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  • CLASSES

    Other General Anesthetics

    DEA CLASS

    Rx, schedule III

    DESCRIPTION

    Nonbarbiturate, sedative hypnotic; analgesic effects; produces dissociative anesthesia; efficacy is offset by the frequent occurrence of dysphoria; similar in structure, mechanism of action, and activity to PCP; has been associated with substance abuse and illicit use.

    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: As with other general anesthetic agents, the individual response to ketamine is somewhat varied depending on the dose, administration route, and patient age; dosage recommendations cannot be absolutely fixed. Titrate the ketamine dose according to the patient's requirements.
    NOTE: Ketamine hydrochloride injection is indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. Ketamine hydrochloride injection is best suited for short procedures but it can be used, with additional doses, for longer procedures.
    NOTE: Ketamine is clinically compatible with the commonly used general and local anesthetic agents when an adequate respiratory exchange is maintained. The regimen of a reduced dose of ketamine supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents such as nitrous oxide and oxygen.
    Intravenous dosage
    Adults

    1 to 4.5 mg/kg IV slowly over 60 seconds. On average, 2 mg/kg will produce 5 to 10 minutes of surgical anesthesia. If a longer effect is desired, additional increments can be administered IV to maintain anesthesia without producing significant cumulative effects. Alternatively, 1 to 2 mg/kg IV may be given at a rate of 0.5 mg/kg/minute for induction in combination with diazepam (2 to 5 mg IV given in a separate syringe over 60 seconds). In most cases, diazepam doses of 15 mg or less IV will be sufficient. The occurrence of an emergence reaction may be less with the combination.

    Adolescents 16 to 17 years

    1 to 4.5 mg/kg IV as a single dose administered slowly over 60 seconds. Of note, a dose of 2 mg/kg IV typically produces surgical anesthesia within 30 seconds that persists for 5 to 10 minutes. Alternatively, ketamine 1 to 2 mg/kg IV may be given at a rate of 0.5 mg/kg/minute in combination with diazepam (2 to 5 mg IV given in a separate syringe over 60 seconds); emergence reactions may be less with this combination.

    Infants†, Children†, and Adolescents younger than 16 years†

    0.5 to 2 mg/kg IV as a single dose administered slowly over 60 seconds.

    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 of subjects were neonates, the youngest being 10 hours old and 1.4 kg. Neonates were premedicated with chloral hydrate and atropine 45 minutes prior to the procedure.

    Intramuscular dosage
    Adults

    6.5 to 13 mg/kg IM. Approximately 10 mg/kg will usually produce 12 to 25 minutes of surgical anesthesia. If a longer effect is desired, additional increments can be administered intramuscularly to maintain anesthesia without producing significant cumulative effects.

    Adolescents 16 to 17 years

    6.5 to 13 mg/kg IM as a single dose. Of note, a dose of 10 mg/kg IM typically produces surgical anesthesia within 3 to 4 minutes that persists for 12 to 25 minutes.

    Infants†, Children†, and Adolescents younger than 16 years†

    4 to 10 mg/kg IM as a single dose. Some experts recommend an initial induction dose of 4 to 6 mg/kg IM , while others have utilized initial doses of 10 mg/kg IM for diagnostic and minor surgical procedures. Total dosage range: 4 to 13 mg/kg IM.

    For general anesthesia maintenance.
    NOTE: As with other general anesthetic agents, the individual response to ketamine is somewhat varied depending on the dose, administration route, and patient age; dosage recommendations cannot be absolutely fixed. Titrate the ketamine dose according to the patient's requirements. Adjust the maintenance dose according to the patient's anesthetic needs and whether an additional anesthetic agent is employed.
    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 the anesthetic.
    Intermittent Intravenous dosage
    Adults

    Increments of one-half to the full induction dose (i.e., 0.5 to 4.5 mg/kg) IV over 60 seconds and repeated as needed. Adults induced with ketamine augmented with intravenous diazepam may be maintained on a ketamine infusion of 0.1 to 0.5 mg/minute. The dose of diazepam is 2 to 5 mg IV as needed (usually not more than 20 mg diazepam IV for combined induction and maintenance will be sufficient). The occurrence of an emergence reaction may be less with the combination.

    Adolescents 16 to 17 years

    Increments of one-half to the full induction dose (i.e., 0.5 to 4.5 mg/kg/dose) IV may be repeated as needed; administer doses over 60 seconds. Adjust dose based on patient requirements and adjunctive anesthetic use.

    Infants†, Children†, and Adolescents younger than 16 years†

    Increments of one-half to the full induction dose (i.e., 0.25 to 2 mg/kg/dose) IV may be repeated every 5 to 10 minutes as needed; administer doses over 60 seconds. 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. Maintenance of anesthesia with ketamine 1 to 2 mg/kg/dose IV and sevoflurane has been described without incident in a single case report of a newborn (gestational age: 33 weeks; weight: 2,050 grams) 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 IV as a continuous infusion augmented with diazepam (2 to 5 mg IV as needed; total diazepam doses less than or equal to 20 mg are usually sufficient) may be used to maintain patients induced with both agents; emergence reactions may be less with this combination compared to ketamine alone. Adjust dose based on patient requirements and adjunctive anesthetic use.

