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  • CLASSES

    Other General Anesthetics

    DEA CLASS

    Rx, schedule III

    DESCRIPTION

    General anesthetic
    Used for induction and maintenance of anesthesia and procedural sedation
    Fewer adverse reactions than opioids and benzodiazepines

    COMMON BRAND NAMES

    Ketalar

    HOW SUPPLIED

    Ketalar/Ketamine Hydrochloride Intramuscular Inj Sol: 1mL, 10mg, 50mg, 100mg
    Ketalar/Ketamine Hydrochloride Intravenous Inj Sol: 1mL, 10mg, 50mg, 100mg

    DOSAGE & INDICATIONS

    For general anesthesia induction.
    NOTE: Ketamine should NOT be used as a sole anesthetic agent for procedures that involve the pharynx, larynx, or bronchial tree or require skeletal muscle relaxation.
    Intravenous dosage
    Adults

    1 to 4.5 mg/kg IV as a single dose.

    Adolescents 16 to 17 years

    1 to 4.5 mg/kg IV as a single dose.

    Infants†, Children†, and Adolescents 1 to 15 years†

    0.5 to 2 mg/kg IV as a single dose.

    Neonates†

    Limited data available; some experts do not recommend the use of ketamine in neonates. Doses of 0.5 to 1 mg/kg IV have been reported. As an adjunct agent, ketamine 0.5 mg/kg IV followed immediately by a propofol bolus and infusion was effective in a prospective study of 23 pediatric patients (mean age: 3.2 years; range: 9 days to 7 years) undergoing magnetic resonance imaging. An induction dose of 1 mg/kg IV was well-tolerated and effective as a sole anesthetic agent in a retrospective observational study of 107 pediatric patients (age range: 10 hours to 14 years) undergoing interventional cardiac procedures; 29 patients were neonates, the youngest being 10 hours old and 1.4 kg.

    Intramuscular dosage
    Adults

    6.5 to 13 mg/kg IM as a single dose.

    Adolescents 16 to 17 years

    6.5 to 13 mg/kg IM as a single dose.

    Infants†, Children†, and Adolescents 1 to 15 years†

    4 to 10 mg/kg IM as a single dose.

    For general anesthesia maintenance.
    NOTE: Purposeless and tonic-clonic movements of extremities may occur during the course of anesthesia. These movements do not imply a light plane and are not indicative of the need for additional doses of anesthetic.
    Intravenous dosage
    Adults

    0.5 to 4.5 mg/kg/dose IV as needed; adjust dose based on patient requirements and adjunctive anesthetic use.

    Adolescents 16 to 17 years

    0.5 to 4.5 mg/kg/dose IV as needed; adjust dose based on patient requirements and adjunctive anesthetic use.

    Infants†, Children†, and Adolescents 1 to 15 years†

    0.25 to 2 mg/kg/dose IV every 5 to 10 minutes as needed; adjust dose based on patient requirements and adjunctive anesthetic use.

    Neonates†

    Limited data available; some experts do not recommend the use of ketamine in neonates. 1 to 2 mg/kg/dose IV and sevoflurane has been described without incident in a case report of a neonate (gestational age: 33 weeks; weight: 2,050 g) undergoing pacemaker placement. Adjust dose based on patient requirements and adjunctive anesthetic use.

    Continuous Intravenous Infusion dosage
    Adults

    0.1 to 0.5 mg/minute continuous IV infusion; adjust dose based on patient requirements and adjunctive anesthetic use.

    Adolescents 16 to 17 years

    0.1 to 0.5 mg/minute continuous IV infusion; adjust dose based on patient requirements and adjunctive anesthetic use.

    Infants†, Children†, and Adolescents 1 to 15 years†

    1.5 to 6 mg/kg/hour (25 to 100 mcg/kg/minute) continuous IV infusion; adjust dose based on patient requirements and adjunctive anesthetic use. Mean infusion rate: 3 to 6 mg/kg/hour (50 to 100 mcg/kg/minute); dose range: 0.6 to 13 mg/kg/hour (10 to 215 mcg/kg/minute).

    Neonates†

    Limited data available; some experts do not recommend the use of ketamine in neonates. Mean infusion rate of 3 to 6 mg/kg/hour (50 to 100 mcg/kg/minute) IV has been reported in studies including neonates (n = 283; age range: 10 hours to 16 years) undergoing interventional cardiology procedures. Dose range: 0.6 to 13 mg/kg/hour (10 to 215 mcg/kg/minute). Adjust dose based on patient requirements and adjunctive anesthetic use.

    Intramuscular dosage
    Adults

    3.25 to 13 mg/kg/dose IM as needed; adjust dose based on patient requirements and adjunctive anesthetic use.

    Adolescents 16 to 17 years

    3.25 to 13 mg/kg/dose IM as needed; adjust dose based on patient requirements and adjunctive anesthetic use.

    For preanesthesia sedation†.
    Intranasal dosage
    Children

    3 to 6 mg/kg intranasally (divided and given into both nostrils) as a single dose 15 to 40 minutes prior to mask induction.

    Infants 6 to 11 months

    3 mg/kg intranasally (divided and given into both nostrils) as a single dose 15 minutes prior to mask induction.

    Oral dosage
    Children

    6 to 8 mg/kg PO as a single dose 30 minutes prior to mask induction. 3 mg/kg may be sufficient when used with oral midazolam.

    Rectal dosage
    Infants and Children

    8 to 10 mg/kg PR as a single dose 15 to 45 minutes prior to mask induction.

    For procedural sedation† .
    Intravenous dosage
    Adults

    1 mg/kg IV; may repeat 0.5 to 1 mg/kg/dose IV every 5 to 10 minutes as needed. 

    Infants, Children, and Adolescents 3 months to 17 years

    0.5 to 2 mg/kg IV; may repeat 0.25 to 1.5 mg/kg/dose IV every 5 to 15 minutes as needed.[45333] [55125] [57131] [57147] [64934] Max: 100 mg/dose IV has been suggested while others have utilized a fixed-dose protocol in older patients.[57122] [57132] Adolescent patients (n = 43; 26 with a BMI of 25 kg/m2 or less, 17 with a BMI more than 25 kg/m2) achieved adequate sedation for various procedures (e.g., fracture reduction, abscess drainage, chest tube placement) in the emergency department when receiving a fixed-dose ketamine protocol. Patients received ketamine 50 mg IV followed by 25 mg IV as needed to maintain a Ramsay Sedation Score (RSS) of at least 5. Adequate RSS scores were observed in 81.4% of patients after the initial 50 mg IV dose; the remaining patients achieved an RSS of at least 5 after a total ketamine dose of 75 mg.[57132]

    Infants 1 to 2 months

    Some experts do not recommend the use of ketamine in non-intubated patients younger than 3 months. 0.5 to 2 mg/kg IV; may repeat 0.25 to 1.5 mg/kg/dose IV every 5 to 15 minutes as needed.

    Neonates

    Some experts do not recommend the use of ketamine in neonates. Limited data available; 0.5 to 2 mg/kg IV.   An initial dose of 0.2 to 1 mg/kg IV, followed by repeat doses of 0.5 mg/kg IV has been reported for sedation prior to cardiac catheterization and treatment of retinopathy of prematurity.

