Ketamine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Ketalar: 10 mg/mL (20 mL); 50 mg/mL (10 mL); 100 mg/mL (5 mL)

Generic: 10 mg/mL (20 mL); 50 mg/mL (10 mL); 100 mg/mL (5 mL, 10 mL)

Pharmacology

Mechanism of Action

Produces a cataleptic-like state in which the patient is dissociated from the surrounding environment by direct action on the cortex and limbic system. Ketamine is a noncompetitive NMDA receptor antagonist that blocks glutamate. Low (subanesthetic) doses produce analgesia, and modulate central sensitization, hyperalgesia and opioid tolerance. Reduces polysynaptic spinal reflexes.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 2.4 L/kg (Wagner 1997)

Metabolism

Hepatic via N-dealkylation (metabolite I [norketamine]), hydroxylation of the cyclohexone ring (metabolites III and IV), conjugation with glucuronic acid and dehydration of the hydroxylated metabolites to form the cyclohexene derivative (metabolite II); metabolite I (norketamine) is 33% as potent as parent compound. When administered orally, norketamine concentrations are higher compared to other routes of administration due to extensive first-pass metabolism in the liver (Blonk 2010; Soto 2012).

Excretion

Urine (91%); feces (3%) (Ghoneim 1977)

Onset of Action

IV: Anesthetic effect: Within 30 seconds

IM: Anesthetic effect: 3 to 4 minutes; Analgesia: Within 10 to 15 minutes

Intranasal: Analgesic effect: Within 10 minutes (Carr 2004); Sedation: Children 2 to 6 years: 5 to 8 minutes (Bahetwar 2011)

Oral: Analgesia: Within 30 minutes; Sedation: Children 2 to 8 years (Turhanoglu 2003):

4 mg/kg/dose: 12.9 ± 1.9 minutes

6 mg/kg/dose: 10.4 ± 2.9 minutes

8 mg/kg/dose: 9.5 ± 1.9 minutes

Time to Peak

Plasma:

IM: 5 to 30 minutes (Clements 1982)

Intranasal: 10 to 14 minutes (Huge 2010); Children 2 to 9 years: ~20 minutes (Malinovsky 1996)

Oral: ~30 minutes (Soto 2012)

Rectal: Children 2 to 9 years: ~45 minutes (Malinovsky 1996)

Duration of Action

IV: Anesthetic effect: 5 to 10 minutes; Recovery: 1 to 2 hours

IM: Anesthetic effect: 12 to 25 minutes; Analgesia: 15 to 30 minutes; Recovery: 3 to 4 hours

Intranasal: Analgesic effect: Up to 60 minutes (Carr 2004); Recovery: Children 2 to 6 years: 34 to 46 minutes (Bahetwar 2011)

Half-Life Elimination

Alpha: 10 to 15 minutes; Beta: 2.5 hours

Protein Binding

27% (Brunton 2006)

Use: Labeled Indications

Anesthesia: Induction and maintenance of general anesthesia

Use: Off Label

Agitation, severecyes

Data from a limited number of patients in open-label, prospective clinical trials suggest that ketamine may be beneficial for the treatment of severe agitation and violent behavior Cole 2016, Isbister 2016, Riddell 2017.

Based on the American College of Emergency Physicians clinical policy for critical issues in the diagnosis and management of the adult psychiatric patient in the emergency department, ketamine is an option for immediate sedation of severely agitated patients in the emergency department who may become violent or aggressive and have not responded to benzodiazepines and/or antipsychotics, particularly when immediate control is required for patient and/or staff safety.

Analgesia (subanesthetic dosing)b

A number of clinical trials have evaluated IV and intranasal ketamine for the treatment of various pain syndromes (eg, central and peripheral neuropathic pain, postherpetic neuralgia, peripheral nerve injury, fibromyalgia, cancer pain, severe pain due to acute musculoskeletal injury) demonstrating effectiveness in reducing pain Carr 2004, Kosharskyy 2013, Yeaman 2014. Moreover, oral ketamine has been used in a number of descriptive studies (mostly case reports and case series) and a small number of comparative studies with low quality of methodological design suggesting some benefit although adverse effects may limit use. Although the use of oral ketamine is not currently routine, it may be beneficial for some patients with intractable pain Blonk 2010. Additional trials may be necessary to further define the role of ketamine in the treatment of acute and chronic pain syndromes.

