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    Inhalation General Anesthetics

    DEA CLASS

    Rx

    DESCRIPTION

    Halogenated general anesthetic; depth of anesthesia is easily adjusted; induction and recovery from anesthesia is rapid; cardiorespiratory depression is minimal; generally safe in patients with coronary artery disease; appropriate for pediatric patients

    COMMON BRAND NAMES

    Ultane

    HOW SUPPLIED

    Sevoflurane/Ultane Respiratory (Inhalation) Liq: 100%

    DOSAGE & INDICATIONS

    For use in general anesthesia induction during inpatient or outpatient surgery.
    NOTE: Sevoflurane has a nonpungent odor and does not cause respiratory irritability; it is suitable for mask induction in children and adults.
    NOTE: Dosage of sevoflurane must be individualized based on patient response.
    Inhalation dosage
    Adults

    Using a vital capacity induction technique, inspired concentrations of 8% sevoflurane in combination with oxygen (1 L/minute) and nitrous oxide (2 L/minute) were used to obtain loss of consciousness followed by a 30 second IV injection of remifentanil (1 to 1.5 mcg/kg). Induction time was 3.4 +/- 2.2 minutes.

    Children and Adolescents

    Inspired concentrations of 8% or 12% sevoflurane in oxygen/nitrous oxide (1:1 ratio) at 6 L/minute total gas flow was administered after 15 seconds of nitrous oxide/oxygen (1:1 ratio) to patients 5 to 10 years of age. In another study of patients 5 to 15 years of age, induction was performed using a circle-absorber breathing circuit primed with sevoflurane 7% in 6 L/minute 50% nitrous oxide/oxygen fresh gas flow. The inspired sevoflurane concentration was reduced to 4% when the pupils were divergent and to 2% when the pupils were central. At this point, the fresh gas flow was reduced to 2 L/minute. The time to loss of the eyelash reflex was less than 1 minute.

    For general anesthesia maintenance during inpatient or outpatient surgery.
    NOTE: Sevoflurane can be administered with any type of anesthesia circuit. Determine the concentration of sevoflurane being delivered from a vaporizer during anesthesia. The administration of general anesthesia must be individualized based on the patient's response.
    NOTE: No specific premedication is either indicated or contraindicated with sevoflurane. The decision as to whether or not to premedicate and the choice of premedication is left to the discretion of the anesthesiologist.
    Inhalation dosage
    Adults

    The usual maintenance dose is 0.5% to 3% with or without nitrous oxide to maintain surgical anesthesia.

    Children and Adolescents

    The usual maintenance dose is 0.5% to 3% with or without nitrous oxide to maintain surgical anesthesia.

    MAXIMUM DOSAGE

    Adults

    Specific maximum dosage information is not available. Dosage must be individualized.

    Elderly

    Specific maximum dosage information is not available. Dosage must be individualized.

    Adolescents

    Specific maximum dosage information is not available. Dosage must be individualized.

    Children

    Specific maximum dosage information is not available. Dosage must be individualized.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Sevoflurane can be administered to patients with mild-to-moderate hepatic impairment. However, sevoflurane has not been studied in patients with severe hepatic impairment.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. The safety of administering sevoflurane to patients with a serum creatinine > 1.5 mg/dl has not been established and cannot be recommended.

    ADMINISTRATION

    Inhalation Administration

    Administration should only be conducted by individuals trained in the administration of general anesthetics.
    No specific premedication is either indicated or contraindicated. The decision to premedicate and choice of medication is left to the discretion of the anesthesiologist.
    As the level of anesthesia may be altered rapidly, only vaporizers producing predictable concentrations should be used. The concentration being delivered from a vaporizer should be known, which may be accomplished by use of vaporizer calibrated specifically for sevoflurane.
    As with other inhalational anesthetics, degradation and production of degradation products can occur when sevoflurane is exposed to desiccated absorbents. An unusually delayed rise or unexpected decline of inspired sevoflurane concentration compared to the vaporizer setting may be associated with excessive heating of the CO2 absorbent and chemical breakdown of sevoflurane. Replace the CO2 absorbent if it is suspected that it may be desiccated. The exothermic reaction that occurs with sevoflurane and CO2 absorbents is increased when the CO2 absorbent becomes desiccated such as after an extended period of dry gas flow through the CO2 absorbent canisters. The color indicator of most CO2 absorbents may not change upon desiccation. Therefore, the lack of significant color change should not be taken as an assurance of adequate hydration. Replace CO2 absorbents routinely regardless of the state of the color indicator. Rare cases of extreme heat, smoke, and spontaneous fire in the anesthesia breathing circuit have been reported during sevoflurane use in conjunction with the use of desiccated CO2 absorbent, specifically those containing potassium hydroxide. Potassium hydroxide containing CO2 absorbents are not recommended for use with sevoflurane.
    Concurrent administration of sevoflurane is compatible with the use of barbiturates, propofol, and other commonly used intravenous anesthetics.
    The recovery from general anesthesia should be assessed carefully before a patient is discharged from the postanesthesia care unit.

    STORAGE

    Ultane:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Halogenated anesthetics hypersensitivity, malignant hyperthermia

    Sevoflurane is a halogenated anesthetic and is contraindicated in patients with known sensitivity to sevoflurane or with a halogenated anesthetics hypersensitivity. Sevoflurane is also contraindicated in patients with a known or suspected genetic disposition to malignant hyperthermia. Discontinue sevoflurane in the presence of malignant hyperthermia.

    Head trauma, increased intracranial pressure, intracranial mass

    Although not specifically reported with sevoflurane, increases in intracranial pressure have occurred with other volatile anesthetics (e.g., isoflurane). Sevoflurane should be used cautiously in patients with head trauma, intracranial mass, preexisting increased intracranial pressure, or space-occupying intracranial lesions.

    Myasthenia gravis

    Use of sevoflurane in patients with myasthenia gravis may worsen muscular weakness due to the neuromuscular blocking effects of anesthetics.

    Neuromuscular disease

    Although rare, hyperkalemia development with sevoflurane use may occur, especially in patients with latent as well as overt neuromuscular disease such as Duchenne muscular dystrophy. If a patient develops hyperkalemia, evaluation for latent neuromuscular disease is recommended.

    Children, infants, neonates, seizure disorder, seizures

    Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in neonates, infants, and children younger than 3 years, including in utero exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in young children against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development. Sevoflurane's minimal alveolar concentration (MAC) is higher in children than adults; it is highest in very young children and decreases with increasing age. The MAC in premature neonates has not been established. The use of sevoflurane has been associated with seizures. The majority of these have occurred in infants older than 2 months, children, and young adults, most of whom had no predisposing risk factors. Clinical judgment should be exercised when using sevoflurane in patients with a seizure disorder or who are at risk for seizures.

    Renal failure, renal impairment

    The safety of sevoflurane administration in patients with renal impairment or renal failure (serum creatinine more than 1.5 mg/dL) has not been established. Sevoflurane should be used cautiously in these patients. In addition, sevoflurane has the potential (secondary to Compound A) to cause nephrotoxicity. Animal and human studies demonstrate that sevoflurane administered for more than 2 MAC-hours and at fresh gas flow rates of less than 2 L/minute may be associated with proteinuria and glycosuria.

    Breast-feeding

    Because inhalational anesthetics are rapidly cleared from the mother after administration of a single dose, clinically significant exposure to a nursing infant is not expected. Experts recommend that breast-feeding can be resumed once the mother has sufficiently recovered from general anesthesia. According to the manufacturer, sevoflurane concentrations in breast milk are not expected to be clinically important 24 hours after administration. Due to rapid clearance, breast milk sevoflurane concentrations are predicted to be below those of many other volatile anesthetics. Sevoflurane has not been evaluated by the American Academy of Pediatrics (AAP); however, halothane, another halogenated anesthetic, is classified as usually compatible with breast-feeding by the AAP. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Labor, obstetric delivery, pregnancy

    Sevoflurane is classified as FDA pregnancy category B. Animal studies have indicated no impaired fertility or fetotoxicity. However, there are no adequate, well-controlled studies in pregnant women; therefore, use during pregnancy only if clearly needed. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures during the third trimester of pregnancy may have negative effects on fetal brain development. Consider the benefits of appropriate anesthesia in pregnant women against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required prior to delivery. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child and/or mother. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development. Sevoflurane has been used as part of general anesthesia for elective cesarean section with no untoward side effects in mother or neonate. However, the safety of sevoflurane in labor and obstetric delivery has not been established. In general, general anesthetics may cause dose-dependent uterine relaxation that can delay vaginal delivery.