    Intravenous dosage with propofol (i.e., "ketofol")
    Adults

    0.5 to 0.75 mg/kg/dose IV; may repeat dose as needed. The combination of ketamine and propofol allows for reduced dosing of each drug, improving the adverse event profile compared to the 2 drugs individually. Theoretically, the risk of ketamine-induced nausea and emergence reactions may be reduced by the antiemetic and anxiolytic properties of propofol, while propofol-induced hypotension and respiratory depression may be counteracted by ketamine-induced increases in circulatory norepinephrine. In addition, studies have suggested the use of "ketofol" reduces the use of concomitant analgesia in comparison to when propofol is administered alone.

    Children and Adolescents

    0.5 to 0.75 mg/kg/dose IV; may repeat dose as needed. The combination of ketamine and propofol allows for reduced dosing of each drug, improving the adverse event profile compared to the 2 drugs individually. Theoretically, the risk of ketamine-induced nausea and emergence reactions may be reduced by the antiemetic and anxiolytic properties of propofol, while propofol-induced hypotension and respiratory depression may be counteracted by ketamine-induced increases in circulatory norepinephrine. In addition, studies have suggested the use of "ketofol" reduces the use of concomitant analgesia in comparison to when propofol is administered alone.

    Intramuscular dosage
    Adults

    4 to 5 mg/kg IM; may repeat 2 to 5 mg/kg/dose IM after 5 to 10 minutes as needed. 

    Infants, Children, and Adolescents 3 months to 17 years

    2 to 5 mg/kg/dose IM; may repeat dose after 5 to 10 minutes as needed. Low dose ketamine (e.g., 1 to 3 mg/kg/dose) has been used for short-lasting procedures in burn patients (e.g., dressing changes, debridement). Max: 50 mg/dose IM has been suggested.

    Intranasal dosage
    Infants and Children 3 months to 12 years

    3 to 6 mg/kg intranasally (divided and given into both nostrils) as a single dose 5 to 20 minutes prior to the procedure.   Larger doses (9 mg/kg) may be required. Intranasal ketamine is beneficial for acute analgesia and amnesia and should be considered in pediatric patients undergoing procedures.

    Oral dosage

    NOTE: Oral ketamine is not commonly used for procedural sedation. Substantial first pass metabolism results in less predictable effectiveness and delayed onset and recovery compared to parenteral ketamine.

    Children and Adolescents

    5 to 6 mg/kg PO as a single dose in combination with midazolam 20 to 45 minutes before procedure. A lower dose of 3 mg/kg PO with midazolam has been reported as effective in 24 oncology patients (mean age: 3.9 +/- 1.3 years) undergoing bone marrow or lumbar puncture. A higher dose of 10 mg/kg PO, given as monotherapy, has been used successfully for various procedures. Max: 50 to 250 mg/dose PO has been suggested but higher doses have been reported.

    Rectal dosage

    NOTE: Rectal ketamine is not commonly used for procedural sedation. Substantial first pass metabolism results in less predictable effectiveness and delayed onset and recovery compared to parenteral ketamine.

    Children

    1.5 to 3 mg/kg PR as a single dose in combination with midazolam 20 minutes prior to the procedure.

    For the treatment of status asthmaticus†.
    Intravenous dosage
    Adults

    Limited evidence; 0.5 to 2 mg/kg IV, then 0.5 mg/kg/hour continuous IV infusion, initially. Titrate until desired clinical is attained. Max: 2.5 mg/kg/hour. Usually reserved for respiratory failure despite standard accepted treatments.

    Infants, Children, and Adolescents

    Limited evidence; 0.5 to 2 mg/kg IV, then 0.2 to 3.6 mg/kg/hour (3.3 to 60 mcg/kg/minute) continuous IV infusion. Start dosage low and titrate by 0.25 to 0.5 mg/kg/hour (4 to 8 mcg/kg/minute) until desired clinical response is attained. Usually reserved for respiratory failure despite standard accepted treatments.  

    For the treatment of moderate pain† or severe pain†.
    For the treatment of refractory chronic pain.
    Intravenous dosage
    Adults

    0.25 to 0.6 mg/kg/dose (Max: 80 mg/dose) IV up to 3 times daily as needed. Titrate until desired pain score is attained. Infusions can be administered over 4 to 6 hours for up to 10 days. Smaller flat doses of 2.5 to 5 mg/dose IV as needed have been used for cancer pain. Guidelines suggest higher doses of ketamine given over longer time periods, and more frequent administration, in chronic pain. It is reasonable to start with a single outpatient infusion (Min: 80 mg) given over more than 2 hours before reassessing and initiating further treatments.

    Continuous Intravenous Infusion dosage
    Adults

    0.05 to 2 mg/kg/hour (0.83 to 33 mcg/kg/minute), typically 50 to 100 mg/day, continuous IV infusion, initially. Titrate by 2 mg/hour every 2 hours or 25 to 50 mg/day until desired pain score is achieved. Usual Max: 20 mg/hour. Infusion rates up to 50 mg/hour and duration of infusion up to 20 days have been reported in patients with complex regional pain syndrome (CRPS). Doses up to 7 mg/kg/hour (116 mcg/kg/minute) have been used in intensive care settings.

    Children and Adolescents

    0.05 to 0.2 mg/kg/hour (0.83 to 3.3 mcg/kg/minute) continuous IV infusion, initially. Titrate until desired pain score is attained. Do not exceed 1 mg/kg/hour (16.6 mcg/kg/minute) continuous IV infusion without intensive monitoring. Larger doses may be required. Titration up to 4.1 mg/kg/hour (68 mcg/kg/minute) has been reported.

    Subcutaneous dosage
    Adults

    0.1 to 0.6 mg/kg/dose (weight-based) or 2.5 to 25 mg/dose (flat dose) subcutaneously as needed. Titrate by 25% to 33% until desired pain score is attained.

    Continuous Subcutaneous Infusion dosage
    Adults

    0.04 to 1.2 mg/kg/hour (0.66 to 20 mcg/kg/minute) continuous subcutaneous infusion, initially. Titrate by 50 to 100 mg/day until desired pain score is attained.  Usual Max: 500 mg/day. 

    Oral dosage
    Adults

    0.25 to 1.25 mg/kg/dose (weight-based) or 10 to 25 mg/dose (flat dose) PO 3 to 4 times daily as needed. Titrate by 0.5 to 1 mg/kg every 8 hours or 10 to 25 mg until desired pain score is attained. Usual Max: 400 mg/day. Up to 800 mg/day has been used. Effective dosage range: 45 to 1,000 mg/day. Doses are typically divided 3 to 4 times daily, but frequency may range from 1 to 6 times daily.

    For the treatment of acute pain.
    Continuous Intravenous Infusion dosage
    Adults

    0.3 to 0.5 mg/kg IV, then 0.1 to 0.2 mg/kg/hour continuous (1.6 to 3.3 mcg/kg/minute) IV infusion, initially. Titrate until desired pain score is attained. Do not exceed 0.35 mg/kg IV and 1 mg/kg/hour (16.6 mcg/kg/minute) continuous IV infusion without intensive monitoring. Ketamine may be considered for acute pain in patients undergoing surgery, opioid-tolerant patients with sickle cell disease, and patients with sleep apnea.