Depressive episode associated with major depressive disorder (unipolar), treatment refractoryb

In 3 meta-analyses of double-blind, randomized, controlled trials evaluating the role of ketamine for depressive disorders, the use of a single infusion of ketamine has been shown to produce a rapid antidepressant response that lasts approximately seven days. This effect has been seen when ketamine is used as monotherapy and as an antidepressant augmentation strategy Fond 2014, McGirr 2015, Newport 2015. Repeated infusions have been assessed in a limited number of patients in open-label and blinded studies with positive results; however, relapse rates were high within the 2 to 3 weeks following treatment in the open-label studies aan het Rot 2010, Murrough 2013, Rasmussen 2013, Shiroma 2014, Singh 2016.

Despite positive studies for depressive episodes, there are currently no guidelines recommending the use of ketamine in major depressive disorder. Due to a lack of long-term data in patients with depressive episodes without psychotic features associated with major depressive disorder, the American Psychiatric Association's Council of Research Task Force on Novel Biomarkers and Treatments recommends balancing the risk of each infusion with the risk of long-term exposure, including neurotoxicity, cystitis, and abuse potential Sanacora 2017.

Procedural sedation/analgesiayes

Based on the American College of Emergency Physicians (ACEP) clinical policy for procedural sedation and analgesia in the emergency department, ketamine may be safely administered to patients for procedural sedation and analgesia. More specifically, the use of ketamine has been recommended for short, painful procedures, especially those requiring immobilization (eg, facial laceration, burn debridement, etc.) and examinations judged likely to produce excessive emotional disturbance (eg, pediatric sexual assault examination) ACEP [Green 2011]. According to ACEP, the combination of ketamine and propofol may also be safely administered; however, to date, clinical trials have not shown this combination to be more efficacious than either agent alone ACEP [Green 2011], Andolfatto 2012, David 2011. According to the American Society of Critical Care Medicine guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit (ICU), ketamine may also be used as a sedative and an analgesic (as an adjunct to an opioid analgesic for non-neuropathic pain) for critically ill patients.

Status epilepticus (refractory)c

Data from a retrospective review of a limited number of patients (including children) from academic medical centers in North America and Europe and multiple case reports suggest that ketamine may be beneficial for the treatment of refractory status epilepticus Gaspard 2013, Kramer 2012. However, the dosage range varies considerably and an optimal dosage has not been established. Additional data is necessary to further define the role of ketamine in this condition. Since there is limited data on the safety and efficacy of ketamine in this setting, the Neurocritical Care Society recommends reservation of ketamine for patients who do not respond to more frequently recommended antiepileptic drug treatment.

Contraindications

Hypersensitivity to ketamine or any component of the formulation; conditions in which an increase in blood pressure would be hazardous

Note: When used for procedural sedation and analgesia in the emergency department, the following additional absolute contraindications according to the American College of Emergency Physicians have been asserted (ACEP [Green 2011]): Infants <3 months of age; known or suspected schizophrenia (even if currently stable or controlled with medications)

Canadian labeling: Additional contraindications (not in US labeling): History of cerebrovascular accident; severe cardiac decompensation; surgery of the pharynx, larynx, or bronchial tree unless adequate muscle relaxants are used

Dosage and Administration

Dosing: Adult

May administer atropine, scopolamine, or another drying agent prior to induction and at appropriate intervals to decrease hypersalivation. Note: Titrate dose for desired effect.

Agitation, severe (alternative agent) (off-label use): Note: For patients nonresponsive to antipsychotics and/or benzodiazepine (ACEP [Nazarian 2017]). Based on limited data:

IM: 4 to 6 mg/kg once (ACEP [Nazarian 2017]; Cole 2016; Isbister 2016)

IV: Some experts suggest 1 to 2 mg/kg once (Moore 2018; Riddell 2017).

Anesthesia:

Induction of anesthesia:

Note: Lower doses may be used if adjuvant drugs (eg, midazolam) are administered (Miller 2010).

