, due to the risk for severe hypertension.
    Dorzolamide; Timolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Doxacurium: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    Doxapram: (Moderate) Doxapram may potentiate the pressor effects of epinephrine.
    Doxazosin: (Moderate) Alpha-blockers antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by an alpha-blocker, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Doxepin: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Dronabinol: (Moderate) Concurrent use of dronabinol, THC with sympathomimetics may result in additive hypertension, tachycardia, and possibly cardiotoxicity. Dronabinol, THC has been associated with occasional hypotension, hypertension, syncope, and tachycardia. In a study of 7 adult males, combinations of IV cocaine and smoked marijuana, 1 g marijuana cigarette, 0 to 2.7% delta-9-THC, increased the heart rate above levels seen with either agent alone, with increases plateauing at 50 bpm.
    Dronedarone: (Moderate) Concomitant use of systemic lidocaine and dronedarone may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; dronedarone inhibits CYP3A4. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Dulaglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Dyphylline: (Moderate) Use of sympathomimetics with dyphylline should be approached with caution. Coadministration may lead to adverse effects, such as tremors, insomnia, seizures, or cardiac arrhythmias.
    Dyphylline; Guaifenesin: (Moderate) Use of sympathomimetics with dyphylline should be approached with caution. Coadministration may lead to adverse effects, such as tremors, insomnia, seizures, or cardiac arrhythmias.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Efavirenz: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and thus, may decrease serum concentrations of lidocaine. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range (e.g., systemic lidocaine).
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and thus, may decrease serum concentrations of lidocaine. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range (e.g., systemic lidocaine).
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and thus, may decrease serum concentrations of lidocaine. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range (e.g., systemic lidocaine).
    Elagolix: (Moderate) Concomitant use of systemic lidocaine and elagolix may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; elagolix is a weak to moderate CYP3A4 inducer.
    Elagolix; Estradiol; Norethindrone acetate: (Moderate) Concomitant use of systemic lidocaine and elagolix may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; elagolix is a weak to moderate CYP3A4 inducer.
    Elbasvir; Grazoprevir: (Moderate) Administering lidocaine with elbasvir; grazoprevir may result in elevated lidocaine plasma concentrations. Lidocaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Empagliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Empagliflozin; Linagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Empagliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Enalapril, Enalaprilat: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Enalapril; Felodipine: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Encainide: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Enflurane: (Moderate) Monitor patients who are concomitantly receiving epinephrine and enflurane for the development of arrhythmias. Halogenated anesthetics, such as enflurane, sensitize the myocardium and may potentiate the arrhythmogenic effects of epinephrine. If occur, such arrhythmias may respond to beta-blocker administration.
    Entacapone: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with enzalutamide is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Eplerenone: (Moderate) Antihypertensives, including eplerenone, antagonize the vasopressor effects of parenteral epinephrine.
    Epoprostenol: (Major) Avoid use of sympathomimetic agents with epoprostenol. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including epoprostenol. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Eprosartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Ergoloid Mesylates: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Ergonovine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Ergot alkaloids: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Ergotamine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Ergotamine; Caffeine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension. (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Ertugliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Ertugliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Ertugliflozin; Sitagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Erythromycin; Sulfisoxazole: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Eslicarbazepine: (Moderate) Concomitant use of systemic lidocaine and eslicarbazepine may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; eslicarbazepine induces CYP3A4.
    Esmolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Ethacrynic Acid: (Moderate) Loop diuretics may antagonize the pressor effects and potentiate the arrhythmogenic and hypokalemic effects of epinephrine.
    Ethotoin: (Moderate) Lidocaine is a substrate for the cytochrome P450 isoenzymes 1A2 and 3A4. Ethotoin may enhance lidocaine clearance by inducing cytochrome P-450 enzymes.
    Ethyl Chloride: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics 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. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Etomidate: (Major) General anesthetics are known to increase cardiac irritability via myocardial sensitization to catecholamines. These anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine.
    Etravirine: (Major) Etravirine is an inducer of CYP3A4; systemic lidocaine concentrations may be decreased with coadministration. Coadminister these drugs with caution. It is recommended to monitor lidocaine concentrations when possible.
    Everolimus: (Moderate) Monitor for lidocaine toxicity if coadministration with everolimus is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor.
    Exenatide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Famotidine: (Moderate) Concomitant use of systemic lidocaine and famotidine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; famotidine inhibits CYP1A2.
    Famotidine; Ibuprofen: (Moderate) Concomitant use of systemic lidocaine and famotidine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; famotidine inhibits CYP1A2.
    Felbamate: (Moderate) Concomitant use of systemic lidocaine and felbamate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; felbamate induces CYP3A4.
    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.
    Fexofenadine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Flecainide: (Major) Although causality for torsades de pointes has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation, such as local anesthetics, may have an increased risk of developing proarrhythmias. Use with caution. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Fluconazole: (Moderate) Concomitant use of systemic lidocaine and fluconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluconazole inhibits CYP3A4.
    Fludrocortisone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Flunisolide: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Fluoxetine: (Moderate) Concomitant use of systemic lidocaine and fluoxetine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluoxetine inhibits CYP3A4.
    Fluphenazine: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Flutamide: (Moderate) Coadministration of lidocaine with oxidizing agents, such as flutamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Fluticasone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Fluticasone; Salmeterol: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects. (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects. (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Fluticasone; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects. (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Fluvoxamine: (Moderate) Concomitant use of systemic lidocaine and fluvoxamine increases lidocaine exposure by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine plasma clearance is decreased by 41% to 60% and the mean half-life prolonged by 1 hour when used in combination with fluvoxamine. Lidocaine is a CYP1A2 and CYP3A4 substrate; fluvoxamine inhibits both of these hepatic isoenzymes.