    Intranasal dosage
    Adults

    0.5 to 1 mg/kg (Max: 50 mg) intranasally. May repeat 0.25 to 0.5 mg/kg in 10 to 15 minutes if visual analog scale score remains 50 mm or more. Intranasal ketamine may be considered in patients for whom IV access is difficult.

    Children and Adolescents 6 to 17 years

    0.5 to 1 mg/kg (Max: 50 mg) intranasally. May repeat 0.25 mg/kg in 10 minutes if visual analog scale score remains 50 mm or more after initial administration of a 0.5 mg/kg dose.

    For use in treatment-resistant depression†.
    Intravenous dosage
    Adults 18 to 64 years

    0.5 mg/kg IV as a single dose or 1 to 3 times weekly for up to 6 doses. Optimal dose/duration and standards for monitoring and assessment are not established.

    For use as an induction agent during rapid-sequence intubation (RSI)†.
    Intravenous dosage
    Adults

    1 to 2 mg/kg/dose IV. Onset of intubating conditions is less than 2 minutes. Ketamine is especially useful for induction during rapid-sequence intubation in patients with bronchospasm or hypotension.

    Infants, Children, and Adolescents

    1 to 2 mg/kg/dose IV. Onset of intubating conditions is 1 to 2 minutes. Ketamine is especially useful for induction during rapid-sequence intubation in patients with bronchospasm or hypotension.

    Intramuscular dosage
    Adults

    4 to 10 mg/kg/dose IM. Onset of intubating conditions is less than 2 minutes. Ketamine is especially useful for induction during rapid-sequence intubation in patients with bronchospasm or hypotension.

    For intensive care sedation induction† and sedation maintenance†.
    Continuous Intravenous Infusion dosage
    Infants, Children, and Adolescents

    0.5 to 2 mg/kg IV, then 0.25 to 2 mg/kg/hour (4 to 33 mcg/kg/minute) continuous IV infusion, initially. May repeat bolus dose as needed and titrate infusion by 0.25 to 0.5 mg/kg/hour (4 to 8 mcg/kg/minute) until desired clinical response is attained. Max: up to 3.6 mg/kg/hour (60 mcg/kg/minute) has been used in mechanically ventilated children with refractory bronchospasm. Ketamine may be an effective alternative to conventional sedation in certain clinical scenarios (e.g., patients who develop adverse cardiovascular effects with opioids or benzodiazepines, sedation with preservation of spontaneous ventilation, patients with acute severe asthma).

    For the treatment of severe acute agitation† or excited delirium† during prehospital or emergency department care.
    Intravenous dosage
    Adults

    1 to 2 mg/kg/dose IV; may repeat in incremental doses of 0.5 to 1 mg/kg IV if initial sedation is inadequate.

    Intramuscular dosage
    Adults

    4 to 6 mg/kg/dose IM; may repeat in half or full dose if initial sedation is inadequate after 5 to 10 minutes.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

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

    Geriatric

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

    Adolescents

    16 to 17 years: Specific maximum dosage information is not available. Dosage must be individualized.
    13 to 15 years: Safety and efficacy have not been established. Specific maximum dosage information is not available. Dosage must be individualized.

    Children

    Safety and efficacy have not been established. Specific maximum dosage information is not available. Dosage must be individualized.

    Infants

    Safety and efficacy have not been established. Specific maximum dosage information is not available. Dosage must be individualized.

    Neonates

    Safety and efficacy have not been established; some experts do not recommend the use of ketamine in this age group. Specific maximum dosage information is not available. Dosage must be individualized.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

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

    ADMINISTRATION

    Oral Administration
    Oral Liquid Formulations

    NOTE: Ketamine is not FDA-approved for oral administration.
    Oral ketamine is less predictably effective with a delayed onset and recovery compared to parenteral routes.
    To administer ketamine orally, use the 100 mg/mL solution for injection. Mix the appropriate dose in 0.2 to 0.4 mL/kg of cola-flavored soft drink, sour cherry juice, or other beverage immediately prior to administration.
    Administer the solution 20 to 45 minutes before sedation is required.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Ketamine is a clear, colorless solution.
    To prevent vomiting and aspiration, administer ketamine on an empty stomach.
    Administer an anticholinergic prior to ketamine induction to limit oral secretions.
    Monitor heart rate, respiratory rate, and blood pressure during ketamine use.
    Purposeless and tonic-clonic movements may occur during the course of anesthesia. These movements do not imply a light plane and do not necessitate additional doses of ketamine.
    Emergence reactions (e.g., hallucinations, delirium) may be reduced by minimizing verbal, tactile, and visual stimulation during drug recovery. Use of a short- or ultra short-acting benzodiazepine or barbiturate may terminate severe reactions.

    Intravenous Administration

    Because of rapid induction after intravenous injection, the patient should be in a supported position during administration.
     
    IV Push
    Do not administer the 100 mg/mL concentration without proper dilution. Dilute the desired dose with an equal volume of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. Use immediately after dilution.
    Administer slowly over a period of 60 seconds not to exceed 0.5 mg/kg/minute. More rapid administration may result in respiratory depression and enhanced pressor response.
     
    Continuous IV Infusion
    Dilute to a concentration of 1 mg/mL with 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
    For fluid restricted patients, a concentration of 2 mg/mL may be used.

    Intramuscular Administration

    No dilution necessary.
    Inject into a large muscle mass.

    Inhalation Administration
    Intranasal Inhalation Administration

    NOTE: Ketamine is not FDA-approved for intranasal administration.
    Use the 50 or 100 mg/mL parenteral solution to minimize volume. May administer undiluted or diluted with saline to a final volume of 0.5 to 2 mL.
    Administer half of the dose into each nare with a mucosal atomizer device or needleless syringe, with the patient in the recumbent position. If the total dose is equal to or less than 0.5 mL, it may be administered into 1 nare.
    Onset of procedural sedation is 5 to 20 minutes. If used as a preanesthetic, administer 30 minutes prior to induction of anesthesia.

    Rectal Administration

    NOTE: Ketamine is not FDA-approved for rectal administration.
    Rectal ketamine is less predictably effective with a delayed onset and recovery compared to parenteral routes.
    To administer ketamine rectally, use ketamine injection at a concentration of 10 to 50 mg/mL.
    Administer the ketamine solution through a lubricated catheter, injecting air through the catheter prior to its withdrawal to ensure the entire drug dose is administered. Appose buttocks tightly for 5 minutes to avoid drug loss. Pre-cleansing enemas are not necessary.
    Administer the solution 45 minutes before sedation is required.