IM: 4 to 10 mg/kg (Green 1990; Miller 2010; White 1982)

IV: 0.5 to 2 mg/kg (Miller 2010; White 1982)

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice.

IM: 6.5 to 13 mg/kg

IV: 1 to 4.5 mg/kg

Maintenance of anesthesia: May administer supplemental doses of one-half to the full induction dose or a continuous infusion of 0.1 to 0.5 mg/minute (per manufacturer). Note: To maintain an adequate concentration of ketamine for maintenance of anesthesia, 1 to 2 mg/minute has been recommended (White 1982); doses in the range of 15 to 90 mcg/kg/minute (~1 to 6 mg/minute in a 70-kg patient) have also been suggested (Miller 2010). Concurrent use of nitrous oxide reduces ketamine requirements. Recent laboratory/clinical studies support the use of low-dose ketamine to improve postoperative analgesia/outcome (Adam 2005; Menigaux 2000).

Analgesia (subanesthetic dosing) (off-label use):

Acute pain: Intranasal (off-label route): 0.5 to 1 mg/kg; may repeat in 10 to 15 minutes with 0.25 to 0.5 mg/kg if necessary (Andolfatto 2013; Corrigan 2015; Yeaman 2014)

Chronic pain:

Intranasal (off-label route): 10 mg every 90 seconds as needed until a maximum total dose of 50 mg is reached or pain relieved (Carr 2004).

IV: Note: Various dosing protocols have been utilized. One suggested inpatient protocol is presented. Consider the concomitant use of a benzodiazepine (eg, lorazepam) to prevent or reduce psychotomimetic effects and glycopyrrolate for excessive salivation or lacrimation.

Initial: IV infusion: 0.5 mg/kg over 6 hours. If pain improved by 50% or more after completion of initial dose, then continue infusion at 1.5 mg/kg/24 hours for 48 hours. If pain not improved after completion of initial dose, increase to 2 mg/kg over 12 hours. If pain recurs after initial improvement, titrate upwards by 50% to 100% every 24 hours as needed. Discontinue infusion if pulse >110 bpm, SBP increases >25% of baseline, sustained respiratory rate <7, agitation or severe psychotomimetic effects (Okon 2007).

Oral (off-label route): Initial: 0.5 mg/kg as a single dose to evaluate effect on pain and duration of effect; may increase dose in increments of 0.5 mg/kg as appropriate. For a continuous analgesic effect, may administer 3 to 4 times daily (Blonk 2010).

Acute on chronic episodes of neuropathic pain, severe: Continuous IV or SubQ (off-label route) infusion: 2.3 to 6.7 mcg/kg/minute (equivalent to 0.14 to 0.4 mg/kg/hour) (Hocking 2003).

Postoperative opioid sparing:

IM: 2 to 4 mg/kg (Miller 2010; White 1982); may follow with a continuous infusion if necessary.

IV: 0.2 to 0.8 mg/kg bolus (Miller 2010; Remérand 2009; SCCM [Devlin 2018]; White 1982; Zakine 2008); a maximum bolus dose of 50 mg was used in one study (Remérand 2009). May follow bolus dose with a continuous infusion if necessary.

Continuous IV infusion: 1 to 2 mcg/kg/minute (equivalent to 0.06 to 0.12 mg/kg/hour) (Remérand 2009; SCCM [Devlin 2018]; Zakine 2008)

Depressive episode associated with major depressive disorder (unipolar), treatment refractory (off-label use): IV: 0.5 mg/kg twice weekly as an IV infusion; treatment up to 6 weeks has been studied (Sanacora 2017; Singh 2016)

Procedural sedation/analgesia (off-label use):

IM: The IV route is preferred; however if IV route unavailable, may administer 4 to 5 mg/kg IM as a single dose; may give a repeat dose (range: 2 to 5 mg/kg) if sedation inadequate after 5 to 10 minutes or if additional doses are required. May consider prophylactic use of a benzodiazepine (eg, midazolam) before ketamine administration to reduce the risk of emergence reactions (ACEP [Green 2011]).