    Adolescents 16 to 17 years

    0.1 to 0.5 mg/minute IV as a continuous infusion augmented with diazepam (2 to 5 mg IV as needed; total diazepam doses less than or equal to 20 mg are usually sufficient) may be used to maintain patients induced with both agents; emergence reactions may be less with this combination compared to ketamine alone. Adjust dose based on patient requirements and adjunctive anesthetic use.

    Infants†, Children†, and Adolescents younger than 16 years†

    1.5 to 6 mg/kg/hour (25 to 100 mcg/kg/minute) IV as a continuous infusion has been recommended ; adjust dose based on patient requirements and adjunctive anesthetic use. Mean reported dose: 3 to 6 mg/kg/hour (50 to 100 mcg/kg/minute) IV ; range: 0.6 to 13 mg/kg/hour (10 to 215 mcg/kg/minute) IV. Ketamine 2.4 to 5.1 mg/kg/hour (40 to 85 mcg/kg/minute) IV (mean: 4.2 mg/kg/hour [70 mcg/kg/minute]) plus fentanyl (6 mcg/kg/hour IV) was an effective alternative to isoflurane plus fentanyl in 50 children (age range: 3 months to 12 years) undergoing definitive correction of tetralogy of Fallot. As a sole agent, ketamine 3 mg/kg/hour (50 mcg/kg/minute) IV was safe and effective in a retrospective review of 107 pediatric patients (age range: 10 hours to 14 years) undergoing interventional cardiac procedures. Doses were stepped up to 4.5 mg/kg/hour (75 mcg/kg/minute) IV in 6 patients (5.6%) who reacted to pain at the lower dose; supplemental sedation with IV midazolam was required in 32 patients.

    Neonates†

    Limited data available; some experts do not recommend the use of ketamine in neonates. Mean infusion rates of 3 to 6 mg/kg/hour (50 to 100 mcg/kg/minute) IV have 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) IV. Adjust dose based on patient requirements and adjunctive anesthetic use.

    Intramuscular dosage
    Adults

    Increments of one-half to the full induction dose (i.e., 3.25 to 13 mg/kg) IM as needed may be used for maintenance.

    Adolescents 16 to 17 years

    Increments of one-half to the full induction dose (i.e., 3.25 to 13 mg/kg/dose) IM may be repeated as needed. Adjust dose based on patient requirements and adjunctive anesthetic use.

    For preanesthesia sedation in pediatric patients.
    Intranasal dosage
    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.

    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.

    Oral dosage
    Children

    6 to 8 mg/kg PO as a single dose 30 minutes prior to mask induction. When used with oral midazolam, a lower dose (3 mg/kg) may be sufficient. In a study comparing single agent oral ketamine doses of 4 mg/kg (n = 20; group 1), 6 mg/kg (n = 20; group 2), and 8 mg/kg (n = 20; group 3) to placebo (group 4), children (age: 2 to 8 years) receiving 8 mg/kg were significantly calmer than those in other groups, and anesthesia induction was more comfortable. Adequate sedation was observed within 10 minutes in 80% of patients in group 3, 45% of patients in group 2, and none of the patients in group 1. Nineteen patients (95%) in group 3 and 11 patients (55%) in group 2 were calm upon separation from their parents. Children in group 3 had a significantly muted response to IV catheter insertion than the other groups. Face mask application was rated as easy in groups 1, 2, and 3. Although recovery was longer in groups 2 and 3, differences between groups were not significant after 2 hours. In another study comparing ketamine 3 mg/kg (n = 15), 6 mg/kg (n = 15), and placebo (n = 15), 100% of children given the higher dose were sedated, with sedation occurring within approximately 10 minutes and maximum sedation obtained within 20 to 25 minutes; this allowed for calm separation from parents (93% calm; 7% apprehensive) and good induction conditions. Comparatively, 73% of patients given ketamine 3 mg/kg PO obtained some level of sedation within 12.5 minutes; calm parental separation occurred in 73% of patients, but the other 27% were crying. Low dose oral ketamine (3 mg/kg) and midazolam (0.25 mg/kg) provided an earlier onset of sedation (12.5% and 54% had acceptable sedation scores at 10 and 20 minutes, respectively) and earlier recovery time when compared to single agent use of ketamine (6 mg/kg) or midazolam (0.5 mg/kg) in a study of 78 children (age: 1 to 9 years) scheduled for elective ophthalmic surgery. There were no significant differences between groups in the parental separation score, response to induction, or emergence score.