    STORAGE

    Ketalar:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Ketamine is contraindicated in patients with a hypersensitivity to ketamine or any excipients.[43431]
     
    Obtain baseline and periodic liver function tests, including alkaline phosphatase and gamma-glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing. Recurrent ketamine use is associated with hepatobiliary dysfunction (most often a cholestasis pattern).[43431]

    Aneurysm, angina, cardiac disease, coronary artery disease, glaucoma, head trauma, heart failure, hypertension, increased intracranial pressure, increased intraocular pressure, intracranial bleeding, intracranial mass, ocular surgery, ocular trauma, pulmonary hypertension, stroke, thyroid disease, thyrotoxicosis

    Ketamine is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard, such as those with uncontrolled hypertension, aneurysm, thyrotoxicosis, or a history of stroke. Monitor patients with increased intracranial pressure in a setting with frequent neurologic assessments. Use ketamine with great caution in any patient with the potential for increased intracranial pressure, including those with head trauma, intracranial mass lesions or abnormalities, intracranial bleeding, and hydrocephalus. Alternative agents may be preferable in patients with known structural barriers to normal cerebrospinal fluid flow. Similarly, use ketamine with caution in patients with increased intraocular pressure (e.g., glaucoma), ocular trauma, or those undergoing ocular surgery. Ketamine can have direct negative inotropic properties and should be titrated cautiously in patients with poor ventricular function. The sympathomimetic effect of ketamine can produce elevations in blood pressure, heart rate, and cardiac output, which are typically mild-to-moderate. Ketamine increases coronary perfusion, enhancing myocardial contraction and increasing myocardial oxygen consumption. Hence, ketamine should also be used with caution in patients with cardiac disease, especially coronary artery disease (e.g., angina). Ketamine raises pulmonary arterial pressures somewhat more than systemic pressures and may exacerbate preexisting pulmonary hypertension or congestive heart failure. Monitor vital signs and cardiac function during ketamine administration. In addition, cardiac monitoring may be prudent in patients with thyroid disease requiring thyroid replacement therapy. Ketamine-induced hypertension and tachycardia can be attenuated with the administration of a benzodiazepine, a barbiturate, or a synthetic opioid.

    Driving or operating machinery

    Advise patients to avoid driving or operating machinery within 24 hours of receiving ketamine due to the residual anesthetic effects and potential for drowsiness.

    Requires a specialized care setting, requires an experienced clinician

    Ketamine administration requires an experienced clinician trained in the use of general anesthetics, airway maintenance, and assisted ventilation as well as requires a specialized care setting where resuscitation equipment is readily available. Continuously monitor vital signs in patients receiving ketamine.

    Females, psychosis, schizophrenia

    Emergence reactions (e.g., dream-like states, vivid imagery, hallucinations, delirium), sometimes accompanied by confusion, excitement, and irrational behavior may occur during ketamine recovery. Emergence reactions typically last no more than a few hours; however, adverse psychiatric events have occurred and/or persisted days to weeks after ketamine exposure. Incidence can be reduced by using lower recommended doses of ketamine in conjunction with an intravenous benzodiazepine during anesthesia, as well as minimizing verbal, tactile, and visual patient stimulation during recovery. Emergence reactions appear to be less common with intramuscular administration. Reported risk factors include age older than 10 years, females, rapid intravenous administration, preexisting psychosis (e.g., schizophrenia), or patients who normally dream frequently. The use of alternative agents is recommended for procedural sedation in patients with a history of psychosis. Strong psychological factors appear to influence the severity; avoid ketamine in hallucination-prone individuals. Upsetting reactions are much less common in children 10 to 15 years compared to adults and are rare in children younger than 10 years, presumably because a naive child with few life experiences is less likely to interpret unusual dreams or hallucinations as unpleasant. For older children and adults, advanced planning of a pleasant topic to dream about may decrease the incidence of a distressing reaction.

    Substance abuse

    Ketamine has the potential for substance abuse, psychological dependence, and/or criminal diversion. Illicit use of ketamine for its psychological effects (i.e., similar to PCP) and 'date rape' use due to its amnestic effects have been reported. Physical dependence, tolerance, and a withdrawal syndrome may occur with long-term use.

    Porphyria

    The use of ketamine in patients with porphyria is controversial due to contradictory evidence. Many experts consider ketamine anesthesia safe in porphyria patients; safe use in dormant acute intermittent porphyria and hereditary coproporphyria crisis have been reported. Most animal and cell culture models suggest it is non-inducing at clinical concentrations. However, increases in delta-aminolevulinic acid (ALA), porphobilinogen (PBG), and other porphyrins after ketamine anesthesia have been reported and some experts consider porphyria a relative contraindication to its use.

    Head and neck anesthesia, infants, neonates, pulmonary disease, respiratory infection

    Avoid ketamine as a sole agent for head and neck anesthesia during procedures of the pharynx, larynx, or bronchial tree, including mechanical stimulation of the pharynx; muscle relaxants may be required. Ketamine does not suppress pharyngeal and laryngeal reflexes.[43431] Clinicians using ketamine for procedures involving the pharynx (e.g., endoscopy) should make every effort to avoid vigorous stimulation of the posterior pharynx while still preventing accumulation of secretions or blood in the area.[57147] Neonates and infants younger than 3 months have a higher incidence of ketamine-induced respiratory complications (e.g., laryngospasm, apnea, coughing spells, aspiration), most likely attributable to differences in airway anatomy and age-associated laryngeal excitability. Because of these age-related differences, avoid ketamine in non-intubated patients younger than 3 months and use with caution in those younger than 1 year. Ketamine use is relatively contraindicated in patients with an unsupported airway who have a history of airway instability, tracheal surgery, tracheal stenosis, tracheomalacia, laryngomalacia, pulmonary disease, or an acute pulmonary infection including upper respiratory infection.[41115] [45333] [56732] [57147] Ketamine can increase oral secretions, influencing airway patency and further compromising respiratory function, particularly in unsupported patients. Administration of an anticholinergic prior to or concurrently with ketamine may help limit secretions; however, prophylaxis is not routinely recommended during procedural sedation.[41115] [43431] [45333] [56732] [57147] Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in pediatric patients 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 a young child 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.[61572]

    Children

    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.[61572] Animal data has suggested ketamine can induce apoptosis when administered in high doses or for prolonged periods. Neurotoxicity in the developing brain may correlate to learning and behavioral abnormalities later in life. Concern about potential human neurotoxicity has prompted investigation, but current evidence is lacking.[57147] [57152] Results from a small prospective study conducted in 49 young pediatric patients (3 to 22 months, ASA I) undergoing outpatient laser surgery have suggested that repeated exposure to anesthetic ketamine has the potential to negatively impact neurodevelopment. In the study, Bayley Scales of Infant Development-Second Edition scores, a tool used to predict neurodevelopmental outcomes after surgery, were significantly lower after the third exposure to ketamine (each dose = 8 mg/kg IM) compared to baseline in the group with 3 total exposures. In addition, concentrations of the S100B protein were significantly higher after the last procedure compared to baseline in groups with 1, 2, and 3 exposures; elevation of this protein in blood reliably occurs in clinical scenarios associated with central nervous system (CNS) injury.[60974] Although the study designs were much different, these results conflict with those from a study evaluating 24 infant patients treated randomly with either a single dose of ketamine 2 mg/kg IV or placebo prior to cardiopulmonary bypass surgery for ventricular septal defect repair, where no significant differences in markers of CNS injury (including S100B expression and Bayley scores) were noted after ketamine exposure.[60975]

    Geriatric

    In general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

    Labor, obstetric delivery, pregnancy

    Ketamine administration is not recommended during pregnancy, labor, or obstetric delivery because safe use has not been established. 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.

    Breast-feeding

    Use ketamine with careful monitoring in breast-feeding mothers; alternate agents are preferred. Minimal data indicate that ketamine use in breast-feeding mothers may not affect the breast-fed infant or lactation.