IV: 1 to 2 mg/kg (usual adult dose: 100 mg) over 1 to 2 minutes; may consider prophylactic use of a benzodiazepine (eg, midazolam) before ketamine administration to reduce the risk of emergence reactions (ACEP [Green 2011]; Chudnofsky 2000; Green 2000). If initial sedation inadequate or repeated doses are necessary to accomplish a longer procedure, may administer incremental doses of 0.5 to 1 mg/kg every 5 to 15 minutes as needed (ACEP [Green 2011]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Titrate dose to effect. May be used in combination with anticholinergic agents to decrease hypersalivation. Note: The American College of Emergency Physicians considers the use of ketamine in infants <3 months of age to be an absolute contraindication, due to the higher risk of airway complications (ACEP [Green 2011]).

Anesthesia:

Pre-anesthetic sedation: Limited data available:

Intranasal:

Infants ≥6 months: 3 mg/kg/dose (half dose per nostril) administered at least 15 minutes prior to mask induction (Diaz 1997; Lin 1990).

Children <2 years: 3 to 5 mg/kg/dose (half dose per nostril) administered at least 15 minutes prior to mask induction (Diaz 1997; Gautam 2007; Lin 1990).

Children 2 to 7 years: 3 to 6 mg/kg/dose (half dose per nostril) administered 15 to 40 minutes prior to induction (Diaz 1997; Gautam 2007; Lin 1990; Roelofse 2004; Weksler 1993).

Oral: Children ≤8 years: 6 to 8 mg/kg/dose 20 to 30 minutes prior to surgery. Dosing based on two prospective, randomized, double-blind, placebo-controlled, dose finding trials. The larger trial compared 4 mg/kg, 6 mg/kg, and 8 mg/kg (n=20 in each group; age range: 2 to 8 years) and found that patients who received 8 mg/kg were significantly more calm, but also had slightly longer recovery times. Sedation was effective within 10 minutes of administration in 80% and 45% of the patients in the 8 mg/kg and 6 mg/kg, groups respectively, but was not effective in the 4 mg/kg group (Turhanoğlu 2003). The other study compared 3 mg/kg and 6 mg/kg (n=15 in each group, age range: 1 to 7 years) and found that patients who received 6 mg/kg had satisfactory sedation without prolonged recovery times, but the 3 mg/kg dose did not provide uniform sedation nor offer a significant improvement in premedicated emotional state compared to placebo (Gutstein 1992).

Rectal: Administer 15 to 45 minutes prior to surgery as a single agent; when used in combination with other sedatives, lower doses should be considered. Efficacy was reported in trials comparing rectal ketamine to rectal doses of other agents (fentanyl/droperidol, midazolam) (Lin 1990; Tanaka 2000; Van der Bijl 1991; Wang 2010; Zanette 2010). Reported effective range:

Infants 2 to 6 months: 8 mg/kg/dose.

Infants ≥7 months and Children ≤9 years: 8 to 10 mg/kg/dose.

Note: Although lower doses of 4 to 7 mg/kg/dose have been reported, they were less effective. In some patients, the 10 mg/kg/dose was associated with prolonged postoperative sedation. When used in combination with midazolam, a lower rectal dose of 3 mg/kg/dose has been effective (Beebe 1992).

Induction of anesthesia:

Infants ≥3 months, Children, and Adolescents <16 years: Limited data available:

IM: 5 to 10 mg/kg has been reported and suggested by experts (Coté 2013; Lin 2005; Sungur Ulke 2008).

IV: 1 to 3 mg/kg has been reported and suggested by experts (Coté 2013; Lin 2005).

Adolescents ≥16 years:

IM: 6.5 to 13 mg/kg.

IV: 1 to 4.5 mg/kg.

Maintenance of anesthesia: Adolescents ≥16 years: May administer supplemental doses of one-half to the full induction dose as needed.

Endotracheal intubation: Limited data available: Infants, Children, and Adolescents: IV: 1 to 2 mg/kg as part of rapid sequence sedation (AAP [Hegenbarth 2008]; Ballow 2012; Fuhrman 2011).

Sedation/analgesia, procedural: Limited data available: Infants, Children, and Adolescents: Note: Due to risk of airway obstruction, laryngospasm, and apnea, ACEP only recommends use in patients ≥3 months of age (ACEP [Green 2011]).