    Hepatic disease

    Results of evaluations of laboratory parameters (e.g., ALT, AST, alkaline phosphatase, and total bilirubin, etc.) and investigator-reported incidence of adverse events relating to liver function demonstrate that sevoflurane can be administered to patients with normal or mild-to-moderately impaired hepatic function. However, patients with severe hepatic dysfunction were not investigated. Occasional cases of transient changes in postoperative hepatic function tests were reported with both sevoflurane and reference agents. Sevoflurane was found to be comparable to isoflurane with regard to these changes in hepatic function. Mild to moderate hepatic impairment has been shown to prolong the terminal disposition of fluoride. Very rare cases of mild, moderate, and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from postmarketing experiences. Exercise clinical judgment when sevoflurane is used in patients with underlying hepatic disease or under treatment with drugs known to cause hepatic dysfunction.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Sevoflurane has been reported to cause prolongation of the QT interval, which constitutes a risk for ventricular tachycardia, including torsade de pointes. Use sevoflurane with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

    Geriatric, hypotension

    During maintenance anesthesia, increasing the concentration of sevoflurane produces dose-dependent hypotension. Due to sevoflurane's insolubility in blood, these hemodynamic changes may occur more rapidly than with other volatile anesthetic agents. Excessive decreases in blood pressure or respiratory depression may be related to the depth of anesthesia and may be corrected by decreasing the inspired concentration of sevoflurane. Use sevoflurane with caution in geriatric patients because they often have significantly decreased minimum alveolar concentration (MAC) and are more susceptible to anesthetic-induced hypotension and circulatory depression. The average concentration to achieve MAC in an 80-year-old is approximately 50% of that required in a 20-year-old patient.

    ADVERSE REACTIONS

    Severe

    laryngospasm / Rapid / 2.0-8.0
    bradycardia / Rapid / 5.0-5.0
    apnea / Delayed / 0-2.0
    bronchospasm / Rapid / 0-1.0
    malignant hyperthermia / Rapid / 0-1.0
    proteinuria / Delayed / 0-1.0
    oliguria / Early / 0-1.0
    hyperkalemia / Delayed / 0-1.0
    myoglobinuria / Delayed / 0-1.0
    atrial fibrillation / Early / 0-1.0
    AV block / Early / 0-1.0
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known

    Moderate

    hypotension / Rapid / 4.0-11.0
    sinus tachycardia / Rapid / 2.0-6.0
    hypertension / Early / 2.0-2.0
    wheezing / Rapid / 0-1.0
    hypertonia / Delayed / 0-1.0
    confusion / Early / 0-1.0
    glycosuria / Early / 0-1.0
    urinary retention / Early / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    hypophosphatemia / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    ST-T wave changes / Rapid / 0-1.0
    amblyopia / Delayed / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    dyspnea / Early / 0-1.0
    hypoventilation / Rapid / 0-1.0
    hypoxia / Early / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    contact dermatitis / Delayed / Incidence not known
    delirium / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    respiratory depression / Rapid / Incidence not known