    Food: (Major) Avoid concurrent use of marijuana and epinephrine as use may result in adverse cardiovascular effects, such as tachycardia and cardiac arrhythmias. Marijuana is known to produce significant increases in heart rate and cardiac output lasting for 2 to 3 hours. Further, rare case reports of myocardial infarction and cardiac arrhythmias have been associated with marijuana use. Epinephrine has also been reported to produce a wide range of cardiovascular effects including cardiac arrhythmias, palpitations, hypertension, premature ventricular contractions (PVCs), and sinus tachycardia.
    Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Formoterol; Mometasone: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects. (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Fosamprenavir: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    Fosinopril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Fosphenytoin: (Moderate) Concomitant use of systemic lidocaine and fosphenytoin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; fosphenytoin induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as fosphenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Furazolidone: (Moderate) Combined hypotensive effects are possible with the combined use of monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, tranylcypromine, or isocarboxazid) and spinal anesthetics. If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking MAOIs may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a MAOI or drugs with monoamine oxidase inhibitor activity such as furazolidone should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Furosemide: (Moderate) Loop diuretics may antagonize the pressor effects and potentiate the arrhythmogenic and hypokalemic effects of epinephrine.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Ginger, Zingiber officinale: (Minor) In vitro studies have demonstrated the positive inotropic effects of ginger, Zingiber officinale. It is theoretically possible that ginger could affect the action of antiarrhythmics, however, no clinical data are available. (Minor) In vitro studies have demonstrated the positive inotropic effects of ginger, Zingiber officinale. It is theoretically possible that ginger could affect the action of inotropic agents, however, no clinical data are available.
    Glimepiride; Rosiglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Glycopyrrolate; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Green Tea: (Moderate) Some, but not all, green tea products contain caffeine. Caffeine should be avoided or used cautiously with epinephrine. CNS stimulants and sympathomimetics are associated with adverse effects such as nervousness, irritability, insomnia, and cardiac arrhythmias.
    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: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (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; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Guanabenz: (Moderate) Sympathomimetics can antagonize the antihypertensive effects of guanabenz when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Guanfacine: (Moderate) Antihypertensives, including guanfacine, antagonize the vasopressor effects of parenteral epinephrine.
    Halothane: (Contraindicated) The manufacturer for epinephrine contraindicates the use of epinephrine with halogenated anesthetics. Halothane is known to increase cardiac irritability via myocardial sensitization to catecholamines. General anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine.
    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.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Antihypertensives, including methyldopa, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    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: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (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: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (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.
    Hydrocortisone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Hydrocortisone; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics 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. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    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.
    Hydroxyurea: (Moderate) Coadministration of lidocaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    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.
    Ibuprofen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Ibutilide: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with lidocaine, a CYP3A substrate, as lidocaine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Ifosfamide: (Moderate) Coadministration of lidocaine with oxidizing agents, such as ifosfamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Iloprost: (Major) Avoid use of sympathomimetic agents with iloprost. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including iloprost. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Imatinib: (Moderate) Monitor for lidocaine-related toxicity when administering with imatinib; lidocaine exposure may increase. Imatinib is a moderate CYP3A4 inhibitor; lidocaine is a CYP3A4 substrate.
    Imipramine: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Incretin Mimetics: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Indacaterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as indacaterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Indacaterol; Glycopyrrolate: (Moderate) Administer sympathomimetics with caution with beta-agonists such as indacaterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Indapamide: (Moderate) Sympathomimetics can antagonize the antihypertensive effects of vasodilators when administered concomitantly. Patients should be monitored to confirm that the desired antihypertensive effect is achieved.
    Indinavir: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    Insulin Degludec; Liraglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Insulin Glargine; Lixisenatide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Insulins: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Iobenguane I 131: (Major) Discontinue sympathomimetics for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart sympathomimetics until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as sympathomimetics, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
    Ionic Contrast Media: (Major) The intravascular injection of a contrast medium should never be made after the administration of vasopressors since they strongly potentiate neurologic effects. Serious neurologic sequelae, including permanent paralysis, have been reported after cerebral arteriography, selective spinal arteriography, and arteriography of vessels supplying the spinal cord.
    Ipratropium; Albuterol: (Moderate) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Irbesartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with lidocaine may result in increased serum concentrations of lidocaine. Lidocaine 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: (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use. (Major) Patients receiving local anesthetics may have an increased risk of hypotension. Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. When local anesthetics containing sympathomimetic vasoconstrictors (e.g., epinephrine) are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Phenelzine and tranylcypromine are contraindicated for use for at least 10 days prior to elective surgery.
    Isoflurane: (Moderate) Monitor patients who are concomitantly receiving epinephrine and isoflurane for the development of arrhythmias. Halogenated anesthetics, such as isoflurane, sensitize the myocardium and may potentiate the arrhythmogenic effects of epinephrine. If occur, such arrhythmias may respond to beta-blocker administration. A study investigating the epinephrine induced arrhythmogenic effect of isoflurane in adult patients undergoing transsphenoidal hypophysectomy demonstrated that the threshold dose of epinephrine (i.e., the dose at which the first sign of arrhythmia was observed) producing multiple ventricular arrhythmias was 5 mcg/kg.