    Rectal dosage
    Infants and Children

    8 to 10 mg/kg PR administered as a single dose 15 to 45 minutes prior to mask induction. Smaller doses (4 to 7 mg/kg) have been reported but were not as effective. Significantly more patients given ketamine 6 mg/kg PR (n = 25; age: 2 months to 6 years) were calm at parental separation and mask induction compared to placebo; however, the ketamine dosage was not sufficient to keep the child calm for intravenous cannulation. Administration of ketamine 4 mg/kg (n = 34) or 8 mg/kg (n = 33) PR with midazolam 0.5 mg/kg and atropine 0.02 mg/kg PR resulted in calm parental separation in 94% and 93% of patients, respectively, in a comparative study in infants and young children (2 months to 2 years). However, significantly more patients receiving the higher ketamine dose were asleep during parental separation (62% vs. 35%) and either asleep or not crying during venipuncture (63% vs. 32%). All patients were ready for discharge from the recovery room with 1 hour. Ketamine 10 mg/kg PR eased parental separation and facilitated mask induction without struggling or crying in a significantly higher percentage of patients than those receiving ketamine 5 mg/kg or 7 mg/kg PR, but comparable to midazolam 1 mg/kg PR, in a small blinded dose-response study in patients undergoing minor inpatient surgery (n = 66; age: 7 months to 5 years). Recovery time was significantly longer with larger doses of ketamine; time to emergence was 1.4 +/- 1.4 hours, 1.3 +/- 1.2 hours, 0.3 +/- 0.2 hours, and 0.6 +/- 0.4 hours in those receiving ketamine 10 mg/kg, 7 mg/kg, 5 mg/kg, and midazolam 1 mg/kg PR, respectively.

    For procedural sedation† in pediatric patients.
    NOTE: Some experts do not recommend the use of ketamine for procedural sedation in non-intubated patients younger than 3 months of age.
    Intravenous dosage
    Infants, Children, and Adolescents 3 months to 17 years

    1 to 2 mg/kg (range: 0.5 to 2 mg/kg) IV as a single dose administered over 60 seconds; may repeat 0.5 to 1 mg/kg/dose (range: 0.25 to 1.5 mg/kg/dose) IV every 5 to 15 minutes as needed. Clinical onset usually occurs within 1 minute and effective dissociation persists for 5 to 10 minutes after a single dose. Max single dose is not well-defined; some have suggested 100 mg/dose IV while others have utilized a fixed-dose protocol in older patients. 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 a RSS of at least 5 after a total ketamine dose of 75 mg.

    Infants 1 to 2 months

    Some experts do not recommend the use of ketamine for procedural sedation in non-intubated patients younger than 3 months of age. In general, 1 to 2 mg/kg (range: 0.5 to 2 mg/kg) IV as a single dose administered over 60 seconds has been recommended for pediatric patients; may repeat 0.5 to 1 mg/kg/dose (range: 0.25 to 1.5 mg/kg/dose) IV every 5 to 15 minutes as needed. Clinical onset usually occurs within 1 minute and effective dissociation persists for 5 to 10 minutes after a single dose.

    Neonates

    Limited data available; some experts do not recommend the use of ketamine in neonates. A dose of 0.5 to 2 mg/kg IV has been recommended. An initial dose of 0.2 to 1 mg/kg IV, followed by repeated doses of 0.5 mg/kg IV has been reported for sedation prior to cardiac catheterization and treatment of retinopathy of prematurity. Ketamine doses of 0.5, 1, and 2 mg/kg IV administered prior to tracheal suction have been studied in mechanically ventilated neonates (n = 16; mean gestational age: 33 weeks); however, only after the 1 mg/kg dose was an attenuation of the pain score significant compared to placebo (p = 0.043). Heart rate and blood pressure were not significantly decreased at this dose.

    Intravenous dosage with propofol (i.e., "ketofol")
    Children and Adolescents

    0.5 to 0.75 mg/kg IV for each agent; repeat boluses as required to achieve adequate sedation. 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
    Infants, Children, and Adolescents 3 months to 17 years

    4 to 5 mg/kg IM as a single dose (range: 2 to 5 mg/kg/dose IM); may repeat 2 to 5 mg/kg/dose IM after 5 to 10 minutes. Clinical onset usually occurs within 5 minutes and effective dissociation persists for 20 to 30 minutes after a single dose. Ketamine 4 to 5 mg/kg IM resulted in adequate procedural sedation in more than 93% of emergency department patients, according to a retrospective analysis of a prospective case series including 1,022 children 15 years and younger. 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 single dose is not well-defined; some have suggested 50 mg/dose IM.

    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 prior to imaging or dental procedures has been described. Administer 5 to 20 minutes prior to the procedure. Larger doses may be required for adequate sedation of painful procedures. In a preliminary report evaluating intranasal ketamine sedation for laceration repair, 3 of 4 patients receiving 9 mg/kg achieved adequate sedation within approximately 5 to 10 minutes, while patients receiving 3 mg/kg (n = 3) and 6 mg/kg (n = 5) did not achieve adequate sedation with intranasal ketamine and were subsequently given intravenous ketamine. Duration of sedation ranged from 36 to 69 minutes.