    Mild

    nausea / Early / 25.0-25.0
    vomiting / Early / 18.0-18.0
    agitation / Early / 7.0-15.0
    cough / Delayed / 5.0-11.0
    shivering / Rapid / 6.0-6.0
    dizziness / Early / 4.0-4.0
    hypersalivation / Early / 2.0-4.0
    pruritus / Rapid / 0-1.0
    rash (unspecified) / Early / 0-1.0
    insomnia / Early / 0-1.0
    headache / Early / 1.0-1.0
    syncope / Early / 0-1.0
    hyperventilation / Early / 0-1.0
    hiccups / Early / 0-1.0
    pharyngitis / Delayed / 0-1.0
    xerostomia / Early / 0-1.0
    dysgeusia / Early / 0-1.0
    fever / Early / 1.0-1.0
    asthenia / Delayed / 0-1.0
    hypothermia / Delayed / 1.0-1.0
    leukocytosis / Delayed / 0-1.0
    urticaria / Rapid / Incidence not known
    restlessness / Early / Incidence not known
    drowsiness / Early / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation including sevoflurane.
    Acetaminophen; Butalbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates. (Moderate) Concurrent use of sevoflurane with opiate agonists such as codeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concurrent use of sevoflurane with opiate agonists such as dihydrocodeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids and they are commonly used in surgical practice.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Acetaminophen; Codeine: (Moderate) Concurrent use of sevoflurane with opiate agonists such as codeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice.
    Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine.
    Acetaminophen; Diphenhydramine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Acetaminophen; Guaifenesin; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as general anesthetics, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Propoxyphene: (Moderate) Concomitant use of central nervous system depressants can potentiate the effects of propoxyphene, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Acetaminophen; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine.
    Acetaminophen; Tramadol: (Moderate) Tramadol can cause additive CNS depression and respiratory depression when used with other agents that are CNS depressants, such as general anesthetics. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Acrivastine; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Alfentanil: (Moderate) Concurrent use of sevoflurane with opiate agonists such as alfentanil can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. Postoperative respiratory depression associated with alfentanil may also be augmented. If alfentanil is used with one of these drugs, the dose of one or both agents may need to be reduced. Requirements for volatile inhalation anesthetics or alfentanil infusion are reduced by 30% to 50% for the first hour of maintenance following an anesthetic induction dose of alfentanil. Discontinue alfentanil infusions at least 10 to 15 minutes before the end of surgery during general anesthesia.
    Alfuzosin: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with alfuzosin. Halogenated anesthetics can prolong the QT interval. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. The manufacturer warns that the QT effect of alfuzosin should be considered prior to administering the drug to patients taking other medications known to prolong the QT interval.
    Aliskiren: (Moderate) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Aliskiren; Amlodipine: (Moderate) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Aliskiren; Valsartan: (Moderate) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Ambenonium Chloride: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Ambrisentan: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
    Amikacin: (Moderate) Patients receiving general anesthetics should be observed for exaggerated effects if they are receiving amikacin.
    Amiodarone: (Major) In general, adverse cardiovascular effects such as hypotension and atropine-resistant bradycardia can occur in patients receiving amiodarone who subsequently are administered any general anesthetics, particularly volatile anesthetics. Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated anesthetics, which may include QT prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is also possible for days to weeks after discontinuation of amiodarone.
    Amobarbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Amoxapine: (Moderate) Because amoxapine can cause sedation, an enhanced CNS depressant effect may occur during combined use with general anesthetics such as enflurane.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
    Amphetamine; Dextroamphetamine Salts: (Major) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the myocardium to the effects of stimulants. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include halogenated anesthetics.
    Angiotensin II receptor antagonists: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Angiotensin-converting enzyme inhibitors: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Apomorphine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with apomorphine. Halogenated anesthetics can prolong the QT interval. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. In one study, a single mean dose of 5.2 mg (range 2-10 mg) prolonged the QT interval by about 3 msec. However, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended. Concomitant administration of apomorphine and halogenated anesthetics could also result in additive depressant effects. Careful monitoring is recommended during combined use of a CNS depressant and apomorphine. A dose reduction of one or both drugs may be warranted.
    Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as general anesthetics.
    Arformoterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Aripiprazole: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Halogenated anesthetics can prolong the QT interval and should be used cautiously and with close monitoring with aripirazole.
    Arsenic Trioxide: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with arsenic trioxide. Halogenated anesthetics can prolong the QT interval. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported.
    Artemether; Lumefantrine: (Major) Halogenated anesthetics should be avoided with artemether; lumefantrine. Halogenated anesthetics can prolong the QT interval. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if halogenated anesthetics must be used with or after artemether; lumefantrine treatment.
    Articaine; Epinephrine: (Severe) The manufacturer for epinephrine contraindicates the use of epinephrine with halogenated anesthetics or cyclopropane. Halothane, cyclopropane, and other general anesthetics (e.g., amobarbital, etomidate, ketamine, methohexital, nitrous oxide, propofol, thiopental) are known to increase cardiac irritability via myocardial sensitization to catecholamines. General anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer, asenapine should not be used with other agents also known to have this effect (e.g., halogenated anesthetics). Halogenated anesthetics can prolong the QT interval.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates. (Moderate) Concurrent use of sevoflurane with opiate agonists such as codeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concurrent use of sevoflurane with opiate agonists such as dihydrocodeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids and they are commonly used in surgical practice.
    Aspirin, ASA; Carisoprodol: (Moderate) General anesthetics potentiate the effect of other CNS depressants including carisoprodol.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concurrent use of sevoflurane with opiate agonists such as codeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice. (Moderate) General anesthetics potentiate the effect of other CNS depressants including carisoprodol.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as general anesthetics, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include halogenated anesthetics.
    Atracurium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Atropine; Edrophonium: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Azelastine: (Minor) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including general anesthetics.
    Azelastine; Fluticasone: (Minor) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including general anesthetics.
    Azithromycin: (Major) Halogenated Anesthetics should be used cautiously and with close monitoring with azithromycin. Halogenated Anesthetics can prolong the QT interval. There have been case reports of QT prolongation and torsade de pointes (TdP) with the use of azithromycin in post-marketing reports.
    Bacitracin: (Moderate) General anesthetics should be used cautiously in patients receiving systemic bacitracin. Systemic bacitracin may act synergistcally to increase or prolong skeletal muscle relaxation produced by neuromuscular blocking agents and/or general anesthetics. If bacitracin is administered parenterally during surgery, there may be increased skeletal muscle relaxation, and postoperative use may reinstate neuromuscular blockade.
    Baclofen: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants like general anesthetics can result in additive CNS depression.
    Barbiturates: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with halogenated anesthetics. Both bedaquiline and halogenated anesthetics have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Belladonna; Opium: (Moderate) Concomitant use of central nervous system depressants, such as sevoflurane, can potentiate the effects of opium, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Benzodiazepines: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Beta-adrenergic blockers: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include halogenated anesthetics.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include halogenated anesthetics.
    Brompheniramine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Brompheniramine; Carbetapentane; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Brompheniramine; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Budesonide; Formoterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Bupivacaine Liposomal: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Bupivacaine: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Bupivacaine; Lidocaine: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of halogenated anesthetics and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Halogenated anesthetics have a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, during co-administration of buprenorphine with other CNS depressants, hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects. Monitor patients for sedation or respiratory depression. The buprenorphine dose may also need to be lowered when given with drugs that reduce hepatic blood flow, such as halothane, which causes a reduction in hepatic blood flow by about 30%.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of halogenated anesthetics and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Halogenated anesthetics have a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, during co-administration of buprenorphine with other CNS depressants, hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects. Monitor patients for sedation or respiratory depression. The buprenorphine dose may also need to be lowered when given with drugs that reduce hepatic blood flow, such as halothane, which causes a reduction in hepatic blood flow by about 30%.
    Buspirone: (Moderate) General anesthetics potentiate the effects of CNS depressants.
    Butabarbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
    Calcium-channel blockers: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Capreomycin: (Moderate) Partial neuromuscular blockade has been reported with capreomycin after the administration of large intravenous doses or rapid intravenous infusion. General anesthetics could potentiate the neuromuscular blocking effect of capreomycin by transmission of impulses at the motor nerve terminals. If these drugs are used in combination, monitor patients for increased adverse effects.
    Capsaicin; Metaxalone: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Carbamazepine: (Moderate) Caution is advised with the concomitant use of sevoflurane and carbamazepine as concurrent use may increase the risk of hepatotoxicity.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics.
    Carbetapentane; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics.
    Carbetapentane; Phenylephrine; Pyrilamine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbetapentane; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbidopa; Levodopa: (Major) If administered before halogenated anesthetics, levodopa without a concurrent decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthesia is required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
    Carbidopa; Levodopa; Entacapone: (Major) If administered before halogenated anesthetics, levodopa without a concurrent decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthesia is required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
    Carbinoxamine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbinoxamine; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbinoxamine; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carisoprodol: (Moderate) General anesthetics potentiate the effect of other CNS depressants including carisoprodol.
    Central-acting adrenergic agents: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Ceritinib: (Major) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and halogenated anesthetics; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Cetirizine: (Minor) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, such as general anesthetics.
    Cetirizine; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Minor) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, such as general anesthetics.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlophedianol; Guaifenesin; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension.
    Chlorcyclizine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chloroprocaine: (Major) Due to the cardiotoxic potential of all local anesthetics, they should be used with caution with other agents that can prolong the QT interval, such as general anesthetics. If epinephrine is added to chloroprocaine, do not use the mixture in a patient during or following treatment with general anesthetics.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as halogenated anesthetics, with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Halogenated anesthetics can prolong the QT interval.