    Isoniazid, INH: (Moderate) Concomitant use of systemic lidocaine and isoniazid may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; isoniazid inhibits CYP3A4.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Concomitant use of systemic lidocaine and isoniazid may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; isoniazid inhibits CYP3A4. (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of lidocaine,
    Isoniazid, INH; Rifampin: (Moderate) Concomitant use of systemic lidocaine and isoniazid may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; isoniazid inhibits CYP3A4. (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of lidocaine,
    Isoproterenol: (Major) Do not administer isoproterenol and epinephrine simultaneously due to additive cardiac stimulation, which may induce serious arrhythmias. These drugs may be administered alternately provided a proper interval has elapsed between doses.
    Isosorbide Dinitrate, ISDN: (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Isosorbide Mononitrate: (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Itraconazole: (Moderate) Concomitant use of systemic lidocaine and itraconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; itraconazole inhibits CYP3A4.
    Ketamine: (Moderate) Closely monitor vital signs when ketamine and epinephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Epinephrine may enhance the sympathomimetic effects of ketamine.
    Ketoconazole: (Moderate) Concomitant use of systemic lidocaine and ketoconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; ketoconazole inhibits CYP3A4.
    Labetalol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as Class IB antiarrhythmics, because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    Lamotrigine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IB antiarrhythmics. Concomitant use of class IB antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4.
    Lapatinib: (Major) Monitor for lidocaine toxicity if coadministration with lapatinib is necessary. Concomitant use of systemic lidocaine and lapatinib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Lidocaine is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor.
    Lesinurad: (Moderate) Concomitant use of systemic lidocaine and lesinurad may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; lesinurad induces CYP3A4.
    Lesinurad; Allopurinol: (Moderate) Concomitant use of systemic lidocaine and lesinurad may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; lesinurad induces CYP3A4.
    Letermovir: (Moderate) An increase in the plasma concentration of lidocaine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Lidocaine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Levalbuterol: (Moderate) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Levamlodipine: (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Levobetaxolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Levobunolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Levoketoconazole: (Moderate) Concomitant use of systemic lidocaine and ketoconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; ketoconazole inhibits CYP3A4.
    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.
    Levomilnacipran: (Major) Due to the effects of levomilnacipran on noradrenergic pathways, paroxysmal hypertension and arrhythmias may occur during concurrent use of epinephrine.
    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.
    Levothyroxine: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Levothyroxine; Liothyronine (Porcine): (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Levothyroxine; Liothyronine (Synthetic): (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Lidocaine; Prilocaine: (Moderate) Use lidocaine and prilocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Linezolid: (Major) Linezolid may enhance the hypertensive effect of epinephrine. Initial doses of epinephrine, if given by intravenous infusion, should be reduced and subsequent dosing titrated to desired response. Closely monitor blood pressure during coadministration. Linezolid is an antibiotic that is also a weak, reversible nonselective inhibitor of monoamine oxidase (MAO). Therefore, linezolid has the potential for interaction with adrenergic agents, such as epinephrine.
    Liothyronine: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Liraglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Lisinopril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Lixisenatide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Lonafarnib: (Moderate) Monitor for lidocaine toxicity if coadministration with lonafarnib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
    Loop diuretics: (Moderate) Loop diuretics may antagonize the pressor effects and potentiate the arrhythmogenic and hypokalemic effects of epinephrine.
    Lopinavir; Ritonavir: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    Loratadine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Losartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Loxapine: (Major) Patients taking loxapine can have reduced pressor response to ephedrine, phenylephrine, metaraminol, or norepinephrine, but these drugs are preferred over epinephrine if a vasopressor agent is required. The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of loxapine. This reaction can result in an apparently paradoxical condition called 'epinephrine reversal.' Epinephrine reversal can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction.
    Macitentan: (Major) Avoid use of sympathomimetic agents with macitentan. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including macitentan. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    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.
    Maprotiline: (Moderate) Use maprotiline and sympathomimetics together with caution and close clinical monitoring. Regularly assess blood pressure, heart rate, the efficacy of treatment, and the emergence of sympathomimetic/adrenergic adverse events. Carefully adjust dosages as clinically indicated. Maprotiline has pharmacologic activity similar to tricyclic antidepressant agents and may cause additive sympathomimetic effects when combined with agents with adrenergic/sympathomimetic activity.
    Maribavir: (Moderate) Monitor for lidocaine toxicity if coadministration with maribavir is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and maribavir is a weak CYP3A inhibitor.
    Mecamylamine: (Major) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by mecamylamine. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Meglitinides: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Mepenzolate: (Moderate) Anticholinergics, such as mepenzolate, antagonize the effects of antiglaucoma agents. Mepenzolate is contraindicated in patients with glaucoma and therefore should not be coadministered with medications being prescribed for the treatment of glaucoma. In addition, anticholinergic drugs taken concurrently with corticosteroids in the presence of increased intraocular pressure may be hazardous.
    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) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure. (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.
    Mepivacaine: (Moderate) Use mepivacaine and lidocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mepivacaine; Levonordefrin: (Moderate) Use mepivacaine and lidocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mesoridazine: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Metaproterenol: (Major) Caution and close observation should also be used when metaproterenol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Metformin; Rosiglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    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: (Major) General anesthetics are known to increase cardiac irritability via myocardial sensitization to catecholamines. These anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine.
    Methyclothiazide: (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Methyldopa: (Moderate) Antihypertensives, including methyldopa, antagonize the vasopressor effects of parenteral epinephrine.