    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 given in combination with midazolam 20 to 45 minutes before procedure. A lower dose of 3 mg/kg PO, also given 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 single dose is not well-defined; 50 to 250 mg/dose PO has been suggested but higher doses have been reported. The combination of oral ketamine and midazolam was more effective than the intramuscular combination of meperidine, promethazine, and chlorpromazine (commonly referred to as DPT) for sedation and amnesia in 51 children (age range: 9 months to 10 years) undergoing cardiac catheterization. Dosing was adjusted to give younger patients a larger dose; children 3 years and younger received ketamine 10 mg/kg and midazolam 1 mg/kg, whereas children older than 4 years received ketamine 6 mg/kg and midazolam 0.6 mg/kg. Sedation was supplemented with IV propofol as needed but was required in a lower percentage of patients in the PO group with a median of 1 dose total vs. 6 doses total in the IM DPT group.

    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 administered in combination with midazolam 20 minutes prior to the procedure. In a study comparing intravenous (n = 25; ketamine 1 mg/kg with midazolam 0.05 mg/kg IV), oral (n = 24; ketamine 3 mg/kg with midazolam 0.5 mg/kg PO), and rectal (n = 24; ketamine 3 mg/kg with midazolam 0.5 mg/kg PR) ketamine for invasive oncologic procedures, optimal sedation (grade 4 or 5, drowsy and asleep) was provided in 78% of all patients with no statistical difference between the 3 groups. Onset of sedation after rectal administration was similar to that after oral administration (15 to 20 minutes). Mean recovery time was 24 minutes in the PR group, compared to 19 minutes in the PO group, and 38 minutes in the IV group (p less than 0.05 for IV vs. PR groups). In another study, administration of rectal S(+) ketamine (0.75 mg/kg, which is equivalent to 1.5 mg/kg racemic ketamine) and midazolam (0.4 mg/kg) resulted in adequate sedation and analgesia in 94% of outpatient dressing changes (n = 47) in 30 pediatric burn patients (age range: 10 months to 7 years).

    For the adjunctive treatment of refractory acute bronchospasm† due to status asthmaticus† or other respiratory conditions in pediatric patients.
    Intravenous dosage
    Infants, Children, and Adolescents

    Limited evidence; not first line therapy. A bolus of 0.5 to 2 mg/kg IV followed by a 0.2 to 3.6 mg/kg/hour (3.3 to 60 mcg/kg/minute) IV continuous infusion has been reported as beneficial. Start low and titrate by 0.25 to 0.5 mg/kg/hour (4 to 8 mcg/kg/minute) to achieve desired clinical effect. Ketamine has bronchodilatory properties and may be useful for acute bronchospasm in patients refractory to standard therapy; however, trials in non-intubated children (n = 68; ketamine 0.2 mg/kg IV load and infusion of 0.5 mg/kg/hour [8 mcg/kg/minute] for 2 hours) and adults (n = 53; 0.1 to 0.2 mg/kg IV load and infusion of 0.5 mg/kg/hour [8 mcg/kg/minute] for 3 hours) presenting with moderately severe asthma exacerbations have not shown clinical benefit. Some speculate doses used were suboptimal. Doses utilized with reported benefit in non-intubated patients (n = 13; age range: 4 to 18 years) have ranged from a 1 to 2 mg/kg IV bolus followed by a 0.75 to 3 mg/kg/hour (12.5 to 50 mcg/kg/minute) IV continuous infusion. In mechanically ventilated patients (n = 21; age range: 6 months to 17 years) beneficial doses have ranged from a 0.5 to 2 mg/kg IV bolus followed by 0.2 to 3.6 mg/kg/hour (3.3 to 60 mcg/kg/minute) IV continuous infusion.

    For use in treatment-resistant depression† in adult patients.
    Intravenous dosage
    Adults

    Optimal dose and standards for monitoring and assessment is not established. A commonly reported treatment dose is ketamine 0.5 mg/kg by IV infusion either as a single dose, or as multiple doses administered 1 to 3 times weekly for up to 6 infusions. Further study is needed to determine the optimal dose and duration of treatment. Not well studied in older adults 65 year of age and older; do not use in the elderly. Use requires monitoring from anesthesiologists and hospitalization of patients for at least 24 hours post-infusion. Adverse hemodynamic effects (e.g., hypertensive or hypotensive episodes, tachycardia, bradycardia, or bradypnea) or centrally-mediated effects (e.g., dissociative symptoms, confusion, euphoria) can occur. Significant reductions in treatment-resistant major depressive disorder symptoms have been observed with single or multiple dose regimens as measured by the Hamilton Depression Rating Scale (HDRS) or the Montgomery-Asberg Depression Rating Scale (MADRS). However, response rates (25% to 85% at 24 hours post-infusion) and the duration of effect are highly variable.