    ADVERSE REACTIONS

    Severe

    diabetes insipidus / Delayed / 0-1.0
    arrhythmia exacerbation / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    laryngospasm / Rapid / Incidence not known
    apnea / Delayed / Incidence not known
    increased intracranial pressure / Early / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    hemorrhagic cystitis / Delayed / Incidence not known

    Moderate

    hallucinations / Early / 12.0-12.0
    delirium / Early / 12.0-12.0
    hypertension / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    respiratory depression / Rapid / Incidence not known
    nystagmus / Delayed / Incidence not known
    confusion / Early / Incidence not known
    excitability / Early / Incidence not known
    tolerance / Delayed / Incidence not known
    dysphoria / Early / Incidence not known
    psychosis / Early / Incidence not known
    physiological dependence / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    involuntary movements / Delayed / Incidence not known
    myoclonia / Delayed / Incidence not known
    hypertonia / Delayed / Incidence not known
    erythema / Early / Incidence not known
    cystitis / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    hematuria / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known
    cholestasis / Delayed / Incidence not known

    Mild

    nightmares / Early / 12.0-12.0
    bronchial secretions / Early / Incidence not known
    hypersalivation / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    diplopia / Early / Incidence not known
    insomnia / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    rash / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    urinary urgency / Early / Incidence not known
    increased urinary frequency / Early / Incidence not known