    Chlorpheniramine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Codeine: (Moderate) Concurrent use of sevoflurane with opiate agonists such as codeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Dextromethorphan: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Concurrent use of sevoflurane with opiate agonists such as dihydrocodeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids and they are commonly used in surgical practice. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Moderate) Concurrent use of sevoflurane with opiate agonists such as dihydrocodeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids and they are commonly used in surgical practice. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpromazine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with chlorpromazine. Halogenated anesthetics can prolong the QT interval. Phenothiazines have been associated with a risk of QT prolongation and/or torsade de pointes (TdP). This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine. Agents that prolong the QT interval could lead to torsade de pointes when combined with a phenothiazine, and therefore are generally not recommended for combined use. In addition, phenothiazines can potentiate the CNS-depressant action of anesthetics.
    Ciprofloxacin: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ciprofloxacin. Halogenated anesthetics can prolong the QT interval. Rare cases of QT prolongation and torsade de pointe (TdP) have been reported with ciprofloxacin during post-marketing surveillance. Ciprofloxacin should be used with caution in patients receiving drugs that prolong the QT interval.
    Cisapride: (Severe) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Because of the potential for TdP, use of the halogenated anesthetics with cisapride is contraindicated.
    Cisatracurium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Citalopram: (Major) Halogenated anesthetics are associated with a risk for QT prolongation. Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended.
    Clarithromycin: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
    Class IA Antiarrhythmics: (Major) Halogenated anesthetics should be used cautiously with class IA antiarrhythmics (disopyramide, procainamide, quinidine). Halogenated anesthetics can prolong the QT interval and class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP).
    Clemastine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Clobazam: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (i.e., increased sedation or respiratory depression) may occur when clobazam is combined with other CNS depressants such as general anesthetics.
    Clozapine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clozapine. Halogenated anesthetics can prolong the QT interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Clozapine can also potentiate the actions of other CNS depressants such as the general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects. Neuroleptic malignant syndrome has been reported in association with antipsychotic medications, including clozapine. In the presence of high fever, the possibility of this complication should be considered.
    Codeine: (Moderate) Concurrent use of sevoflurane with opiate agonists such as codeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice.
    Codeine; Guaifenesin: (Moderate) Concurrent use of sevoflurane with opiate agonists such as codeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice.
    Codeine; Phenylephrine; Promethazine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Concurrent use of sevoflurane with opiate agonists such as codeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice. (Moderate) Halogenated anesthetics carry a possible risk for QT prolongation and torsade de pointes (TdP). Promethazine carries a possible risk of QT prolongation and should be used cautiously with these anesthetics, with proper blood pressure and heart rate monitoring.
    Codeine; Promethazine: (Moderate) Concurrent use of sevoflurane with opiate agonists such as codeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice. (Moderate) Halogenated anesthetics carry a possible risk for QT prolongation and torsade de pointes (TdP). Promethazine carries a possible risk of QT prolongation and should be used cautiously with these anesthetics, with proper blood pressure and heart rate monitoring.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with halogenated anesthetics. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; halogenated anesthetics can also prolong the QT interval.
    Cyclizine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Cyclobenzaprine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with cyclobenzaprine. Halogenated anesthetics can prolong the QT interval. Cyclobenzaprine is structurally similar to tricyclic antidepressants. Tricyclic antidepressants have been reported to prolong the QT interval, especially when given in excessive doses (or in overdosage settings). Cyclobenzaprine is associated with a possible risk of QT prolongation and torsade de pointes (TdP), particularly in the event of acute overdose.
    Cyproheptadine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Dantrolene: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include halogenated anesthetics.
    Dasatinib: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with dasatinib. Halogenated anesthetics can prolong the QT interval. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Cautious dasatinib administration is recommended to patients who have or may develop QT prolongation such as patients taking drugs that lead to QT prolongation.
    Daunorubicin: (Major) Since halogenated anesthetics can prolong the QT interval, it should be used cautiously with anthracyclines due to the potential risks for anthracycline cardiac toxicity. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Degarelix: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with degarelix. Halogenated anesthetics can prolong the QT interval. Since degarelix can cause QT prolongation, degarelix should be used cautiously with other drugs that are associated with QT prolongation. Prescribers need to weigh the potential benefits and risks of degarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval.
    Desloratadine; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine.
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with halogenated anesthetics, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Halogenated anesthetics can prolong the QT interval.
    Dexchlorpheniramine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Dexmedetomidine: (Moderate) Coadministration of dexmedetomidine with general anesthetics is likely to lead to an enhancement of anesthetic, sedative, or cardiovascular effects. Due to possible pharmacodynamic interactions, when co-administered with dexmedetomidine, a reduction in dosage of dexmedetomidine or the concomitant anesthetic may be required. Specific studies have confirmed these pharmacodynamic effects with sevoflurane, isoflurane, and propofol. No pharmacokinetic interactions between dexmedetomidine and isoflurane or propofol have been demonstrated.
    Dexmethylphenidate: (Moderate) Halogenated anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the cardiovascular system to the effects of dexmethylphenidate. While the sympathomimetic effects of dexmethylphenidate are weaker than those of the amphetamines, and evidence of an interaction is lacking, caution is advised.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine.
    Dextromethorphan; Promethazine: (Moderate) Halogenated anesthetics carry a possible risk for QT prolongation and torsade de pointes (TdP). Promethazine carries a possible risk of QT prolongation and should be used cautiously with these anesthetics, with proper blood pressure and heart rate monitoring.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Moderate) Concurrent use of sevoflurane with opiate agonists such as dihydrocodeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids and they are commonly used in surgical practice.
    Dimenhydrinate: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Diphenhydramine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Diphenhydramine; Ibuprofen: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Diphenhydramine; Naproxen: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Diphenhydramine; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Disulfiram: (Moderate) Disulfiram decreases the activity of cytochrome P450 2E1 isoenzyme and may inhibit sevoflurane metabolism.
    Dofetilide: (Severe) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Halogenated anesthetics can prolong the QT interval.Because of the potential for TdP, use of halogenated anesthetics with dofetilide is contraindicated.
    Dolasetron: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with dolasetron. Halogenated anesthetics can prolong the QT interval. Dolasetron has been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Use of dolasetron injection for the prevention of chemotherapy-induced nausea and vomiting is contraindicated because the risk of QT prolongation is higher with the doses required for this indication; when the injection is used at lower doses (i.e., those approved for post-operative nausea and vomiting) or when the oral formulation is used, the risk of QT prolongation is lower and caution is advised.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Doxacurium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Doxazosin: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Doxorubicin: (Major) Since halogenated anesthetics can prolong the QT interval, they should be used cautiously with anthracyclines due to the potential risks for anthracycline cardiac toxicity. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Doxylamine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Doxylamine; Pyridoxine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Dronabinol, THC: (Moderate) Concomitant use of dronabinol with other CNS depressants like general anesthetics can potentiate the effects of dronabinol on respiratory depression.
    Dronedarone: (Severe) Concurrent use of halogenated anesthetics and dronedarone is contraindicated. Halogenated anesthetics prolong the QT interval. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with droperidol. Halogenated anesthetics can prolong the QT interval. Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. According to the revised 2001 labeling for droperidol, any drug known to have potential to prolong the QT interval should not be coadministered with droperidol.
    Dyphylline: (Moderate) Methylxanthines and inhaled general anesthetics have been associated with adverse cardiovascular effects. Concurrent use may increase the risk of such effects including cardiac arrhythmias.
    Dyphylline; Guaifenesin: (Moderate) Methylxanthines and inhaled general anesthetics have been associated with adverse cardiovascular effects. Concurrent use may increase the risk of such effects including cardiac arrhythmias.
    Edrophonium: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Efavirenz: (Major) Although data are limited, coadministration of efavirenz and halogenated anesthetics may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Although data are limited, coadministration of efavirenz and halogenated anesthetics may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval.
    Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include halogenated anesthetics.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Epinephrine: (Severe) The manufacturer for epinephrine contraindicates the use of epinephrine with halogenated anesthetics or cyclopropane. Halothane, cyclopropane, and other general anesthetics (e.g., amobarbital, etomidate, ketamine, methohexital, nitrous oxide, propofol, thiopental) are known to increase cardiac irritability via myocardial sensitization to catecholamines. General anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine.
    Epirubicin: (Major) Since halogenated anesthetics can prolong the QT interval, it should be used cautiously with anthracyclines due to the potential risks for anthracycline cardiac toxicity. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Eplerenone: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Epoprostenol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Eribulin: (Major) Eribulin and halogenated anesthetics have been associated with QT prolongation. If eribulin must be coadministered with a halogenated anesthetic, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with erythromycin. Halogenated anesthetics can prolong the QT interval and erythromycin administration is associated with QT prolongation and torsades de pointes (TdP).
    Erythromycin; Sulfisoxazole: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with erythromycin. Halogenated anesthetics can prolong the QT interval and erythromycin administration is associated with QT prolongation and torsades de pointes (TdP).
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as halogenated anesthetics, should be done with caution and close monitoring.
    Eszopiclone: (Moderate) A temporary dose reduction of eszopiclone should be considered following administration of general anesthetics. The risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethanol: (Major) Anesthetic requirements may be increased for sevoflurane with chronic ethanol ingestion. The cytochrome P450 (CYP) 2E1 isoenzyme appears to be a predominant enzyme responsible for human oxidative sevoflurane metabolism. Ethanol has been shown to induce CYP2E1. Additionally, the concurrent use of sevoflurane in patients with chronic ethanol ingestion may increase the risk of hepatotoxicity.
    Ezogabine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ezogabine. Halogenated anesthetics can prolong the QT interval and ezogabine has been associated with QT prolongation. The manufacturer of ezogabine recommends caution during concurrent use of medications known to increase the QT interval.
    Fentanyl: (Moderate) Concurrent use of sevoflurane with opiate agonists such as fentanyl can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. Concurrent use of sevoflurane is compatible with opioids and is common surgical practice. If concurrent use of fentanyl and a CNS depressant is desired, consider a reduction in fentanyl dose. Perform blood pressure, level of consciousness, and respiration monitoring as clinically warranted.