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

    10 to 50 mg/hour IV for severe pain associated with complex regional pain syndrome led to complete pain relief in 25 of 33 patients. An additional 6 patients had partial pain relief. The mean infusion duration was 4.7 days (range, 0.75 to 20 days). Twelve of the 33 patients relapsed and received another dose of ketamine that caused complete relief for all patients. Furthermore, 7 of the 12 patients maintained complete relief for at least a year. In another study, significant improvements in pain relief, as determined by use of the Brief Pain Inventory, occurred in patients with severe ischemic limb pain who got opioids and a single infusion of 0.6 mg/kg of ketamine as compared with patients who only got opioids. A single dose of ketamine 0.25 mg/kg or 0.5 mg/kg was also effective for patients with cancer and neuropathic pain who were already taking morphine.

    Children and Adolescents

    0.05 to 0.2 mg/kg/hour (0.83 to 3.3 mcg/kg/minute) IV as a continuous infusion, titrated to clinical response has been reported to provide good supplementary analgesia and potentially spare opioid consumption. In a case series of 11 children (median age: 10 years [range: 3 to 17 years]) with advanced-stage cancer, the addition of ketamine reduced opioid requirements and subjectively improved analgesia in 73% of patients; the opioid-sparing effect in these patients ranged from 28% to 100%. In addition, caregiver reports suggested increased mental alertness and social interaction in these patients. Duration of ketamine treatment ranged from 1 to 75 days with a maximum reported infusion rate of 1 mg/kg/hour (17 mcg/kg/minute) IV. Larger doses may be required. Titration up to 4.1 mg/kg/hour (68 mcg/kg/minute) has been reported in an 11 year old AML patient with severe retractable pain on the night before his death.

    For the treatment of acute moderate to severe pain.
    Intranasal dosage
    Children 6 to 12 years

    1 mg/kg intranasally as a single dose (Max: 50 mg/dose) may be an effective alternative intranasal analgesic for children with moderate to severe pain from limb injury, based on a results from a small study (n = 73 ; age 6 to 11 years) comparing it to intranasal fentanyl (1.5 mcg/kg). In the randomized double-blind study, similar pain reduction was observed with either agent; clinically significant reductions in VAS ratings within 30 minutes were reported in 80% of patients in both groups. However, ketamine administration was associated with a higher rate of adverse events, most of which were mild and well-tolerated (e.g., dizziness, drowsiness).

    For use as an induction agent during rapid-sequence intubation†.
    NOTE: Ketamine is especially useful for induction during rapid-sequence intubation in patients with bronchospasm or hypotension. It may cause laryngospasm, hypersalivation, increased intracranial pressure (ICP), or hypertension. Avoid use in patients with hypertension, increased ICP, or increased intraocular pressure.
    Intravenous dosage
    Adults

    2 mg/kg IV has been recommended. Onset of intubating conditions usually occurs in 1 to 2 minutes and duration is usually 5 to 15 minutes.

    Infants, Children, and Adolescents

    1 to 2 mg/kg/dose IV; titrate repeat doses to desired effect. Onset of intubating conditions usually occurs in 1 to 2 minutes and persists 10 to 30 minutes after a single dose. Ketamine is especially useful for induction during rapid-sequence intubation in patients with bronchospasm or hypotension.

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

    0.5 to 2 mg/kg IV load followed by a continuous infusion of 0.25 to 2 mg/kg/hour (4 to 33 mcg/kg/minute) IV; may repeat bolus dose as needed and titrate infusion by 0.25 to 0.5 mg/kg/hour (4 to 8 mcg/kg/minute) to desired clinical effect. Max: not established; up to 3.6 mg/kg/hour (60 mcg/kg/minute) has been used in mechanically ventilated children with refractory bronchospasm. Although ketamine is not a first-line agent, it 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 status asthmaticus).

    †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

    Because of rapid induction after intravenous injection, the patient should be in a supported position during administration.
    To prevent vomiting and aspiration, administer ketamine on an empty stomach.
    Monitor heart rate, respiratory rate, and blood pressure during IV use.
    Do not mix ketamine and diazepam or barbiturates in the same syringe.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Color of solution may vary from colorless to very slightly yellowish and may darken upon prolonged exposure to light. Darkening does not affect potency, but do not use if a precipitate appears.

    Intravenous Administration

    Direct IV injection
    Dilute the desired dose of the 100 mg/mL concentration with equal parts of sterile water for injection, 0.9% sodium chloride injection, or 5% Dextrose injection. Do not inject the 100 mg/mL concentration of ketamine intravenously without proper dilution.
    Inject intravenously over 60 seconds. More rapid injection can cause respiratory depression or an enhanced pressor response.
     
    Continuous IV infusion
    Dilute 10 mL of the 50 mg/mL injection or 5 mL of the 100 mg/mL injection in 500 mL of 0.9% sodium chloride injection or 5% dextrose injection and mix well. The resultant infusion solution should contain 1 mg/mL of ketamine. If fluid restriction is necessary, 250 mL of diluent may be used to give a concentration of 2 mg/mL.
    Infuse intravenously at a rate of 1—2 mg/minute. Titrate rate based on patient response. The development of tonic-clonic movements during ketamine anesthesia does not necessitate a dosage increase.