    DRUG INTERACTIONS

    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: (Major) Concomitant use of codeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of dihydrocodeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Acetaminophen; Codeine: (Major) Concomitant use of codeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Propoxyphene: (Moderate) The use of ketamine with other CNS depressants, including opiate agonists, potentiate CNS depression and/or increase the risk of developing respiratory depression.
    Acetaminophen; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    Acetaminophen; Tramadol: (Major) Concomitant use of tramadol with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acrivastine; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Alfentanil: (Major) Both the magnitude and duration of central nervous system and cardiorespiratory effects may be potentiated when alfentanil is given concurrently with ketamine. Monitor for CNS depression, hypotension, and respiratory depression during use together. Prolonged recovery time may occur. Postoperative confusional states may occur during the recovery period during use of ketamine. The patient should be cautioned that driving an automobile, operating hazardous machinery or engaging in hazardous activities should not be undertaken for 24 hours or more (depending upon the dosage of ketamine and consideration of other drugs employed) after anesthesia.
    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.
    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. Due to the extremely long half-life of amiodarone, a drug interaction is also possible for days to weeks after discontinuation of amiodarone. For example, when fentanyl was administered to patients receiving amiodarone, the incidence of bradycardia and other adverse cardiovascular effects was much higher than in patients not on amiodarone who received fentanyl.
    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.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Closely monitor vital signs when ketamine and amphetamine; dextroamphetamine salts are coadministered; consider dose adjustment individualized to the patient's clinical situation. Amphetamine; dextroamphetamine salts may enhance the sympathomimetic effects of ketamine.
    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: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
    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.
    Articaine; Epinephrine: (Moderate) Closely monitor vital signs when ketamine and epinephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Epinephrine may enhance the sympathomimetic effects of ketamine.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of codeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of dihydrocodeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Aspirin, ASA; Carisoprodol: (Moderate) General anesthetics potentiate the effect of other CNS depressants including carisoprodol.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of codeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) General anesthetics potentiate the effect of other CNS depressants including carisoprodol.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with ketamine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with ketamine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    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.
    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.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Belladonna; Opium: (Major) Concomitant use of opium with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of benzhydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Benzodiazepines: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Benzphetamine: (Moderate) Closely monitor vital signs when ketamine and benzphetamine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Benzphetamine may enhance the sympathomimetic effects of ketamine.
    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.
    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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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; Dextromethorphan; Phenylephrine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (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) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Brompheniramine; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    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) If general anesthetics are required during treatment with buprenorphine, consider the potential for additive pharmacological effects during dose selection. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Major) If general anesthetics are required during treatment with buprenorphine, consider the potential for additive pharmacological effects during dose selection. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Monitor patients for sedation or respiratory depression.
    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, Magnesium, Potassium, Sodium Oxybates: (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.
    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.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and ketamine. CNS depressants can potentiate the effects of cannabidiol.
    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.
    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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (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.
    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: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (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) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbinoxamine; Phenylephrine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbinoxamine; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (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.
    Cenobamate: (Moderate) Although CNS depression is a desired effect of general anesthetics, monitor patients also receiving cenobamate closely for additive CNS depression that may prolong recovery after administration of a general anesthetic.
    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.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with general anesthetics should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. CNS depression is a desired effect of general anesthetics; however, concurrent use with a CNS depressant may prolong recovery. If concurrent use is necessary, monitor patients closely.
    Cetirizine; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (Moderate) Concurrent use of cetirizine/levocetirizine with general anesthetics should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. CNS depression is a desired effect of general anesthetics; however, concurrent use with a CNS depressant may prolong recovery. If concurrent use is necessary, monitor patients closely.
    Chlophedianol; Dexbrompheniramine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine.
    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.
    Chlorpheniramine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Codeine: (Major) Concomitant use of codeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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) Concomitant use of dihydrocodeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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) Concomitant use of dihydrocodeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (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) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (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) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Phenylephrine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpromazine: (Moderate) Phenothiazines 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.
    Chlorzoxazone: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Cholinesterase inhibitors: (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.
    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: (Moderate) Clozapine can 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.
    Codeine: (Major) Concomitant use of codeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Codeine; Guaifenesin: (Major) Concomitant use of codeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of codeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine.
    Codeine; Promethazine: (Major) Concomitant use of codeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    COMT inhibitors: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery.
    Cyclizine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    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: (Moderate) Use caution if ritonavir is coadministered with ketamine due to the potential for increased ketamine exposure which may increase the risk of toxicity. Ketamine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Desloratadine; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    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: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine. (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) Closely monitor vital signs when ketamine and dexmethylphenidate are coadministered; consider dose adjustment individualized to the patient's clinical situation. Dexmethylphenidate may enhance the sympathomimetic effects of ketamine.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    Diethylpropion: (Moderate) Closely monitor vital signs when ketamine and diethylpropion are coadministered; consider dose adjustment individualized to the patient's clinical situation. Diethylpropion may enhance the sympathomimetic effects of ketamine.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of dihydrocodeine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    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) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (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: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Dobutamine: (Moderate) Closely monitor vital signs when ketamine and dobutamine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Dobutamine may enhance the sympathomimetic effects of ketamine.
    Donepezil; Memantine: (Moderate) Ketamine is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of ketamine with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dopamine: (Moderate) Closely monitor vital signs when ketamine and dopamine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Dopamine may enhance the sympathomimetic effects of ketamine.
    Doxazosin: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    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: (Moderate) Concomitant use of dronabinol with other CNS depressants like general anesthetics can potentiate the effects of dronabinol on respiratory depression.
    Droperidol: (Major) Central nervous system (CNS) depressants (e.g., general anesthetics) have additive or potentiating effects with droperidol. Following administration of droperidol, the dose of the other CNS depressant should be reduced.
    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.
    Ephedrine: (Moderate) Closely monitor vital signs when ketamine and ephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Ephedrine may enhance the sympathomimetic effects of ketamine.
    Ephedrine; Guaifenesin: (Moderate) Closely monitor vital signs when ketamine and ephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Ephedrine may enhance the sympathomimetic effects of ketamine.
    Epinephrine: (Moderate) Closely monitor vital signs when ketamine and epinephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Epinephrine may enhance the sympathomimetic effects of ketamine.
    Eplerenone: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Epoprostenol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Esketamine: (Major) Although CNS depression is a desired effect of general anesthetics, patients also receiving esketamine should be closely monitored for additive effects that may prolong recovery after administration of a general anesthetic. If possible, avoid scheduling a treatment session with esketamine on the same day that general anesthesia is required. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
    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) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and general anesthetics. Concurrent use may result in additive CNS depression.
    Fentanyl: (Major) Concomitant use of fentanyl with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Fexofenadine; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    Gabapentin: (Major) Concomitant use of general anesthetics with gabapentin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of excessive respiratory depression. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
    Gentamicin: (Moderate) Patients receiving general anesthetics should be observed for exaggerated effects if they are receiving gentamicin.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    Guaifenesin; Phenylephrine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine.
    Guaifenesin; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    Haloperidol: (Major) Haloperidol 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.
    Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydrocodone: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    Hydromorphone: (Major) Concomitant use of hydromorphone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydroxyzine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Ibuprofen; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    Iloprost: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    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.
    Isoproterenol: (Moderate) Closely monitor vital signs when ketamine and isoproterenol are coadministered; consider dose adjustment individualized to the patient's clinical situation. Isoproterenol may enhance the sympathomimetic effects of ketamine.
    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.
    Lasmiditan: (Moderate) Although CNS depression is a desired effect of general anesthetics, patients also receiving lasmiditan should be closely monitored for additive effects that may prolong recovery after administration of a general anesthetic.
    Lemborexant: (Moderate) Although CNS depression is a desired effect of general anesthetics, monitor patients also receiving lemborexant closely for additive CNS depression that may prolong recovery after administration of a general anesthetic.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with general anesthetics should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. CNS depression is a desired effect of general anesthetics; however, concurrent use with a CNS depressant may prolong recovery. If concurrent use is necessary, monitor patients closely.
    Levomethadyl: (Moderate) The use of ketamine with other CNS depressants, including opiate agonists, potentiate CNS depression and/or increase the risk of developing respiratory depression.
    Levorphanol: (Major) Concomitant use of levorphanol with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial dose of levorphanol by approximately 50% or more. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Levothyroxine: (Moderate) Ketamine should be administered cautiously to patients receiving levothyroxine because concomitant use can cause marked hypertension and tachycardia.
    Levothyroxine; Liothyronine (Porcine): (Moderate) Ketamine should be administered cautiously to patients receiving levothyroxine because concomitant use can cause marked hypertension and tachycardia.
    Levothyroxine; Liothyronine (Synthetic): (Moderate) Ketamine should be administered cautiously to patients receiving levothyroxine because concomitant use can cause marked hypertension and tachycardia.
    Lidocaine; 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.
    Liothyronine: (Moderate) Ketamine should be administered cautiously to patients receiving levothyroxine because concomitant use can cause marked hypertension and tachycardia.
    Lisdexamfetamine: (Moderate) Closely monitor vital signs when general anesthetics and lisdexamfetamine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Lisdexamfetamine may enhance the sympathomimetic effects of general anesthetics.
    Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and ketamine. Lofexidine can potentiate the effects of CNS depressants
    Loop diuretics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Lopinavir; Ritonavir: (Moderate) Use caution if ritonavir is coadministered with ketamine due to the potential for increased ketamine exposure which may increase the risk of toxicity. Ketamine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Loratadine; Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    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.
    Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and general anesthetics. Concurrent use may result in additive CNS depression. Monitor patients closely for additive effects that may prolong recovery after use of a general anesthetic.
    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: (Moderate) General anesthetics may produce additive CNS depression when used in patients taking maprotiline.
    Mecamylamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Meclizine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Memantine: (Moderate) Ketamine is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of ketamine with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Meperidine: (Major) Concomitant use of meperidine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meperidine; Promethazine: (Major) Concomitant use of meperidine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    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: (Moderate) Phenothiazines 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.
    Metaxalone: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Methadone: (Moderate) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma; examples include general anesthetics. Prior to concurrent use of methadone 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. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; in opioid-naive adults, use an initial methadone dose of 2.5 mg every 12 hours. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression
    Methamphetamine: (Moderate) Closely monitor vital signs when general anesthetics and methamphetamine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Methamphetamine may enhance the sympathomimetic effects of general anesthetics.
    Methocarbamol: (Moderate) The use of general anesthetics with other CNS depressants, including skeletal muscle relaxants, can potentiate CNS depression and/or increase the risk of developing respiratory depression.
    Methohexital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Methylphenidate: (Moderate) Closely monitor vital signs when ketamine and methylphenidate are coadministered; consider dose adjustment individualized to the patient's clinical situation. Methylphenidate may enhance the sympathomimetic effects of ketamine.
    Midodrine: (Moderate) Closely monitor vital signs when ketamine and midodrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Midodrine may enhance the sympathomimetic effects of ketamine.
    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: (Moderate) Consistent with the pharmacology of mirtazapine and the CNS depression that may occur, additive effects may occur with other CNS depressants, including ketamine. Close monitoring is recommended in patients receiving mirtazapine and requiring an anesthetic.
    Monoamine oxidase inhibitors: (Major) Discontinue monoamine oxidase inhibitors (MAOIs) at least 10 days prior to elective surgery requiring use of general anesthetics due to the potential for significant hypotension. If this is not possible, carefully consider the risk of agents and techniques (e.g., epidural or spinal anesthesia) that increase the risk for hypotension.
    Morphine: (Major) Concomitant use of morphine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at 1/3 to 1/2 the recommended starting dosage. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Morphine; Naltrexone: (Major) Concomitant use of morphine with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at 1/3 to 1/2 the recommended starting dosage. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Nabilone: (Major) Concomitant use of nabilone with other CNS depressants like general anesthetics can potentiate the effects of nabilone on the central nervous system. Additive drowsiness and CNS depression can occur.
    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: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with other hypotensive drugs, including general anesthetics.
    Norepinephrine: (Moderate) Closely monitor vital signs when ketamine and norepinephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Norepinephrine may enhance the sympathomimetic effects of ketamine.
    Oliceridine: (Major) Concomitant use of oliceridine with general anesthetics may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with general anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Use caution if ritonavir is coadministered with ketamine due to the potential for increased ketamine exposure which may increase the risk of toxicity. Ketamine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Orphenadrine: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Oxycodone: (Major) Concomitant use of oxycodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Oxymorphone: (Major) Concomitant use of oxymorphone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxymorphone dosage by 1/3 to 1/2. Educate patients about the risks and symptoms of respiratory depression and sedation.
    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.
    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.
    Pentobarbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Phendimetrazine: (Moderate) Closely monitor vital signs when ketamine and phendimetrazine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phendimetrazine may enhance the sympathomimetic effects of ketamine.
    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: (Moderate) Closely monitor vital signs when ketamine and phentermine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phentermine may enhance the sympathomimetic effects of ketamine.
    Phentermine; Topiramate: (Moderate) Closely monitor vital signs when ketamine and phentermine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phentermine may enhance the sympathomimetic effects of ketamine.
    Phenylephrine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine.
    Phenylephrine; Promethazine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine.
    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.
    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: (Major) Concomitant use of general anesthetics with pregabalin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of excessive respiratory depression. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
    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: (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. (Moderate) Closely monitor vital signs when ketamine and epinephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Epinephrine may enhance the sympathomimetic effects of ketamine.
    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: (Moderate) Additive CNS effects may occur if prochlorperazine is administered concomitantly with general anesthetics.
    Propoxyphene: (Moderate) The use of ketamine with other CNS depressants, including opiate agonists, potentiate CNS depression and/or increase the risk of developing respiratory depression.
    Pseudoephedrine: (Moderate) Closely monitor vital signs when ketamine and pseudoephedrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Pseudoephedrine may enhance the sympathomimetic effects of ketamine.
    Pyrilamine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Racepinephrine: (Moderate) Closely monitor vital signs when ketamine and racepinephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Racepinephrine may enhance the sympathomimetic effects of ketamine.
    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.
    Remifentanil: (Major) Both the magnitude and duration of central nervous system and cardiorespiratory effects may be potentiated when remifentanil is given concurrently with ketamine. Monitor for CNS depression, hypotension, and respiratory depression during use together. Prolonged recovery time may occur. Postoperative confusional states may occur during the recovery period during use of ketamine. The patient should be cautioned that driving an automobile, operating hazardous machinery or engaging in hazardous activities should not be undertaken for 24 hours or more (depending upon the dosage of ketamine and consideration of other drugs employed) after anesthesia.
    Reserpine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Ritodrine: (Moderate) Closely monitor vital signs when ketamine and ritodrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. ritodrine may enhance the sympathomimetic effects of ketamine.
    Ritonavir: (Moderate) Use caution if ritonavir is coadministered with ketamine due to the potential for increased ketamine exposure which may increase the risk of toxicity. Ketamine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Secobarbital: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
    Sedating H1-blockers: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Selegiline: (Moderate) Although CNS depression is a desired effect of general anesthetics, patients also receiving selegiline should be closely monitored for additive effects that may prolong recovery after administration of general anesthetics.
    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.
    Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as general anesthetics. Caution should be exercised when using these agents concurrently.
    Sotalol: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension.
    Streptomycin: (Moderate) Patients receiving general anesthetics should be observed for exaggerated effects if they are receiving streptomycin.
    Sufentanil: (Major) Both the magnitude and duration of central nervous system and cardiorespiratory effects may be potentiated when sufentanil is given concurrently with ketamine. Monitor for CNS depression, hypotension, and respiratory depression during use together. Prolonged recovery time may occur. Postoperative confusional states may occur during the recovery period during use of ketamine. The patient should be cautioned that driving an automobile, operating hazardous machinery or engaging in hazardous activities should not be undertaken for 24 hours or more (depending upon the dosage of ketamine and consideration of other drugs employed) after anesthesia.
    Suvorexant: (Moderate) CNS depressant drugs, including general anesthetics, may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of either suvorexant or the CNS depressant may be needed in some cases.
    Tapentadol: (Major) Concomitant use of tapentadol with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Terazosin: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    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: (Major) Consider using an alternative to ketamine in patients receiving aminophylline; concomitant use may lower the seizure threshold. (Major) Consider using an alternative to ketamine in patients receiving theophylline; concomitant use may lower the seizure threshold.
    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: (Moderate) The use of ketamine with other CNS depressants, such as phenothiazines, can potentiate CNS depression and/or increase the risk of developing respiratory depression.
    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.
    Thyroid hormones: (Moderate) Ketamine should be administered cautiously to patients receiving levothyroxine because concomitant use can cause marked hypertension and tachycardia.
    Tobramycin: (Moderate) Patients receiving general anesthetics should be observed for exaggerated effects if they are receiving tobramycin.
    Tramadol: (Major) Concomitant use of tramadol with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Treprostinil: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Tricyclic antidepressants: (Moderate) General anesthetics, including ketamine, may generally produce additive CNS depression when used in patients taking tricyclic antidepressants (TCAs). Specific interactions between ketamine and TCAs are not certain.
    Triprolidine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Trovafloxacin, Alatrofloxacin: (Moderate) General anesthetics may potentiate the hypotension associated alatrofloxacin administration.
    Vancomycin: (Moderate) The concurrent administration of vancomycin and anesthetics has been associated with erythema, histamine-like flushing, and anaphylactoid reactions.
    Vasodilators: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Vasopressin, ADH: (Moderate) Closely monitor vital signs when ketamine and vasopressin are coadministered; consider dose adjustment individualized to the patient's clinical situation. Vasopressin may enhance the sympathomimetic effects of ketamine.
    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.
    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