    Methylergonovine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Methylphenidate Derivatives: (Moderate) Methylphenidate derivatives can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Methylprednisolone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Methysergide: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Metoclopramide: (Moderate) Coadministration of lidocaine with metoclopramide may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other agents associated with methemoglobinemia. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Metolazone: (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Metoprolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Mexiletine: (Major) Mexiletine is chemically and pharmacologically similar to lidocaine; cardiac and toxic effects may be additive. In addition, concurrent use may increase plasma lidocaine concentrations due to the displacement of lidocaine from tissue binding sites by mexiletine. If used together, monitor lidocaine plasma concentrations and adjust the dosage as required.
    Miglitol: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Milnacipran: (Major) Concomitant use of milnacipran with drugs that increase blood pressure and heart rate has not been systematically evaluated and such combinations should be used with caution. Due to the effects of milnacipran on noradrenergic pathways, paroxysmal hypertension and arrhythmias may occur during concurrent use of epinephrine. Monitor heart rate and blood pressure, and the patients clinical response to therapy if co-use is necessary. Milnacipran is associated with a mean increase in heart rate of 7 to 8 beats per minute, and higher increases in heart rate (13 beats per minute or more) occur more commonly in patients treated with milnacipran than in those receiving placebo. The mean increase from baseline was 5 to 6 mmHg in systolic blood pressure (SBP) and diastolic blood pressure (DBP), and cases of hypertension with milnacipran have been reported, some requiring immediate treatment.
    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: (Major) Use caution if mitotane and lidocaine are used concomitantly, and monitor for decreased efficacy of lidocaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lidocaine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lidocaine.
    Mivacurium: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    Modafinil: (Moderate) Concomitant use of systemic lidocaine and modafinil may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; modafinil induces both isoenzymes.
    Moexipril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Mometasone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Monoamine oxidase inhibitors: (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use. (Major) Patients receiving local anesthetics may have an increased risk of hypotension. Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. When local anesthetics containing sympathomimetic vasoconstrictors (e.g., epinephrine) are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Phenelzine and tranylcypromine are contraindicated for use for at least 10 days prior to elective surgery.
    Moricizine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    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.
    Nabilone: (Moderate) Concurrent use of nabilone with sympathomimetics (e.g., amphetamine or cocaine) may result in additive hypertension, tachycardia, and possibly cardiotoxicity. In a study of 7 adult males, combinations of cocaine (IV) and smoked marijuana (1 g marijuana cigarette, 0 to 2.7% delta-9-THC) increased the heart rate above levels seen with either agent alone, with increases reaching a plateau at 50 bpm.
    Nadolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Naproxen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Nebivolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Nebivolol; Valsartan: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Nefazodone: (Moderate) Concomitant use of systemic lidocaine and nefazodone may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; nefazodone inhibits CYP3A4.
    Nelfinavir: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Concomitant use of systemic lidocaine and netupitant may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; inhibition of CYP3A4 by netupitant can last for multiple days after a single dose.
    Neuromuscular blockers: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    Nevirapine: (Moderate) Nevirapine is an inducer of the cytochrome P4503A enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme, such as lidocaine, may require dosage adjustments.
    Nicotine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Systemic lidocaine has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate CYP3A4 inhibitor and lidocaine is a CYP3A4 substrate; administering these drugs together may result in increased lidocaine levels. If the use of lidocaine is required, hold nilotinib therapy. If the use of nilotinib and lidocaine cannot be avoided, a lidocaine dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Nirmatrelvir; Ritonavir: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    Nitrates: (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Nitrofurantoin: (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrofurantoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Nitroglycerin: (Moderate) Coadministration of lidocaine with oxidizing agents, such as nitrates, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Non-Ionic Contrast Media: (Major) Do not administer non-ionic contrast media intra-arterially after the administration of vasopressors since they strongly potentiate neurologic effects.
    Nortriptyline: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as lidocaine. Lidocaine is extensively metabolized in the liver into two active compounds, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). The major metabolic pathway, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4. Therapeutic monitoring is recommended with coadministration.
    Octreotide: (Moderate) Concomitant use of systemic lidocaine and octreotide may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; somatostatin analogs decrease growth hormone secretion, which in turn may inhibit 3A4 enzyme function.
    Olanzapine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
    Olanzapine; Fluoxetine: (Moderate) Concomitant use of systemic lidocaine and fluoxetine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluoxetine inhibits CYP3A4. (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
    Olanzapine; Samidorphan: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
    Olmesartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Concomitant use of systemic lidocaine and rifabutin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; rifabutin induces CYP3A4.
    Opicapone: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
    Oritavancin: (Moderate) Lidocaine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of lidocaine may be reduced if these drugs are administered concurrently.
    Osilodrostat: (Moderate) Monitor for lidocaine toxicity if coadministration with osilodrostat is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 and CYP3A4 substrate; osilodrostat is a moderate CYP1A2 inhibitor and weak CYP3A4 inhibitor.
    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.
    Oxytocin: (Moderate) Oxytocin may potentiate the pressor effects of epinephrine. Severe hypertension has been reported when oxytocin was given 3 to 4 hours after prophylactic administration of a vasoconstrictor in conjunction with caudal block anesthesia.
    Ozanimod: (Major) Coadministration of ozanimod with sympathomimetics such as epinephrine is not routinely recommended due to the potential for hypertensive crisis. If coadministration is medically necessary, closely monitor the patient for hypertension. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. Sympathomimetics may increase blood pressure by increasing norepinephrine concentrations and monoamine oxidase inhibitors (MAOIs) are known to potentiate these effects. Concomitant use of ozanimod with pseudoephedrine did not potentiate the effects on blood pressure. However, hypertensive crisis has occurred with administration of ozanimod alone and also during coadministration of sympathomimetic medications and other selective or nonselective MAO inhibitors.