    Intramuscular Administration

    No dilution necessary.
    Inject into a large muscle mass. Aspirate prior to injection to avoid injection into a blood vessel.

    Inhalation Administration
    Intranasal Inhalation Administration

    NOTE: Ketamine is not FDA-approved for intranasal administration.
    Use the 50 mg/mL 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 child 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 the drug or to any of its components.
     
    During surgical procedures involving visceral pain pathways, supplement ketamine with an agent that manages visceral pain (e.g., opioid agonist).

    Angina, cardiac disease, coronary artery disease, dehydration, glaucoma, head trauma, heart failure, hypertension, hypovolemia, increased intracranial pressure, increased intraocular pressure, intracranial bleeding, intracranial mass, myocardial infarction, ocular surgery, ocular trauma, stroke

    Ketamine is contraindicated in patients in whom a significant elevation of blood pressure would constitute a serious hazard, such as those patients with hypertension, stroke, head trauma or intracranial mass, or intracranial bleeding. Similarly, ketamine should be used with caution in patients with increased intracranial pressure or increased intraocular pressure (e.g., glaucoma) because these pressures may increase significantly after a single dose of ketamine. Carefully evaluate patients with ocular trauma or space occupying lesions (i.e., brain neoplasms) prior to administration of ketamine. Ketamine should be used cautiously in ocular surgery. Because of the substantial increase in myocardial oxygen consumption, ketamine should be used with caution in patients with hypovolemia, dehydration, or cardiac disease, especially coronary artery disease (e.g., angina, congestive heart failure, and myocardial infarction).

    Driving or operating machinery, females

    Emergence reactions are more common in adolescents and adults 15 to 45 years of age, in females, following short procedures, large doses (more than 2 mg/kg), or after rapid administration (more than 40 mg/minute). These reactions are less frequent when the drug is given by intramuscular administration and if lower doses of ketamine are used in conjunction with diazepam during induction and maintenance of anesthesia. These reactions may be reduced if verbal, tactile, and visual stimulation of the patient is minimized during the recovery period. This does not preclude the monitoring of vital signs. Outpatient surgery patients should not be released until recovery is complete and should be accompanied by a caregiver. Patients should be instructed to avoid driving or operating machinery for at least 24 hours or until they have recovered from the effects of the anesthesia.

    Alcoholism, ethanol intoxication

    Use ketamine with caution in patients with chronic alcoholism or acute ethanol intoxication.

    Intravenous administration

    Ketamine must be administered slowly over at least 60 seconds; more rapid intravenous administration can result in respiratory depression, apnea, and enhanced pressor response.

    Pain

    During surgical procedures involving visceral pain pathways, ketamine should be supplemented with an agent that manages visceral pain (e.g., opiate agonist).

    Psychosis, schizophrenia

    Because ketamine can cause psychosis and exacerbate symptoms of chronic schizophrenics, it should be used with caution in patients with psychiatric disorders, such as schizophrenia or acute psychosis.

    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.

    Thyrotoxicosis

    Use ketamine with caution in patients with a history of thyrotoxicosis because they are at an increased risk of developing tachycardia and hypertension due to ketamine-induced cardiac stimulation.

    Head and neck anesthesia

    Use with caution for head and neck anesthesia during surgical procedures of the pharynx, larynx, or trachea because ketamine increases salivary and tracheal-bronchial secretions and usually does not suppress pharyngeal and laryngeal reflexes. Ketamine should not be used alone in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree. Mechanical stimulation of the pharynx should be avoided, whenever possible, if ketamine is used alone. Give atropine, scopolamine or other drying agent prior to induction of anesthesia.

    Vomiting

    Vomiting has been reported following ketamine administration. Intact laryngeal-pharyngeal reflexes may offer some protection, however the possibility of aspiration must be considered due to the use of supplemental anesthetics and muscle relaxants.

    Labor, obstetric delivery, pregnancy

    Safe use of ketamine during pregnancy, labor, and obstetric delivery has not been established and such use is not recommended. 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

    The elimination half-life of ketamine is short (2.5 hours). The drug should be undetectable in the mother's plasma approximately 11 hours after a dose, and therefore, it is unlikely that breast-feeding would pose a significant risk to the infant at this time.

    Geriatric

    Ketamine 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.

    Children, infants, neonates

    The safety and efficacy of ketamine have not been established in neonates, infants, or children younger than 16 years of age ; however, ketamine has been used off-label for anesthesia induction and analgesia in pediatric patients. Neonates and infants younger than 3 months of age 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 of age and use with caution in those younger than 1 year. 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. 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. 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. 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.

    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.