    Use ketamine with careful monitoring in breast-feeding mothers; alternate agents are preferred. Minimal data indicate that ketamine use in breast-feeding mothers may not affect the breast-fed infant or lactation.

    MECHANISM OF ACTION

    Ketamine is a nonbarbiturate, phencyclidine derivative that produces sedation, amnesia, and analgesia.[41115] [43431] Potent analgesia occurs even at subanesthetic doses.[56641] Unlike narcotics and inhalational anesthetics, ketamine is capable of producing an anesthetic state characterized by cardiovascular and respiratory stimulation, normal or slightly enhanced skeletal muscle tone, normal pharyngeal-laryngeal reflexes, and independent airway maintenance.[41115] [43431] [56633] [56642] Ketamine's analgesic and anesthetic effects are a result of N-methyl-D-aspartate (NMDA) receptor antagonism (which blocks the excitatory neurotransmitter glutamate) as well as interaction with opioid and cholinergic transmission.[41115] [54589] [54822] [56633] Ketamine selectively interrupts association pathways of the brain before producing somatesthetic sensory blockade; 'dissociative anesthesia' is induced through inhibition of thalamoneocortical pathways and limbic stimulation.[41115] [43431] [54822] Functional and electrophysiological dissociation between the cortical and limbic systems prevents higher centers from perceiving visual, auditory, or painful stimuli.[41115] [43431] [56641] Clinically, adequate ketamine anesthesia results in a state of catalepsy in which patients are unresponsive to nociceptive stimuli, but the eyes remain open (and are usually nystagmic) with intact corneal and light reflexes.[41115] [56633] [56641] It is believed emergence phenomena (e.g., alterations in mood state and body image, out-of-body experiences, floating sensations, vivid dreams/illusions, delirium) are caused by an alteration of auditory and visual relays that leads to the misinterpretation of visual and auditory stimuli.[56641] [56642]
     