    Fexofenadine; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine.
    Fingolimod: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with fingolimod. Halogenated anesthetics can prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with flecainide. Halogenated anesthetics can prolong the QT interval. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Major) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with fluconazole include the halogenated anesthetics Halogenated anesthetics can prolong the QT interval and have been associated with QT prolongation and rare cases of torsades de pointes (TdP).
    Fluoxetine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
    Fluoxetine; Olanzapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics. (Major) Halogenated anesthetics should be used cautiously and with close monitoring with olanzapine. Halogenated anesthetics can prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP).
    Fluphenazine: (Minor) Halogenated anesthetics should be used cautiously and with close monitoring with fluphenazine. Halogenated anesthetics can prolong the QT interval and fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, phenothiazines can potentiate the CNS-depressant action of general anesthetics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Fluticasone; Salmeterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Fluticasone; Vilanterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Formoterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Formoterol; Mometasone: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as halogenated anesthetics. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Halogenated anesthetics can also prolong the QT interval. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Moderate) Caution is advised with the concomitant use of sevoflurane and fosphenytoin as concurrent use may increase the risk of hepatotoxicity.
    Galantamine: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Gemifloxacin: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with gemifloxacin. Halogenated anesthetics can prolong the QT interval. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5-10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and halogenated anesthetics together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Halogenated anesthetics can prolong the QT interval.
    Gentamicin: (Moderate) Patients receiving general anesthetics should be observed for exaggerated effects if they are receiving gentamicin.
    Glycopyrrolate; Formoterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Goserelin: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with goserelin. Halogenated anesthetics can prolong the QT interval. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with granisetron. Halogenated anesthetics can prolong the QT interval. Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, may result in clinical consequences.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Guaifenesin; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension.
    Guaifenesin; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine.
    Halofantrine: (Severe) Halofantrine is considered to have a well-established risk for QT prolongation and torsades de pointes and should be avoided in patients receiving drugs which may induce QT prolongation, such as sevoflurane.
    Haloperidol: (Major) QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. According to the manufacturer of haloperidol, caution is advisable when prescribing the drug concurrently with medications known to prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with haloperidol include halogenated anesthetics.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Hydrocodone; Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Hydrocodone; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Hydromorphone: (Moderate) Concomitant use of hydromorphone with other central nervous system (CNS) depressants can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Examples of drugs associated with CNS depression include general anesthetics. Prior to concurrent use of hydromorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and halogenated anesthestics. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Halogenated anesthetics can prolong the QT interval.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include halogenated anesthetics. Also, because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as general anesthetics, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Ibuprofen; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine.
    Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Halogenated anesthetics can prolong the QT interval and should be used cautiously with ibutilide.
    Idarubicin: (Major) Since halogenated anesthetics can prolong the QT interval, they should be used cautiously and with close clinical monitoring with anthracyclines due to the potential risks for anthracycline cardiac toxicity. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with halogenated anesthetics which canalso prolong the QT interval.
    Iloprost: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Indacaterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Indacaterol; Glycopyrrolate: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with halogenated anesthetics due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, monitor the ECG and electrolytes. Inotuzumab has been associated with QT interval prolongation. Halogenated anesthetics can also prolong the QT interval.
    Ionic Contrast Media: (Moderate) General anesthesia may be indicated in the performance of some procedures in young or uncooperative children and in selected adult patients; however, a higher incidence of adverse reactions has been reported to ionic contrast media in these patients. This may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia, which can prolong the circulation time and increase the duration of contact of the contrast agent.
    Isoniazid, INH: (Major) Anesthetic requirements may be increased for sevoflurane with concomitant use of isoniazid, INH. The cytochrome P450 (CYP) 2E1 isoenzyme appears to be a predominant enzyme responsible for human oxidative sevoflurane metabolism. Isoniazid, INH has been shown to induce CYP2E1. Additionally, the concurrent use of sevoflurane and isoniazid may increase the risk of hepatotoxicity.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Anesthetic requirements may be increased for sevoflurane with concomitant use of isoniazid, INH. The cytochrome P450 (CYP) 2E1 isoenzyme appears to be a predominant enzyme responsible for human oxidative sevoflurane metabolism. Isoniazid, INH has been shown to induce CYP2E1. Additionally, the concurrent use of sevoflurane and isoniazid may increase the risk of hepatotoxicity. (Moderate) Caution is advised with the concomitant use of sevoflurane and rifampin as concurrent use may increase the risk of hepatotoxicity.
    Isoniazid, INH; Rifampin: (Major) Anesthetic requirements may be increased for sevoflurane with concomitant use of isoniazid, INH. The cytochrome P450 (CYP) 2E1 isoenzyme appears to be a predominant enzyme responsible for human oxidative sevoflurane metabolism. Isoniazid, INH has been shown to induce CYP2E1. Additionally, the concurrent use of sevoflurane and isoniazid may increase the risk of hepatotoxicity. (Moderate) Caution is advised with the concomitant use of sevoflurane and rifampin as concurrent use may increase the risk of hepatotoxicity.
    Itraconazole: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include halogenated anesthetics.
    Kanamycin: (Moderate) General anesthetics may be associated with enhanced neuromuscular blocking effects. Many pharmacy references mention neuromuscular blockade as an adverse reaction of aminoglycoside antibiotics, however, it appears this is only seen when aminoglycosides are used to irrigate the abdominal cavity during surgery, a practice which has been discouraged. It is believed that this effect is less likely to occur with parenteral aminoglycoside therapy since patients are exposed to smaller amounts of drug. Nevertheless, patients receiving general anesthetics should be observed for exaggerated effects if they are receiving aminoglycosides.
    Ketoconazole: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include halogenated anesthetics.
    Lapatinib: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include halogenated anesthetics.
    Lenvatinib: (Major) Halogenated anesthetics can prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with halogenated anesthetics include lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Leuprolide: (Major) Halogenated anesthetics are associated with a risk for QT prolongation and potential cardiac arrhythmias. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Halogenated anesthetics should be used cautiously and with close monitoring in patients receiving leuprolide.
    Leuprolide; Norethindrone: (Major) Halogenated anesthetics are associated with a risk for QT prolongation and potential cardiac arrhythmias. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Halogenated anesthetics should be used cautiously and with close monitoring in patients receiving leuprolide.
    Levocetirizine: (Minor) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, such as general anesthetics.
    Levodopa: (Major) If administered before halogenated anesthetics, levodopa without a concurrent decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthesia is required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
    Levofloxacin: (Major) Halogenated anesthetics can prolong the QT interval. Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Rare cases of torsade de pointes (TdP) have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. According to the manufacturer, levofloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval, such as halogenated anesthetics.
    Levomethadyl: (Severe) Sevoflurane can prolong the QT interval and should generally be avoided in combination with drugs that have been established to have a causal association with QT prolongation and torsade de pointe including levomethadyl.
    Levorphanol: (Moderate) Concomitant use of levorphanol with other CNS depressants such as general anesthetics (sevoflurane) can potentiate the effects of levorphanol on respiration, blood pressure, and alertness. Severe hypotension, respiratory depression, profound sedation, or coma may occur. Prior to concurrent use of levorphanol in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. When concomitant treatment with levorphanol with another CNS depressant is necessary, reduce the dose of 1 or both drugs. The initial dose of levorphanol should be reduced by approximately 50% or more when levorphanol is used with another drug that may depress respiration.
    Lincosamides: (Moderate) Concurrent use of sevoflurane with systemic clindamycin can result in an additive neuromuscular blockade.
    Lisdexamfetamine: (Major) Inhalational general anesthetics may sensitize the myocardium to the effects of lisdexamfetamine. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    Lithium: (Major) Because both lithium and halogenated anesthetics can prolong the QT interval, combine with caution and close clinical monitoring.
    Lomefloxacin: (Major) Lomefloxacin has been associated with QT prolongation and infrequent cases of arrhythmia. Other medications which may prolong the QT interval, such as halogenated anesthetics, should be used cautiously when given concurrently with lomefloxacin.
    Long-acting beta-agonists: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Loop diuretics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Loperamide: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like halogenated anesthetics, should be used cautiously and with close monitoring with loperamide.
    Loperamide; Simethicone: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like halogenated anesthetics, should be used cautiously and with close monitoring with loperamide.
    Lopinavir; Ritonavir: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with lopinavir; ritonavir. Halogenated anesthetics can prolong the QT interval. Lopinavir; ritonavir is associated with QT prolongation. Coadministration of lopinavir; ritonavir with other drugs that prolong the QT interval may result in additive QT prolongation. (Major) The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include halogenated anesthetics.
    Loratadine; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine.
    Loxapine: (Moderate) Loxapine can potentiate the actions of other CNS depressants such as general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    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 general anesthetics. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Major) Halogenated anesthetics can prolong the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with halogenated anesthetics include maprotiline.
    Meclizine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Mefloquine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with mefloquine. Halogenated anesthetics can prolong the QT interval. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Meperidine: (Moderate) Concomitant use sevoflurane can potentiate the effects of meperidine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Meperidine; Promethazine: (Moderate) Concomitant use sevoflurane can potentiate the effects of meperidine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. (Moderate) Halogenated anesthetics carry a possible risk for QT prolongation and torsade de pointes (TdP). Promethazine carries a possible risk of QT prolongation and should be used cautiously with these anesthetics, with proper blood pressure and heart rate monitoring.
    Mephobarbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Meprobamate: (Moderate) The effects of CNS depressant drugs, such as meprobamate, may increase when administered concurrently with general anesthetics. A temporary dose reduction of meprobamate should be considered following administration of general anesthetics. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Mesoridazine: (Severe) Sevoflurane can prolong the QT interval, and should generally be avoided in combination with certain drugs that may be associated with QT prolongation and torsade de pointe, including mesoridazine.