    ADVERSE REACTIONS

    Severe

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

    Moderate

    hallucinations / Early / 12.0-12.0
    delirium / Early / 12.0-12.0
    hypertension / Early / 10.0
    sinus tachycardia / Rapid / 10.0
    hypotension / Rapid / Incidence not known
    respiratory depression / Rapid / Incidence not known
    nystagmus / Delayed / Incidence not known
    excitability / Early / Incidence not known
    confusion / Early / Incidence not known
    withdrawal / Early / Incidence not known
    tolerance / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    psychosis / Early / Incidence not known
    dysphoria / Early / Incidence not known
    physiological dependence / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    hypertonia / Delayed / Incidence not known
    involuntary movements / Delayed / Incidence not known
    myoclonia / Delayed / Incidence not known
    erythema / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    dysuria / Early / Incidence not known
    cystitis / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known

    Mild

    nightmares / Early / 12.0-12.0
    injection site reaction / Rapid / 1.0-10.0
    hypersalivation / Early / Incidence not known
    bronchial secretions / Early / Incidence not known
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    diplopia / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    insomnia / Early / Incidence not known
    maculopapular rash / Early / 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: (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: (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: (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; Phenylephrine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Acetaminophen; Diphenhydramine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    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; 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: (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: (Major) Inhalational general anesthetics may sensitize the myocardium to the effects of dextroamphetamine. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    Angiotensin II receptor antagonists: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Angiotensin-converting enzyme inhibitors: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Apomorphine: (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: (Major) General anesthetics are known to increase cardiac irritability via myocardial sensitization to catecholamines. These anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine.
    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; 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.
    Atracurium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    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.
    Benzodiazepines: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Benzphetamine: (Major) Inhalational general anesthetics may sensitize the myocardium to the effects of sympathomimetics. Dosages of sympathomimetics should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    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) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding general anesthetics. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Brompheniramine; Guaifenesin; Hydrocodone: (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. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Brompheniramine; Pseudoephedrine: (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-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) 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) 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) 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) 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) 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) 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: (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. (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. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbinoxamine; Phenylephrine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carbinoxamine; Pseudoephedrine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Carisoprodol: (Moderate) General anesthetics potentiate the effect of other CNS depressants including carisoprodol.
    Central-acting adrenergic agents: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Cetirizine: (Minor) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, such as general anesthetics.
    Cetirizine; Pseudoephedrine: (Minor) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, such as general anesthetics.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    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: (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. (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. (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. (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. (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. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Phenylephrine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Chlorpheniramine; Pseudoephedrine: (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.
    Cisatracurium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    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.
    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.
    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.
    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: (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.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    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.
    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. (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: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    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.
    Doxacurium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Doxazosin: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    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: (Major) General anesthetics may sensitize the myocardium to the effects of sympathomimetics, including ephedrine.
    Epinephrine: (Major) General anesthetics are known to increase cardiac irritability via myocardial sensitization to catecholamines. These anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine.
    Eplerenone: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Epoprostenol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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: (Major) Both isoproterenol and general anesthetics sensitize myocardial tissue to the development of potentially life-threatening cardiac arrhythmias. Concomitant use of isoproterenol with general anesthetics can increase the risk of developing this adverse reaction.
    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.
    Levocetirizine: (Minor) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, such as general anesthetics.
    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.
    Liothyronine: (Moderate) Ketamine should be administered cautiously to patients receiving levothyroxine because concomitant use can cause marked hypertension and tachycardia.
    Lisdexamfetamine: (Major) Inhalational general anesthetics may sensitize the myocardium to the effects of lisdexamfetamine. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    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.
    Loxapine: (Moderate) Loxapine can potentiate the actions of other CNS depressants such as general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as general anesthetics. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Moderate) General anesthetics may produce additive CNS depression when used in patients taking maprotiline.
    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: (Major) General anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the myocardial conduction system to the action of sympathomimetics. Use extreme caution with the concomitant use of a general anesthetic and methamphetamine, as serious cardiac arrhythmias such as ventricular tachycardia or fibrillation may result.
    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.
    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.
    Mivacurium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Monoamine oxidase inhibitors: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Morphine: (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: (Moderate) Concomitant use of nabilone with other CNS depressants like general anesthetics can potentiate the effects of nabilone on respiratory depression.
    Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with other hypotensive drugs, including general anesthetics.
    Neuromuscular blockers: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Norepinephrine: (Major) Norepinephrine interacts with general anesthetics because the anesthetics increase cardiac irritability, which can lead to arrhythmias.
    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.
    Pancuronium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    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.
    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.
    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: (Moderate) Concomitant administration of pregabalin with CNS depressant drugs, including general anesthetics, can potentiate the CNS effects of either agent.
    Prilocaine: (Major) Local anesthetics may result in QT prolongation and should be used with caution with other agents that can prolong the QT interval including halogenated anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, and sevoflurane). Also, If epinephrine is added to prilocaine, do not use the mixture in a patient during or following treatment with general anesthetics. Concurrent use has been associated with the development of cardiac arrhythmias, and should be avoided, if possible.
    Prilocaine; Epinephrine: (Major) General anesthetics are known to increase cardiac irritability via myocardial sensitization to catecholamines. These anesthetics can produce ventricular arrhythmias and/or hypertension when used concomitantly with epinephrine. (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.
    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.
    Rapacuronium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Rasagiline: (Moderate) Patients receiving drugs that possess MAOI properties, such as rasagiline, may have an increased risk of hypotension after administration of general anesthetics, although specific studies are not available. Combined hypotensive effects are also possible with the combined use of MAOIs and spinal anesthetics.
    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: (Major) The cardiovascular effects of sympathomimetics, especially hypotension and cardiac arrhythmias, can be potentiated by concomitant use of potent general anesthetics.
    Rocuronium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    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.
    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.
    Sotalol: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension.
    St. John's Wort, Hypericum perforatum: (Severe) St. John's wort, Hypericum perforatum, may intensify or prolong the effects of general anesthetics; profound hypotension has also been reported. The American Society of Anesthesiologists has recommended that patients stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions. In one report, the authors recommend that patients should discontinue taking St. John's Wort at least 5 days prior to anesthesia.
    Streptomycin: (Moderate) Patients receiving general anesthetics should be observed for exaggerated effects if they are receiving streptomycin.
    Succinylcholine: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    Sufentanil: (Major) 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: (Moderate) Theophylline used concurrently with inhaled general anesthetics may increase the risk of cardiac arrhythmias. When ketamine and theophylline are given concurrently a clinically significant reduction in the seizure threshold is observed. (Moderate) When ketamine and theophylline are given concurrently a clinically significant reduction in the seizure threshold is observed. This combination may also increase the risk of cardiac arrhythmias.
    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.
    Tubocurarine: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    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.
    Vecuronium: (Major) Increased neuromuscular blockade may occur if general anesthetics are used with nondepolarizing neuromuscular blockers.
    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