    The sympathomimetic activity of ketamine results in bronchodilation, tachycardia, hypertension, increased myocardial consumption, increased cerebral blood flow, and increased intracranial and intraocular pressure. Bronchodilation occurs as a result of endogenous catecholamine release, direct smooth muscle dilatation, and inhibition of vagal outflow, making ketamine a suitable agent in patients with asthma and/or acute bronchospasm.[41115] [54589] Indirect sympathomimetic activation and an increase in endogenous catecholamines stimulate the cardiovascular system by producing a dose-related increase in blood pressure, heart rate, and cardiac output.[41115] [54589] [56642] In general, indirect sympathomimetic effects compensate for ketamine's direct negative inotropic effect. However, direct negative inotropic effects may predominate in patients with exhausted catecholamine stores or maximal sympathetic stimulation (e.g., critically ill patients, those with diminished myocardial contractility) and hypotension may occur.[41115] [54589] [56642] Stimulation of cholinergic receptors mediates cerebral vasodilation, increased systemic perfusion pressures, and elevated intracranial pressure. Cholinergic stimulation is also responsible for increased salivary and bronchial gland secretions.[41115] [56642]

    PHARMACOKINETICS

    Ketamine is most often administered parenterally; however, the parenteral form can also be administered via oral, intranasal, and rectal routes. When used illicitly, ketamine may be snorted, smoked, swallowed, or injected. Ketamine is a racemic mixture (containing equal amounts of 2 isomers) that rapidly distributes into highly perfused tissues including the brain to achieve concentrations 4 to 5 times that of the plasma. Vd is 2 to 3 L/kg. The drug has high lipid solubility and low plasma protein binding (12%); it is not significantly bound to serum albumin. Ketamine is rapidly distributed into highly perfused tissues (e.g., heart, lung, and brain), followed by muscle and peripheral tissues, and then fat. Alpha phase distribution lasts about 45 minutes, with a half-life of 10 to 15 minutes, which corresponds clinically to the anesthetic effect of the drug. Anesthetic action is terminated by redistribution from the central nervous system to slower equilibrating peripheral tissues and by hepatic metabolism to norketamine.
     
    The major biotransformation pathway begins with N-demethylation via cytochrome P450 enzymes to form norketamine (metabolite I), which possesses an anesthetic potency as much as one-third that of ketamine. The majority of norketamine is hydroxylated in the cyclohexone ring to form hydroxy-norketamine compounds, which in turn are conjugated to water-soluble glucuronide derivatives. Additionally, the hydroxylated metabolites of norketamine can undergo thermal dehydration to form the cyclohexene oxidation derivative dehydronorketamine (metabolite II) which is of little significance in vivo. Ketamine can also undergo ring hydroxylation without prior N-demethylation, though this pathway appears to be of minor importance quantitatively. Of note, chronic administration of ketamine results in hepatic enzyme induction. Reported clearance rates in adults range from 12 to 20 mL/kg/minute, with higher rates in intensive care patients (36 mL/kg/minute after a bolus and 2-hour infusion). After intravenous administration, less than 4% of the dose is recovered in the urine as ketamine or norketamine; 16% appears as hydroxylated derivatives. Small amounts are excreted in the bile and feces. Elimination half-life is 2 to 3 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9, CYP2B6
    CYP3A4 is the principal enzyme responsible for ketamine N-demethylation; CYP2B6 and CYP2C9 also play a minor role in biotransformation. Chronic administration of ketamine results in hepatic enzyme induction.

    Oral Route

    Substantial first-pass metabolism occurs with oral ketamine administration; this results in less predictable effectiveness and delayed onset and recovery compared to parenteral routes. The oral bioavailability of ketamine is approximately 20% to 30%. In a single-dose crossover pharmacokinetic study of 6 healthy adults given ketamine 0.5 mg/kg orally and intramuscularly, oral ketamine absorption was incomplete and delayed with a mean Cmax of 45 ng/mL occurring at 30 minutes. Onset of analgesia was delayed (30 minutes) and associated with lower serum concentrations (40 ng/mL) compared to the intramuscular dose (15 minutes and 150 ng/mL, respectively).

    Intravenous Route

    Ketamine has a 1-arm brain circulation time (i.e., drug effects are seen rapidly, in the time it takes the drug to reach the brain from the injection site in the arm) when given intravenously. A sensation of dissociation occurs in 60 seconds and onset of anesthesia occurs within 30 to 60 seconds. Anesthesia persists for 5 to 10 minutes and recovery occurs in approximately 1 to 2 hours.

    Intramuscular Route

    Ketamine has a high bioavailability (approximately 93%) when given intramuscularly. Anesthesia occurs within 3 to 5 minutes after injection and lasts 12 to 30 minutes. Recovery occurs in approximately 0.5 to 2 hours and, in general, is prolonged and more variable compared to intravenous administration. In a single-dose crossover pharmacokinetic study of 6 healthy adults given ketamine 0.5 mg/kg intramuscularly and orally, intramuscular ketamine absorption was rapid with a mean Cmax of 240 ng/mL occurring at 22 4 minutes. Onset of analgesia was faster (15 minutes) and associated with higher serum concentrations (150 ng/mL) compared to the oral dose (30 minutes and 40 ng/mL, respectively). Mean elimination half-life was approximately 2.5 hours, similar to that after intravenous administration.

    Other Route(s)

    Rectal Route
    Substantial first-pass metabolism occurs with rectal ketamine administration; this results in less predictable effectiveness and delayed onset and recovery compared to parenteral routes. In addition, rectal ketamine displays substantial interpatient variability in its pharmacokinetics. Calculated bioavailability was 25% after rectal administration of ketamine (5% solution) 9 mg/kg to 7 children (age range: 3 to 9 years). In the same study, a mean Cmax of 632 ng/mL was attained in approximately 45 minutes. Other reported parameters include: Vd = 18 L/kg; AUC = 111.2 mg/mL x minute; clearance = 121.5 mL/kg/minute; half-life = 100 minutes. In another small study of 5 children (age range: 6 to 9 years), a median Cmax of 160 ng/mL was attained 45 minutes after a single dose of ketamine (stearine suppositories) 10 mg/kg; of note, these concentrations were deemed unacceptable for anesthesia, but adequate for analgesia. Elimination half-life was 3.15 hours. Another investigation reported loss of verbal contact within 6 minutes in 45% (67/150) of patients, with excellent anesthesia induction in 93% (139/150) of patients receiving ketamine (1% or 5% solution) 8 to 10 mg/kg as a single dose.
     
    Intranasal Route
    Bioavailability of intranasal ketamine is approximately 35% to 50%. In a small pediatric study evaluating the pharmacokinetics of ketamine administered via various routes, the same dose of ketamine (9 mg/kg) induced a more rapid and greater plasma concentration with intranasal administration compared to rectal administration. With administration of intranasal ketamine 3 mg/kg (n = 8) and 9 mg/kg (n = 7), Cmax (496 ng/mL and 2,104 ng/mL, respectively) was attained in approximately 20 minutes. Pharmacokinetic parameters in the 3 mg/kg group were as follows: Vd = 8.5 L/kg; AUC = 76.4 mg/mL x minute; clearance = 49.9 mL/kg/minute; half-life = 123 minutes. While Vd (8.3 L/kg), clearance (59.7 mL/kg/minute), and half-life (120 minutes) were similar in the 9 mg/kg dose group, AUC was expectedly greater (163.6 mg/mL x minute). Onset of procedural sedation is 5 to 20 minutes. In an evaluation of intranasal ketamine in pediatric dental patients (n = 45; age range: 2 to 6 years), mean onset of procedural sedation was 5.8 minutes (range: 5 to 8 minutes) and recovery occurred in 40 minutes (range: 34 to 46 minutes) after a 6 mg/kg dose.