    Metaxalone: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Halogenated anesthetics can prolong the QT interval. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Methamphetamine: (Major) General anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the myocardial conduction system to the action of sympathomimetics. Use extreme caution with the concomitant use of a general anesthetic and methamphetamine, as serious cardiac arrhythmias such as ventricular tachycardia or fibrillation may result.
    Methohexital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Methylphenidate: (Moderate) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the cardiovascular system to the effects of methylphenidate. While the sympathomimetic effects of methylphenidate are weaker than those of the amphetamines, and evidence of interaction is lacking, caution is advised. The use of Metadate CD is contraindicated on the day of surgery due to the risk of sudden blood pressure increases during administration of halogenated anesthetics.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include halogenated anesthetics.
    Midostaurin: (Major) The concomitant use of midostaurin and halogenated anesthetics may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Mifepristone, RU-486: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with mifepristone. Halogenated anesthetics can prolong the QT interval. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used.
    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 general anesthetics. Caution should be exercised when using these agents concurrently. Additionally, the concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Use caution when administering other tetracyclines.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mivacurium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Monoamine oxidase inhibitors: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Morphine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended. Monitor patients for sedation and respiratory depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended. Monitor patients for sedation and respiratory depression.
    Moxifloxacin: (Major) According to the manufacturer, moxifloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval. Halogenated anesthetics can prolong the QT interval. Prolongation of the QT interval has been reported with administration of moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes (TdP), usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants like general anesthetics can potentiate the effects of nabilone on respiratory depression.
    Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Naproxen; Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine.
    Neostigmine: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with other hypotensive drugs, including general anesthetics.
    Neuromuscular blockers: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Nilotinib: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include halogenated anesthetics.
    Norfloxacin: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with norfloxacin. Halogenated anesthetics can prolong the QT interval. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, torsade de pointes has been reported during post-marketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. Norfloxacin should be used cautiously with other agents that may prolong the QT interval or increase the risk of TdP.
    Octreotide: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with octreotide. Halogenated anesthetics can prolong the QT interval. Administer octreotide cautiously in patients receiving drugs that prolong the QT interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ofloxacin. Halogenated anesthetics can prolong the QT interval. Some quinolones, including ofloxacin, have been associated with QT prolongation and infrequent cases of arrhythmia. Post-marketing surveillance for ofloxacin has identified very rare cases of torsades de pointes (TdP).
    Olanzapine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with olanzapine. Halogenated anesthetics can prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP).
    Olodaterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include halogenated anesthetics.
    Ondansetron: (Major) If ondansetron and halogenated anesthetics must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Orphenadrine: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Osimertinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of halogenated anesthetics with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib; halogenated anesthetics can also prolong the QT interval.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of halogenated anesthetics with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Halogenated anesthetics can prolong the QT interval; QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as general anesthetics, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Oxymorphone: (Moderate) The concomitant use of oxymorphone with other CNS depressants may produce additive CNS depressant effects. Respiratory depression, hypotension, profound sedation, or coma may result from combination therapy. Severe hypotension may occur if oxymorphone is administered to a patient taking a CNS depressant that inhibits blood pressure maintenance such as general anesthetics. Prior to concurrent use of oxymorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxymorphone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxymorphone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Slowly titrate the dose as necessary for adequate pain relief and monitor for sedation or respiratory depression.
    Oxytocin: (Major) Adverse cardiovascular effects can develop as a result of concomitant administration of oxytocin with general anesthetics, especially in those with preexisting valvular heart disease. Cyclopropane, when administered with or without oxytocin, has been implicated in producing maternal sinus bradycardia, abnormal atrioventricular rhythms, hypotension, and increases in heart rate, cardiac output, and systemic venous return. In addition, halogenated anesthetics decrease uterine responsiveness to oxytocics (e.g., oxytocin) and, in high doses, can abolish it, increasing the risk of uterine hemorrhage. Halothane is a potent uterine relaxant. Enflurane displaces the myometrial response curve to oxytocin so that at lower concentrations of enflurane oxytocin will restore uterine contractions. However, as the dose of enflurane progresses (somewhere between 1.5 to 3% delivered enflurane) the response to oxytocin is inhibited. It is not clear if other halogenated anesthetics would interact with oxytocics in this manner.
    Paliperidone: (Major) Halogenated anesthetics can prolong the QT interval. Paliperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. However, if coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential.
    Pancuronium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include halogenated anesthetics.
    Papaverine: (Moderate) Papaverine is a benzylisoquinoline alkaloid of opium and may have synergistic effects with potent CNS depressants such as general anesthetics, which could lead to enhanced sedation.
    Pasireotide: (Major) Cautious use of pasireotide and drugs that prolong the QT interval, such as halogenated anesthetics, is needed, as coadministration may have additive effects on the prolongation of the QT interval.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be avoided with pazopanib include halogenated anesthetics.
    Pentamidine: (Major) Pentamidine has been associated with serious cardiac arrhythmias including QT prolongation, and is considered to have an established risk of torsades de pointes. The drug should be used cautiously, if at all, in patients receiving agents which may cause QT prolongation or torsade de pointes including halogenated anesthetics such as sevoflurane.
    Pentobarbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Perphenazine: (Minor) Halogenated anesthetics should be used cautiously and with close monitoring with perphenazine. Halogenated anesthetics can prolong the QT interval. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, Phenothiazines can potentiate the CNS-depressant action of halogenated anesthetics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects.
    Perphenazine; Amitriptyline: (Minor) Halogenated anesthetics should be used cautiously and with close monitoring with perphenazine. Halogenated anesthetics can prolong the QT interval. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, Phenothiazines can potentiate the CNS-depressant action of halogenated anesthetics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects.
    Phendimetrazine: (Major) Halogenated anesthetics, such as sevoflurane, sensitize the myocardium to the effects of sympathomimetics, such as phendimetrazine. Chronic use of sympathomimetics prior to halogenated anesthetics may result in cardiac arrhythmias. Phendimetrazine should be discontinued several days prior to surgery using halogenated anesthetics.
    Phenobarbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Phenoxybenzamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Phentermine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Phentermine; Topiramate: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Phenylephrine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension.
    Phenylephrine; Promethazine: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension. (Moderate) Halogenated anesthetics carry a possible risk for QT prolongation and torsade de pointes (TdP). Promethazine carries a possible risk of QT prolongation and should be used cautiously with these anesthetics, with proper blood pressure and heart rate monitoring.
    Phenytoin: (Moderate) Caution is advised with the concomitant use of sevoflurane and phenytoin as concurrent use may increase the risk of hepatotoxicity.
    Physostigmine: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as halogenated anesthetics. Coadministration may increase the risk for QT prolongation. Patients should discuss their medication regimen with their surgeon or anesthesiologist prior to any surgical or other procedures with these anesthetics.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of sevoflurane with pimozide is contraindicated.
    Polymyxin B: (Moderate) Systemic polymyxin B can increase the neuromuscular blockade effects of neuromuscular blockers, general anesthetics, and skeletal muscle relaxants. Polymyxin B affects both pre- and post-synaptic myoneural areas by inhibiting release of acetylcholine pre-synaptically and/or blocking acetylcholine activity post-synaptically. Thus, polymyxin B acts synergistically with these agents.
    Polymyxins: (Moderate) General anesthetics 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.
    Posaconazole: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with posaconazole. Halogenated anesthetics can prolong the QT interval. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes.
    Potassium-sparing diuretics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Prazosin: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Pregabalin: (Moderate) Concomitant administration of pregabalin with CNS depressant drugs, including general anesthetics, can potentiate the CNS effects of either agent.
    Prilocaine: (Major) Local anesthetics may result in QT prolongation and should be used with caution with other agents that can prolong the QT interval including halogenated anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, and sevoflurane). Also, If epinephrine is added to prilocaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Prilocaine; Epinephrine: (Severe) The manufacturer for epinephrine contraindicates the use of epinephrine with halogenated anesthetics or cyclopropane. Halothane, cyclopropane, and other general anesthetics (e.g., amobarbital, etomidate, ketamine, methohexital, nitrous oxide, propofol, thiopental) are known to increase cardiac irritability via myocardial sensitization to catecholamines. General anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine. (Major) Local anesthetics may result in QT prolongation and should be used with caution with other agents that can prolong the QT interval including halogenated anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, and sevoflurane). Also, If epinephrine is added to prilocaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include halogenated anesthetics.
    Primidone: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Procaine: (Major) Local anesthetics may result in QT prolongation and should be used with caution with other agents that can prolong the QT interval including halogenated anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, and sevoflurane). Also, If epinephrine is added to procaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Procarbazine: (Major) Patients receiving drugs that possess MAOI properties, such as procarbazine, may have an increased risk of hypotension after administration of general anesthetics. Procarbazine should be discontinued for at least 10 days prior to elective surgery.
    Prochlorperazine: (Minor) Halogenated anesthetics should be used cautiously and with close monitoring with prochlorperazine. Halogenated anesthetics can prolong the QT interval. Phenothiazines have been reported to prolong the QT interval. Concurrent use of drugs that are associated with a possible risk for QT prolongation and torsade de pointes (TdP) with prochlorperazine should be approached with caution. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. In addition, additive CNS effects (e.g., oversedation, respiratory depression, and hypotension) may occur if prochlorperazine is administered concomitantly with halogenated anesthetics.
    Promethazine: (Moderate) Halogenated anesthetics carry a possible risk for QT prolongation and torsade de pointes (TdP). Promethazine carries a possible risk of QT prolongation and should be used cautiously with these anesthetics, with proper blood pressure and heart rate monitoring.
    Propafenone: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with propafenone. Halogenated anesthetics can prolong the QT interval. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Propoxyphene: (Moderate) Concomitant use of central nervous system depressants can potentiate the effects of propoxyphene, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Pseudoephedrine: (Major) Avoid administration of pseudoephedrine products to patients who have recently undergone, or will soon undergo, a procedure or treatment that requires general anesthesia. Specifically, halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including pseudoephedrine.