    The elimination half-life of ketamine is short (2.5 hours). The drug should be undetectable in the mother's plasma approximately 11 hours after a dose, and therefore, it is unlikely that breast-feeding would pose a significant risk to the infant at this time.

    MECHANISM OF ACTION

    Ketamine induces sedation, immobility, amnesia, and marked analgesia. Ketamine-induced analgesia is obtained without the induction of deep levels of anesthesia. Increasing doses of ketamine result in anesthesia. The state of unconsciousness it produces is trancelike (eyes may remain open until deep anesthesia is obtained) and cataleptic in nature and has been referred to as dissociative anesthesia due to the strong feeling of dissociation from the environment that is experienced by the subject receiving the drug. Ketamine appears to selectively interrupt association pathways of the brain before producing somatesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding more ancient cerebral centers and pathways. Unlike barbiturates that act on the reticular activating system in the brainstem, ketamine acts on receptors in the cortex and limbic system. Ketamine non-competitively blocks N-methyl-D-aspartate (NMDA) receptors. The activity on NMDA receptors may be responsible for the analgesic as well as psychiatric (psychosis) effects of ketamine. Ketamine has a sympathomimetic activity resulting in tachycardia, hypertension, increased myocardial and cerebral oxygen consumption, increased cerebral blood flow, and increased intracranial and intraocular pressure. Ketamine is a potent bronchodilator and can be used to treat refractory bronchospasm. Clinical effects observed following ketamine administration include increased blood pressure, increased muscle tone (may resemble catatonia), opening of eyes (usually accompanied by nystagmus), increased myocardial oxygen consumption, and minimal respiratory depression. Ketamine has no effects on pharyngeal or laryngeal reflexes, thus, the patient's airway remains intact.

    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. Volume of distribution 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 readily crosses the placenta and is rapidly distributed into highly perfused tissues (e.g., heart, lung, and brain), followed by muscle and peripheral tissues, and then fat. The distribution phase 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 posesses 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 (37 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. The elimination half-life of ketamine is about 2 to 3 hours.
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP2C9, CYP2B6
    CYP3A4 is the principle 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 +/- 10 ng/mL occurring at 30 +/- 5 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 one-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. The analgesic effects of ketamine last from 20 to 45 minutes.

    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 +/- 50 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 +/- 356 ng/mL was attained in approximately 45 minutes. Other reported parameters include: Vd = 18 +/- 9 L/kg; AUC = 111.2 +/- 85.5 mg/mL x minute; clearance = 121.5 +/- 74.8 mL/kg/minute; half-life = 100 +/- 28 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 +/- 266 ng/mL and 2,104 +/- 965 ng/mL, respectively) was attained in approximately 20 minutes. Pharmacokinetic parameters in the 3 mg/kg group were as follows: Vd = 8.5 +/- 2.7 L/kg; AUC = 76.4 +/- 28.2 mg/mL x minute; clearance = 49.9 +/- 20.2 mL/kg/minute; half-life = 123 +/- 35 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.