    Pacritinib: (Moderate) Monitor for lidocaine toxicity if coadministration with pacritinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 and CYP1A2 substrate; pacritinib is a weak CYP3A4 and CYP1A2 inhibitor.
    Palbociclib: (Moderate) Concomitant use of systemic lidocaine and palbociclib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; palbociclib inhibits CYP3A4.
    Paliperidone: (Major) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of paliperidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The use of other agents for vascular support is recommended when needed.
    Pancuronium: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and lidocaine, a CYP3A4 substrate, may cause an increase in systemic concentrations of lidocaine. Use caution when administering these drugs concomitantly.
    Peginterferon Alfa-2b: (Major) Monitor for adverse effects associated with increased exposure to systemic lidocaine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 inhibitor, while lidocaine is a CYP1A2 substrate.
    Penbutolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with other local anesthetics, such as lidocaine, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other local anesthetic. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with other local anesthetics, such as lidocaine, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other local anesthetic. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Pergolide: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Perindopril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Perindopril; Amlodipine: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Perphenazine: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Perphenazine; Amitriptyline: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential. (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Pertuzumab; Trastuzumab; 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.
    Phendimetrazine: (Major) Phendimetrazine is a phenylalkaline sympathomimetic agent. All sympathomimetics and psychostimulants, including other anorexiants, should be used cautiously or avoided in patients receiving phendimetrazine. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmia.
    Phenelzine: (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use. (Major) Patients receiving local anesthetics may have an increased risk of hypotension. Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. When local anesthetics containing sympathomimetic vasoconstrictors (e.g., epinephrine) are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Phenelzine and tranylcypromine are contraindicated for use for at least 10 days prior to elective surgery.
    Phenobarbital: (Moderate) Concomitant use of systemic lidocaine and phenobarbital may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenobarbital induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as phenobarbital, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Concomitant use of systemic lidocaine and phenobarbital may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenobarbital induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as phenobarbital, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Phenothiazines: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Phenoxybenzamine: (Moderate) Alpha-blockers antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by an alpha-blocker, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Phentermine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Phentermine; Topiramate: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias. (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Phentolamine: (Moderate) Alpha-blockers antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by an alpha-blocker, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Phenytoin: (Moderate) Concomitant use of systemic lidocaine and phenytoin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenytoin induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Pindolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Pioglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Pioglitazone; Glimepiride: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Pioglitazone; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Pirbuterol: (Moderate) Caution and close observation should also be used when pirbuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Posaconazole: (Major) Posaconazole and lidocaine should be coadministered with caution due to an increased potential for lidocaine-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. These drugs used in combination may result in elevated lidocaine plasma concentrations, causing an increased risk for lidocaine-related adverse events.
    Potassium-sparing diuretics: (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Pramlintide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics 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. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Pramoxine; Zinc Acetate: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics 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. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Prazosin: (Moderate) Alpha-blockers antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by an alpha-blocker, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Prednisolone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Prednisone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Prilocaine: (Moderate) Use lidocaine and prilocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Prilocaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias. (Moderate) Use lidocaine and prilocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Primaquine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as primaquine, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Primidone: (Moderate) Concomitant use of systemic lidocaine and primidone may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenobarbital, the active metabolite of primidone, induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Probenecid; Colchicine: (Minor) The response to sympathomimetics may be enhanced by colchicine.
    Procainamide: (Major) Concurrent use of systemic lidocaine and other antiarrhythmic drugs such as procainamide may result in additive or antagonistic cardiac effects and additive toxicity. Patients receiving more than one antiarrhythmic drug must be carefully monitored; dosage reduction may be necessary. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Procarbazine: (Major) Because procarbazine exhibits some monoamine oxidase inhibitory (MAOI) activity, sympathomimetic drugs should be avoided. As with MAOIs, the use of a sympathomimetic drug with procarbazine may precipitate hypertensive crisis or other serious side effects. In the presence of MAOIs, drugs that cause release of norepinephrine induce severe cardiovascular and cerebrovascular responses. In general, do not use a sympathomimetic drug unless clinically necessary (e.g., medical emergencies, agents like dopamine) within the 14 days prior, during or 14 days after procarbazine therapy. If use is necessary within 2 weeks of the MAOI drug, in general the initial dose of the sympathomimetic agent must be greatly reduced. Patients should be counseled to avoid non-prescription (OTC) decongestants and other drug products, weight loss products, and energy supplements that contain sympathomimetic agents. (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.
    Prochlorperazine: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Promethazine: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Promethazine; Dextromethorphan: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Promethazine; Phenylephrine: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Propafenone: (Major) There is limited experience with the use of propafenone with Class IB antiarrhythmics. No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, the concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine. When propafenone is coadministered, the dose of lidocaine should be titrated to the desired therapeutic effects. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Propofol: (Major) General anesthetics are known to increase cardiac irritability via myocardial sensitization to catecholamines. These anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine. (Moderate) Concomitant use of systemic lidocaine and propofol may increase lidocaine plasma concentrations by reducing lidocaine clearance. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 substrate and propofol is a CYP3A4 inhibitor.