    Pyridostigmine: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Quetiapine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with quetiapine. Halogenated anesthetics can prolong the QT interval. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase the QT interval.
    Quinine: (Major) Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Avoid concurrent use of quinine with other drugs that may cause QT prolongation and TdP including halogenated anesthetics.
    Ranolazine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Rapacuronium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Rasagiline: (Moderate) Patients receiving drugs that possess MAOI properties, such as rasagiline, may have an increased risk of hypotension after administration of general anesthetics, although specific studies are not available. Combined hypotensive effects are also possible with the combined use of MAOIs and spinal anesthetics.
    Regadenoson: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with regadenoson. Halogenated anesthetics can prolong the QT interval and regadenoson has been associated with QT prolongation.
    Remifentanil: (Moderate) Concurrent use of sevoflurane with opiate agonists such as remifentanil can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice.
    Reserpine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Ribociclib: (Major) Avoid coadministration of ribociclib with halogenated anesthetics due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Halogenated anesthetics can also prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with halogenated anesthetics due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Halogenated anesthetics can also prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    Rifampin: (Moderate) Caution is advised with the concomitant use of sevoflurane and rifampin as concurrent use may increase the risk of hepatotoxicity.
    Rilpivirine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Risperidone: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with risperidone. Halogenated anesthetics can prolong the QT interval. Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes; however, data are currently lacking to establish causality in association with torsades de pointes (TdP). Reports of QT prolongation and torsades de pointes during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. Since risperidone may prolong the QT interval, it should be used cautiously with other agents also known to have this effect, taking into account the patient's underlying disease state(s) and additional potential risk factors.
    Ritodrine: (Major) The cardiovascular effects of ritodrine, especially hypotension and cardiac arrhythmias, can be potentiated by concomitant use of general anesthetics, such as sevoflurane.
    Ritonavir: (Major) The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include halogenated anesthetics.
    Rivastigmine: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Rocuronium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Romidepsin: (Major) Romidepsin has been reported to prolong the QT interval. Halogenated anesthetics can prolong the QT interval. If romidepsin must be coadministered with a halogenated anesthetic, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Salmeterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Saquinavir: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with saquinavir. Halogenated anesthetics can prolong the QT interval. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Secobarbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Sertraline: (Major) There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, caution is advisable when using sertraline in patients with risk factors for QT prolongation, including concurrent use of other drugs that prolong the QTc interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sertraline include halogenated anesthetics.
    Short-acting beta-agonists: (Minor) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Sodium Oxybate: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with general anesthetics.
    Solifenacin: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with solifenacin. Halogenated anesthetics can prolong the QT interval. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsades de pointes (TdP) has been reported with post-marketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation.
    Sorafenib: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with sorafenib. Halogenated anesthetics can prolong the QT interval. Sorafenib has been associated with QT prolongation. If sorafenib and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Sotalol: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery on patients receiving beta-blockers. In addition, sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Drugs with a possible risk for QT prolongation and TdP, such as halogenated anesthetics, should be used cautiously with sotalol.
    Sparfloxacin: (Severe) Sparfloxacin is associated with an established risk for QT prolongation and torsades de pointes and should be avoided or used with extreme caution in combination with other drugs that also prolong the QT interval, including sevoflurane.
    St. John's Wort, Hypericum perforatum: (Major) St. John's wort, Hypericum perforatum, may intensify or prolong the effects of sevoflurane; profound hypotension has also been reported. In one report, the authors recommend that patients should discontinue taking St. John's Wort at least 5 days prior to anesthesia. The American Society of Anesthesiologists has recommended that patients stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions.
    Streptomycin: (Moderate) Patients receiving general anesthetics should be observed for exaggerated effects if they are receiving streptomycin.
    Succinylcholine: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Sufentanil: (Major) Concomitant use of sufentanil with general anesthetics can potentiate sufentanil induced CNS and cardiovascular effects and the duration of these effects. The dosage of sufentanil and/or the general anesthetic should be reduced when used concurrently.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim include halogenated anesthetics.
    Sunitinib: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with sunitinib. Halogenated anesthetics and sunitinib can prolong the QT interval.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the general anesthetics.
    Tacrine: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Tacrolimus: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
    Tamoxifen: (Major) Caution is advised with the concomitant use of tamoxifen and halogenated anesthestics due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Halogenated anesthetics can also prolong the QT interval.
    Tapentadol: (Moderate) Additive CNS depressive effects are expected if tapentadol is used in conjunction with other CNS depressants. Severe hypotension, profound sedation, coma, or respiratory depression may occur. Prior to concurrent use of tapentadol in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with tapentadol, a reduced dosage of tapentadol and/or the CNS depressant is recommended. If the extended-release tapentadol tablets are used concurrently with a CNS depressant, it is recommended to use an initial tapentadol dose of 50 mg PO every 12 hours. Monitor patients for sedation and respiratory depression.
    Telavancin: (Major) Telavancin has been associated with QT prolongation. According to the manufacturer, telavancin should be used with caution when prescribing other agents also known to prolong the QT interval (e.g., halogenated anesthetics).
    Telithromycin: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with telithromycin. Halogenated anesthetics can prolong the QT interval. Telithromycin is associated with QT prolongation and torsades de pointes (TdP).
    Terazosin: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval. The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc including halogenated anesthetics.
    Tetracaine: (Major) Local anesthetics may result in QT prolongation and should be used with caution with other agents that can prolong the QT interval including halogenated anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, and sevoflurane). Also, If epinephrine is added to tetracaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Theophylline, Aminophylline: (Moderate) Aminophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. (Moderate) Theophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. When ketamine and theophylline are given concurrently a clinically significant reduction in the seizure threshold is observed. A similar interaction may occur with other general anesthetics.
    Thiazide diuretics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Thiopental: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Thioridazine: (Severe) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension, such as halogenated anesthetics.
    Thiothixene: (Moderate) Thiothixene can potentiate the CNS-depressant action of other drugs such as general anesthetics. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Tiotropium; Olodaterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Tizanidine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tizanidine. Both halogenated anesthetics and tizanidine administration may result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Tobramycin: (Moderate) Patients receiving general anesthetics should be observed for exaggerated effects if they are receiving tobramycin.
    Tolterodine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tolterodine. Halogenated anesthetics can prolong the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation.
    Toremifene: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with toremifene. Halogenated anesthetics can prolong the QT interval and toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Tramadol: (Moderate) Tramadol can cause additive CNS depression and respiratory depression when used with other agents that are CNS depressants, such as general anesthetics. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Trazodone: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Drugs with a known risk for QT prolongation and TdP include the halogenated anesthetics.
    Treprostinil: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Tricyclic antidepressants: (Minor) Tricyclic antidepressants (TCAs) should be used cautiously and with close monitoring with halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, general anesthetics may produce additive CNS depression when used in patients taking tricyclic antidepressants.
    Trifluoperazine: (Minor) Halogenated anesthetics should be used cautiously and with close monitoring with trifluoperazine. Halogenated anesthetics can prolong the QT interval. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, phenothiazines can potentiate the CNS-depressant action of halogenated anesthetics.
    Triprolidine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include halogenated anesthetics.
    Trovafloxacin, Alatrofloxacin: (Moderate) General anesthetics may potentiate the hypotension associated alatrofloxacin administration.
    Tubocurarine: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Umeclidinium; Vilanterol: (Moderate) Sevoflurane, like other halogenated anesthetics, can prolong the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously with halogenated anesthetics include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. The action of beta-agonists on the cardiovascular system may be potentiated by a halogenated anesthetic.
    Vancomycin: (Moderate) The concurrent administration of vancomycin and anesthetics has been associated with erythema, histamine-like flushing, and anaphylactoid reactions.
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib; halogenated anesthetics can prolong the QT interval. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose.
    Vardenafil: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with vardenafil. Halogenated anesthetics can prolong the QT interval. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug.
    Vasodilators: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Vecuronium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vemurafenib include halogenated anesthetics.
    Venlafaxine: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with venlafaxine. Halogenated anesthetics can prolong the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use.
    Voriconazole: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with voriconazole. Halogenated anesthetics can prolong the QT interval. Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes.
    Vorinostat: (Major) Vorinostat and halogenated anesthetics are associated with a risk of QT prolongation and should be used cautiously in combination.
    Warfarin: (Minor) Sevoflurane may increase the effects of warfarin. Another halogenated anesthetic, halothane, has been associated with an increase in activity of warfarin. The trifluoroacetic acid metabolite of halothane appears to displace warfarin from plasma proteins, which may increase the free-fraction of warfarin. The effects of sevoflurane on the displacement of drugs from serum and tissue proteins have not been investigated.
    Zaleplon: (Moderate) Coadministration of zaleplon and general anesthetics may result in additive CNS depressant effects. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. A similar interaction may occur with zaleplon and other CNS depressants including general anesthetics. If concurrent use is necessary, monitor for additive side effects. A temporary dose reduction of zaleplon should be considered following administration of general anesthetics. The risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ziprasidone: (Severe) According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including sevoflurane.
    Zolpidem: (Moderate) The effects of CNS depressant drugs, such as zolpidem, may increase when administered concurrently with general anesthetics. A temporary dose reduction of the CNS depressant should be considered following administration of general anesthetics. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.