Ketamine without propofol:

IM: 4 to 5 mg/kg as a single dose; may give a repeat dose (range: 2 to 5 mg/kg) if sedation inadequate after 5 to 10 minutes or if additional doses are required (ACEP [Green 2011]). Some have recommended smaller doses (2 to 2.5 mg/kg) for minor procedures (eg, wound suture with local anesthetic) (McGlone 2004).

IV: 1 to 2 mg/kg over 30 to 60 seconds. If initial sedation inadequate or repeated doses are necessary to accomplish a longer procedure, may administer additional doses of 0.5 to 1 mg/kg every 5 to 15 minutes as needed (ACEP [Green 2011]; Asadi 2013; Berkenbosch 2004, Koruk 2010).

Intranasal: Infants ≥3 months and Children: 3 to 6 mg/kg (half dose per nostril). Studies have primarily used this route in the dental or radiology setting. In the largest, randomized, placebo-controlled, double-blind trial, intranasal ketamine was compared to intranasal dexmedetomidine for use prior to propofol for MRI sedation. The ketamine group (n=52, mean age: 4.9 ± 2.4 years) received 5 mg/kg intranasally 30 minutes prior to IV cannulation. Both treatment groups required significantly less propofol during the MRI than the placebo group and had high rates of satisfaction from anesthesiologists and parents (Gyanesh 2014). Another study in the radiology setting was a prospective, observational trial of sedation prior to CT scan. Patients (n=30, mean age: 2.15 years; range: 3 months to 12 years) received intranasal ketamine 5 mg/kg in combination with midazolam. For patients who remained uncooperative after 20 minutes, an IV dose of ketamine was administered. Intranasal therapy alone was effective for 83% of patients (Louon 1994). In the dental setting, three randomized, blinded, comparative studies have found intranasal ketamine (3 to 6 mg/kg) as monotherapy in children (ages 17 months to 11 years) to be either as effective or more effective than intranasal midazolam (Abrams 1993, Bahetwar 2011, Surendar 2014). In all of these studies, intranasal ketamine was well tolerated with no significant adverse effects.

Oral: Children and Adolescents: 5 mg/kg with oral midazolam given 30 to 45 minutes before the procedure. Dosing based on two prospective, randomized, blinded studies involving patients aged 1 to 10 years with either laceration repair or burn wound care (Barkan 2014; Norambuena 2013). A lower dose (3 mg/kg) in addition to midazolam was effective in a study comparing different routes (IV, oral, rectal) of ketamine plus midazolam for invasive procedures in oncology patients. The oral group included 24 patients (mean age: 3.9 ± 1.3 years); incidence of optimal sedation was similar between groups (75% for the oral group) (Ozdemir 2004). Note: A higher dose (10 mg/kg) has been used successfully as monotherapy prior to procedures in pediatric oncology patients (n=35, age: 14 months to 17 years; mean age: 6.5 years) (Tobias 1992).

Rectal: Children 1 to 8 years: 1.5 to 3 mg/kg with midazolam as a single dose 20 minutes prior to painful procedure. Dosing based on two studies. The first was completed in children with burns requiring dressing changes (n=47 procedures in 30 patients, mean age: 1.9 years, range: 10 months to 7.3 years). Patients received 0.75 mg/kg of the S(+) isomer (equivalent to 1.5 mg/kg of racemic ketamine) along with rectal midazolam 20 minutes prior to dressing changes; 94% of the procedures were reported to have good or excellent analgesia (Heinrich 2004). The second study compared different routes (IV, oral, rectal) of ketamine plus midazolam for invasive procedures in oncology patients. The rectal group included 24 patients (mean age: 3.7 ± 1.1 years) who received 3 mg/kg of ketamine in addition to midazolam. Incidence of optimal sedation was similar between groups (79% for the rectal group) (Ozdemir 2004). In both of these studies, rectal ketamine was well tolerated.

Ketamine with propofol ("ketofol"): Infants ≥3 months, Children, and Adolescents: IV: 0.5 to 0.75 mg/kg of each agent. This combination has been used to decrease the dose of each agent required. It has been proposed that these lower doses help decrease adverse effects, ketamine may decrease the propofol-related hypotension and respiratory depression, and propofol may decrease the ketamine associated nausea and emergence reactions (ACEP [Godwin 2014]; Alletag 2012; Shah 2011; Willman 2007).