    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) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Propranolol; Hydrochlorothiazide, HCTZ: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Protriptyline: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Pseudoephedrine; Triprolidine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Pyrimethamine; Sulfadoxine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Quinapril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Quinidine: (Major) Avoid concurrent use of quinidine with other antiarrhythmics with Class I activities, such as lidocaine. Concurrent use may result in additive or antagonistic cardiac effects and additive toxicity. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Quinine: (Moderate) Concomitant use of systemic lidocaine and quinine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; quinine inhibits CYP3A4. Additionally, coadministration of lidocaine with oxidizing agents, such as quinine, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Racepinephrine: (Major) Racepinephrine is a sympathomimetic drug with agonist actions at both the alpha and beta receptors. Patients using racepinephrine inhalation are advised to avoid other non-prescription products containing sympathomimetics since additive adverse effects on the cardiovascular and nervous system are possible, some which may be undesirable. Side effects such as nausea, tremor, nervousness, difficulty with sleep, and increased heart rate or blood pressure may be additive. Patients should avoid use of non-prescription decongestants, such as phenylephrine and pseudoephedrine, while using racepinephrine inhalations. Patients should avoid dietary supplements containing ingredients that are reported or claimed to have a stimulant or weight-loss effect, such as ephedrine and ephedra, Ma huang, and phenylpropanolamine.
    Ramipril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Ranolazine: (Major) Ranolazine is an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A, and lidocaine is a substrate for this pathway. Thus, ranolazine may theoretically reduce lidocaine clearance. If concurrent therapy with ranolazine is necessary, administer lidocaine parenteral infusions with caution and monitor lidocaine serum concentrations.
    Rapacuronium: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    Rasagiline: (Moderate) The concomitant use of rasagiline and sympathomimetics was not allowed in clinical studies; therefore, caution is advised during concurrent use of rasagiline and sympathomimetics including stimulants for ADHD and weight loss, non-prescription nasal, oral, and ophthalmic decongestants, and weight loss dietary supplements containing Ephedra. Although sympathomimetics are contraindicated for use with other non-selective monoamine oxidase inhibitors (MAOIs), hypertensive reactions generally are not expected to occur during concurrent use with rasagiline because of the selective monoamine oxidase-B (MAO-B) inhibition of rasagiline at manufacturer recommended doses. One case of elevated blood pressure has been reported in a patient during concurrent use of the recommended dose of rasagiline and ophthalmic tetrahydrozoline. One case of hypertensive crisis has been reported in a patient taking the recommended dose of another MAO-B inhibitor, selegiline, in combination with ephedrine. It should be noted that the MAO-B selectivity of rasagiline decreases in a dose-related manner as increases are made above the recommended daily dose and interactions with sympathomimetics may be more likely to occur at these higher doses.
    Rasburicase: (Moderate) Coadministration of lidocaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    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.
    Reserpine: (Major) Reserpine can increase the tissue sensitivity to epinephrine leading to severe hypertension and arrhythmias. Reserpine causes increased receptor sensitivity secondary to depletion of either norepinephrine or epinephrine from adrenergic nerve endings. Epinephrine should be used cautiously in patients receiving reserpine.
    Ribociclib: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with ribociclib is necessary. Lidocaine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with ribociclib is necessary. Lidocaine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Rifabutin: (Moderate) Concomitant use of systemic lidocaine and rifabutin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; rifabutin induces CYP3A4.
    Rifampin: (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of lidocaine,
    Rifapentine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with rifapentine is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
    Riociguat: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Risperidone: (Major) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of risperidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The vasoconstrictive properties of dopamine infusion can be decreased due to the alpha-adrenergic blocking capability of risperidone. The use of other agents for vascular support is recommended when needed.
    Ritonavir: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Rocuronium: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    Ropivacaine: (Moderate) Use lidocaine and ropivacaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Rosiglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Rucaparib: (Moderate) Monitor for an increase in lidocaine-related adverse reactions if coadministration with rucaparib is necessary. Lidocaine is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Coadministration may increase lidocaine plasma concentrations.
    Sacubitril; Valsartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Safinamide: (Moderate) Severe hypertensive reactions, including hypertensive crisis, have been reported in patients taking monoamine oxidase inhibitors (MAOIs), such as safinamide, and sympathomimetic medications, such as epinephrine. If concomitant use of safinamide and epinephrine is necessary, monitor for hypertension and hypertensive crisis.
    Salmeterol: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Saquinavir: (Contraindicated) The concurrent use of systemic lidocaine and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. These drugs used together may result in large increases in lidocaine serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as lidocaine.
    Selegiline: (Moderate) Monitor blood pressure for hypertension during concomitant use of selegiline and sympathomimetics such as epinephrine. The use of these drugs together may produce substantial elevations in blood pressure. If a hypertensive crisis occurs, selegiline should be discontinued and therapy to lower blood pressure should be instituted immediately.
    Selexipag: (Major) Avoid use of sympathomimetic agents with selexipag. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including selexipag. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Selpercatinib: (Moderate) Monitor for lidocaine toxicity if coadministration with selpercatinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and selpercatinib is a weak CYP3A4 inhibitor.
    Semaglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Sevoflurane: (Moderate) Monitor patients who are concomitantly receiving epinephrine and sevoflurane for the development of arrhythmias. Halogenated anesthetics, such as sevoflurane, sensitize the myocardium and may potentiate the arrhythmogenic effects of epinephrine. If occur, such arrhythmias may respond to beta-blocker administration. A study investigating the epinephrine induced arrhythmogenic effect of sevoflurane in adult patients undergoing transsphenoidal hypophysectomy demonstrated that the threshold dose of epinephrine (i.e., the dose at which the first sign of arrhythmia was observed) producing multiple ventricular arrhythmias was 5 mcg/kg.