    PREGNANCY AND LACTATION

    Pregnancy

    Sevoflurane is classified as FDA pregnancy category B. Animal studies have indicated no impaired fertility or fetotoxicity. However, there are no adequate, well-controlled studies in pregnant women; therefore, use during pregnancy only if clearly needed. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures during the third trimester of pregnancy may have negative effects on fetal brain development. Consider the benefits of appropriate anesthesia in pregnant women against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required prior to delivery. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child and/or mother. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development. Sevoflurane has been used as part of general anesthesia for elective cesarean section with no untoward side effects in mother or neonate. However, the safety of sevoflurane in labor and obstetric delivery has not been established. In general, general anesthetics may cause dose-dependent uterine relaxation that can delay vaginal delivery.

    MECHANISM OF ACTION

    Mechanism of Action: The exact mechanism of action of inhalational anesthetics is not known. There appears to be a correlation between anesthetic potency and lipid solubility (Meyer-Overton theory), suggesting that inhalation anesthetics likely affect the lipid matrix of nerve cell membranes in the brain. Furthermore, NMR and electron spin resonance studies indicate that anesthetics cause a local disordering of the lipid membrane matrix, possibly decreasing the number of molecules that alternate simultaneously between the gel and crystalline states, and thereby altering membrane function.

    PHARMACOKINETICS

    Sevoflurane is administered by inhalation. In 40-year old adults, the MAC value (minimal alveolar concentration that prevents movements in 50% of patients subjected to a painful stimulus) of sevoflurane is 2.1% when mixed in oxygen, which is roughly equivalent to enflurane. The MAC of sevoflurane decreases with age. Due to the low solubility of sevoflurane in blood (blood/gas coefficient at 37 degrees C is 0.63—0.69), a minimal amount of sevoflurane is required to be dissolved in the blood before alveolar partial pressure is in equilibrium with arterial partial pressure. Therefore, the alveolar (end-tidal) concentration rapidly increases to the inspired concentration during induction. The time for the concentration to reach MAC for sevoflurane is about 1 minute in healthy men. Metabolism and tissue elimination of sevoflurane is similar to isoflurane and enflurane, but distinct from that of methoxyflurane. The rapid and extensive pulmonary elimination of sevoflurane minimizes the amount of anesthetic available for metabolism. In vivo studies suggest that only about 5% of the sevoflurane dose is metabolized. Sevoflurane is metabolized by the hepatic cytochrome P4502E1 isoenzyme to hexafluoroisopropanol (HFIP) with the release of inorganic fluoride and carbon dioxide. HFIP is rapidly conjugated with glucuronic acid and excreted in the urine. Plasma concentration of fluoride ion is influenced by the duration of anesthesia, the concentration of sevoflurane administered, and the composition of the anesthetic gas mixture. In studies where pure sevoflurane was administered for 1—6 hours, peak fluoride concentrations ranged between 12—90 microM. Peak concentrations of fluoride ion occur within 2 hours of the end of anesthesia and are < 25 microM (475 ng/ml) for the majority of patients after 10 hours. Approximately 3.5% of the administered sevoflurane dose appears in the urine as fluoride and 50% of fluoride clearance is due to fluoride being taken up into bone. The half-life of fluoride is about 15—23 hours.

    Inhalation Route

    Following inhalation, sevoflurane is readily absorbed via the pulmonary capillary system.