    SGLT2 Inhibitors: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Sibutramine: (Major) Concurrent use of sibutramine with other serotonergic agents may increase the potential for serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Simeprevir: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of lidocaine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of lidocaine, such as CNS and cardiovascular effects.
    Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (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.
    Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and vasopressors. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated.
    Sotalol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Spironolactone: (Moderate) Monitor for lidocaine toxicity if coadministration with spironolactone is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor. (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for lidocaine toxicity if coadministration with spironolactone is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor. (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    St. John's Wort, Hypericum perforatum: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics or drugs with sympathomimetic-like actions. (Moderate) Concomitant use of systemic lidocaine and St. John's Wort may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; St. John's Wort induces CYP3A4.
    Streptogramins: (Moderate) Coadministration of lidocaine with dalfopristin; quinupristin may result in elevated lidocaine plasma concentrations. If these drugs are used together, closely monitor for signs of lidocaine-related adverse events. Lidocaine is a substrate of CYP3A; dalfopristin; quinupristin is a weak CYP3A inhibitor.
    Succinylcholine: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    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.
    Sulfadiazine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Sulfasalazine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Sulfisoxazole: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Sulfonamides: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Sulfonylureas: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    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; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Telaprevir: (Major) Close clinical monitoring is advised when administering systemic lidocaine with telaprevir due to an increased potential for serious and/or life-threatening lidocaine-related adverse events. If lidocaine 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 metabolic pathways. Lidocaine is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated lidocaine plasma concentrations.
    Telithromycin: (Moderate) Telithromycin, a ketolide antibiotic, can compete with lidocaine for metabolism by CYP3A4. This can result in increased systemic concentrations of lidocaine if the two drugs are coadministered.
    Telmisartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Telmisartan; Amlodipine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Terazosin: (Moderate) Alpha-blockers antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by an alpha-blocker, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Terbutaline: (Major) Concomitant use of sympathomimetics with beta-agonists might result in additive cardiovascular effects such as increased blood pressure and heart rate.
    Teriflunomide: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to lidocaine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, lidocaine doses may need adjustment if teriflunomide treatment is discontinued.
    Tetracaine: (Moderate) Use tetracaine and lidocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Theophylline, Aminophylline: (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity. (Moderate) Theophylline may potentiate the hypokalemic effects of epinephrine.
    Thiabendazole: (Moderate) Concomitant use of systemic lidocaine and thiabendazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; thiabendazole is a potent CYP1A2 inhibitor.
    Thiazide diuretics: (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Thiazolidinediones: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Thiethylperazine: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Thiopental: (Major) General anesthetics are known to increase cardiac irritability via myocardial sensitization to catecholamines. These anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine.
    Thioridazine: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Thiothixene: (Moderate) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of thiothixene. This blockade can cause an apparently paradoxical condition called epinephrine reversal, which can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction.
    Thyroid hormones: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Ticagrelor: (Moderate) Concomitant use of systemic lidocaine and ticagrelor may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; ticagrelor inhibits CYP3A4.
    Ticlopidine: (Moderate) Concomitant use of systemic lidocaine and ticlopidine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; ticlopidine inhibits CYP1A2.
    Timolol: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Tipranavir: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
    Tocainide: (Major) Because tocainide is a lidocaine analog, it would be illogical to administer class 1B antiarrhythmic agents simultaneously unless a patient needs to be converted from parenteral lidocaine therapy to oral tocainide therapy. Additive CNS toxicity can occur during concurrent tocainide and lidocaine therapy.
    Tolcapone: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
    Topiramate: (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Torsemide: (Moderate) Loop diuretics may antagonize the pressor effects and potentiate the arrhythmogenic and hypokalemic effects of epinephrine.
    Tramadol; Acetaminophen: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Trandolapril: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine.
    Trandolapril; Verapamil: (Moderate) Antihypertensives, including angiotensin-converting enzyme inhibitors, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and verapamil may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; verapamil inhibits both hepatic isoenzymes.
    Tranylcypromine: (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use. (Major) Patients receiving local anesthetics may have an increased risk of hypotension. Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. When local anesthetics containing sympathomimetic vasoconstrictors (e.g., epinephrine) are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Phenelzine and tranylcypromine are contraindicated for use for at least 10 days prior to elective surgery.
    Trastuzumab; 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.
    Treprostinil: (Major) Avoid use of sympathomimetic agents with treprostinil. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including treprostinil. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Tretinoin; Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Triamcinolone: (Moderate) Corticosteroids may potentiate the hypokalemic effects of epinephrine.
    Triamterene: (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Potassium-sparing diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Tricyclic antidepressants: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential. (Major) Tricyclic antidepressants may potentiate the pressor effects of epinephrine. Monitor blood pressure and heart rate closely and carefully adjust dosages as required. Avoid decongestants and local anesthetics that contain epinephrine.
    Trifluoperazine: (Moderate) Phenothiazines antagonize the pressor effects of epinephrine. Do not use epinephrine to counteract hypotension caused by a phenothiazine, as a reversal of the pressor effect of epinephrine may result in paradoxical further lowering of blood pressure.
    Trimipramine: (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Tubocurarine: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    Tucatinib: (Moderate) Monitor for lidocaine toxicity if coadministration with tucatinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
    Umeclidinium; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Valproic Acid, Divalproex Sodium: (Moderate) Coadministration of lidocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Valsartan: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.
    Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Thiazide diuretics may antagonize the pressor effects and potentiate the arrhythmogenic effects of epinephrine.
    Vasodilators: (Moderate) Use sympathomimetic agents with caution in patients receiving therapy for hypertension. Patients should be monitored to confirm that the desired antihypertensive effect is achieved. Sympathomimetics can increase blood pressure and heart rate, and antagonize the antihypertensive effects of vasodilators when administered concomitantly. Anginal pain may be induced when coronary insufficiency is present.
    Vecuronium: (Moderate) Concomitant use of neuromuscular blockers and local anesthetics may prolong neuromuscular blockade. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
    Verapamil: (Moderate) Concomitant use of systemic lidocaine and verapamil may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; verapamil inhibits both hepatic isoenzymes.
    Viloxazine: (Moderate) Monitor for lidocaine toxicity if coadministration with viloxazine is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 and CYP3A substrate and viloxazine is a strong CYP1A2 and weak CYP3A inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
    Voriconazole: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with voriconazole is necessary. Lidocaine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
    Voxelotor: (Moderate) Monitor for lidocaine toxicity if coadministration with voxelotor is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
    Yohimbine: (Major) At high doses, yohimbine may nonselectively inhibit monoamine oxidase and also, at normal doses, activates the sympathetic nervous system via selective central alpha 2-adrenoceptor antagonism. Traditional MAOIs can cause serious adverse effects when taken concomitantly with sympathomimetics.
    Zafirlukast: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as lidocaine.
    Ziprasidone: (Major) The alpha-adrenergic effects of epinephrine, and possibly of other adrenergic agonists, can be blocked during concurrent administration of ziprasidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The vasoconstrictive properties of dopamine infusion can be decreased due to the alpha-adrenergic blocking capability of ziprasidone. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. If sympathomimetic agents are used for vascular support, epinephrine and dopamine should not be used, since beta stimulation combined with alpha-1 antagonism associated with ziprasidone may worsen hypotension. Similarly, it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of ziprasidone, resulting in problematic hypotension.

    PREGNANCY AND LACTATION

    Pregnancy

    Use lidocaine; epinephrine with caution in a breast-feeding woman. Lidocaine is excreted in breast milk with a milk to plasma ratio of 0.4. Previous American Academy of Pediatric recommendations considered lidocaine as usually compatible with breast-feeding. When it is used for dental or short-term, limited local anesthesia, the healthy term infant can generally safely nurse as soon as the mother is awake and alert. There is no information regarding the presence of epinephrine in human milk or the effects of epinephrine on the breast-fed infant or on milk production. However, due to its poor oral bioavailability and short half-life, epinephrine exposure is expected to be very low in the breast-fed infant.[56575]

    MECHANISM OF ACTION

    Like all local anesthetics, lidocaine 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. [54589] Clinically, loss of nerve function occurs in the order of 1) pain, 2) temperature, 3) touch, 4) proprioception, and 5) skeletal muscle tone.
     
    Systemic absorption of local anesthetics can produce cardiovascular and central nervous system (CNS) effects. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. Toxic blood concentrations depress cardiac conduction and excitability, which may lead to AV block, ventricular arrhythmia, cardiac arrest, and death. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Systemic absorption of local anesthetics can produce CNS stimulation, depression, or both. CNS stimulation typically manifests as restlessness, tremors, and shivering progressing to seizures and followed by CNS depression, coma, and, ultimately, respiratory arrest. However, local anesthetics have a primary depressant effect on the medulla and higher centers; CNS depression may occur without the initial excitatory stage.
     
    Epinephrine is a vasoconstrictor added to a local anesthetic to slow absorption into the general circulation and thus prolong maintenance of an active tissue concentration.

    PHARMACOKINETICS

    Lidocaine; epinephrine is administered parenterally. Lidocaine is completely absorbed after parenteral administration, its rate of absorption depends upon various factors, such as the site of administration and the presence or absence of a vasoconstrictor agent. The plasma binding of lidocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg/mL of free base, 60% to 80% of lidocaine is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine crosses the blood-brain barrier, presumably by passive diffusion. Lidocaine is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide (MEGX) and glycinexylidide (GX). The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine. Approximately 90% of lidocaine administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. The elimination half-life of lidocaine after an intravenous bolus injection is typically 1.5 to 2 hours. Epinephrine slows local anesthetic absorption into the general circulation and thus prolongs maintenance of an active tissue concentration and prolongs the duration of anesthetic effect.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP3A4
    The major metabolic pathway, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4.

    Other Route(s)

    The onset of anesthesia, the duration of anesthesia, and the degree of muscular relaxation are proportional to the volume and concentration (i.e., total dose) of local anesthetic used. Thus, an increase in volume and concentration of lidocaine will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation, and increase the segmental spread of anesthesia. A dilute concentration of epinephrine (1:200,000) usually reduces the rate of absorption and peak plasma concentration of the local anesthetic, permitting the use of moderately larger total doses and sometimes prolonging the duration of action.
     
    Infiltration Route
    When used for infiltration anesthesia in dental patients, the time of onset averages less than 2 minutes. Lidocaine 2% and epinephrine 1:50,000 or 1:100,000 provides an average pulp anesthesia of at least 60 minutes with an average duration of soft tissue anesthesia of approximately 2.5 hours.
     
    Perineural Route
    Except for intravascular administration, the highest lidocaine blood concentrations are obtained after intercostal nerve block. When used for nerve blocks in dental patients, the time of onset averages 2 to 4 minutes. Lidocaine 2% and epinephrine 1:50,000 or 1:100,000 provides pulp anesthesia averaging at least 90 minutes with an average duration of soft tissue anesthesia of 3 to 3.5 hours.