Sedation/analgesia, critically ill patients: Very limited data available: Infants ≥5 months, Children, and Adolescents: Initial dose: IV: 0.5 to 2 mg/kg, then continuous IV infusion: 5 to 20 mcg/kg/minute (0.3 to 1.2 mg/kg/hour); start at lower dosage listed and titrate to effect (Denmark 2006; Rock 1986; Tobias 1990; White 1982); doses as high as 60 mcg/kg/minute (3.6 mg/kg/hour) have been reported in patients with refractory bronchospasm (Youssef-Ahmed 1996).

Reconstitution

The 50 mg/mL and 100 mg/mL vials may be further diluted in D5W or NS to prepare a maintenance infusion with a final concentration of 1 mg/mL (or 2 mg/mL in patients with fluid restrictions); mix well. The 10 mg/mL vials are not recommended to be further diluted. Do not mix with barbiturates or diazepam (precipitation may occur). Note: The 100 mg/mL concentration should not be administered IV unless properly diluted with an equal volume of SWFI, NS, or D5W.

Administration

Intranasal (using parenteral dosage form): Use the 50 or 100 mg/mL solution; may administer undiluted or further diluted in NS to a concentration of 20 mg/mL (Bahetwar 2011; Louon 1994; Surendar 2014; Yeaman 2014). Administer half dose in each nostril using a needleless syringe or mucosal atomizer device. Note: Intranasal use for adults for procedural sedation is not recommended since volume limits an adequate dose (Rech 2017).

Oral: Mix the appropriate dose (using the injectable solution) in cola or other beverage; administer immediately after preparation (Gutstein 1992).

IM: Inject deep IM into large muscle mass.

IV: According to the manufacturer, administer bolus/induction doses over 1 minute or at a rate of 0.5 mg/kg/minute; more rapid administration may result in respiratory depression and enhanced pressor response. Some experts suggest administration over 2 to 3 minutes (Miller 2010). When used for treatment refractory unipolar depression, administer over 40 minutes (Sanacora 2017). May also be administered as a continuous infusion.

Rectal (using parenteral dosage form): May use the 50 mg/mL solution undiluted or use the 100 mg/mL solution and further dilute prior to administration (Tanaka 2000; Van der Bijl 1991)

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2C9 Inducers (Moderate): May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Memantine: NMDA Receptor Antagonists may enhance the adverse/toxic effect of Memantine. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiopental: Ketamine may enhance the adverse/toxic effect of Thiopental. Monitor therapy

Thiotepa: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

May interfere with urine detection of phencyclidine (false-positive).

Adverse Reactions

>10%: Central nervous system: Prolonged emergence from anesthesia (12%; includes confusion, delirium, dreamlike state, excitement, hallucinations, irrational behavior, vivid imagery)

Frequency not defined:

Cardiovascular: Bradycardia, cardiac arrhythmia, hypotension, increased blood pressure, increased pulse

Central nervous system: Drug dependence, hypertonia (tonic-clonic movements sometimes resembling seizures), increased cerebrospinal fluid pressure

Dermatologic: Erythema, morbilliform rash, rash at injection site

Endocrine & metabolic: Central diabetes insipidus (Hatab 2014)

Gastrointestinal: Anorexia, nausea, sialorrhea (Hatab 2014), vomiting

Genitourinary: Bladder dysfunction (reduced capacity), cystitis (including cystitis noninfective, cystitis interstitial, cystitis ulcerative, cystitis erosive, cystitis hemorrhagic), dysuria, hematuria, urinary frequency, urinary incontinence, urinary urgency

Hypersensitivity: Anaphylaxis

Local: Pain at injection site

Neuromuscular & skeletal: Laryngospasm

Ophthalmic: Diplopia, increased intraocular pressure, nystagmus

Renal: Hydronephrosis

Respiratory: Airway obstruction, apnea, respiratory depression

Warnings/Precautions

Concerns related to adverse effects:

• Airway complications: When used for procedural sedation for major procedures involving the posterior pharynx (eg, endoscopy) or when used for patients with an active pulmonary infection or disease (including upper respiratory disease or asthma), the use of ketamine increases the risk of laryngospasm. Patients with a history of airway instability, tracheal surgery, or tracheal stenosis may be at a higher risk of airway complications. The American College of Emergency Physicians considers these situations relative contraindications for the use of ketamine (ACEP [Green 2011]). The manufacturer recommends against the use of ketamine 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.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving). When used for outpatient surgery, the patient should be accompanied by a responsible adult. Driving, operating hazardous machinery, or engaging in hazardous activities should not be undertaken for ≥24 hours after anesthesia, according to the manufacturer.
• Dependence: May cause dependence (withdrawal symptoms on discontinuation) and tolerance with prolonged use. A withdrawal syndrome with psychotic features has been described following discontinuation of long-term use.
• Emergence reactions: Postanesthetic emergence reactions, which can manifest as vivid dreams, hallucinations, and/or frank delirium, occur; these reactions are less common in patients <16 years of age and >65 years and when given IM (White 1982). Emergence reactions, confusion, or irrational behavior may occur up to 24 hours postoperatively and may be reduced by pretreatment with a benzodiazepine, use of ketamine at the lower end of the dosing range, and minimizing verbal and tactile stimulation of the patient during the recovery period. Use with caution in patients with schizophrenia; may exacerbate psychotic symptoms (Lahti 1995; Malhotra 1997). When used for procedural sedation and analgesia, the American College of Emergency Physicians considers the use of ketamine in patients with known or suspected schizophrenia (even if currently stable or controlled with medications) an absolute contraindication (ACEP [Green 2011]).
• Genitourinary symptoms: Lower urinary tract and bladder symptoms, including dysuria, increased frequency/urgency, urge incontinence, and hematuria have been reported in patients with a history of chronic ketamine use or abuse and may be related to ketamine treatment, not the underlying condition. Additional findings from diagnostic studies have included cystitis, hydronephrosis, and reduced bladder capacity. Consider discontinuation of ketamine for continued genitourinary pain in the setting of other genitourinary symptoms.
• Increased intracranial pressure: Some consider the use of ketamine in patients with CNS masses, CNS abnormalities, or hydrocephalus a relative contraindication due to multiple reports that ketamine may increase intracranial pressure in these patients (ACEP [Green 2011]). However, assuming adequate ventilation, some evidence suggests that ketamine has minimal effects on intracranial pressure and may even improve cerebral perfusion and reduce intracranial pressure (Albanese 1997; Bowles 2012; Zeiler 2014).
• Increased ocular pressure: Use with caution in patients with increased intraocular pressure (IOP). Some recommend avoiding use in patients with an open eye injury or other ophthalmologic disorder where an increase in IOP would prove to be detrimental; however, the effects of ketamine on IOP is mixed with some evidence demonstrating no clinically significant effect on IOP (ACEP [Green 2011]; Cunningham 1986; Drayna 2012; Miller 2010; Nagdeve 2006).
• Porphyria: The American College of Emergency Physicians considers the use of ketamine in patients with porphyria a relative contraindication due to enhanced sympathomimetic effect produced by ketamine (ACEP [Green 2011]).
• Respiratory depression: Rapid IV administration or overdose may cause respiratory depression or apnea. Resuscitative equipment should be available during use.
• Thyroid disorders: The American College of Emergency Physicians considers the use of ketamine in patients with a thyroid disorder or receiving a thyroid medication a relative contraindication due to enhanced sympathomimetic effect produced by ketamine (ACEP [Green 2011]).

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with coronary artery disease, catecholamine depletion, hypertension, and tachycardia. Cardiac function should be continuously monitored in patients with increased blood pressure or cardiac decompensation. Ketamine increases blood pressure, heart rate, and cardiac output thereby increasing myocardial oxygen demand. The mechanism by which ketamine causes a sympathetic surge to stimulate the cardiovascular system has yet to be elucidated. The use of concurrent benzodiazepine, inhaled anesthetics, and propofol or administration of ketamine as a continuous infusion may reduce these cardiovascular effects (Miller 2010). The American College of Emergency Physicians recommends avoidance in patients who are already hypertensive and in older adults with risk factors for coronary artery disease (ACEP [Green 2011]). In a scientific statement from the American Heart Association, ketamine has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).
• Cerebrospinal fluid (CSF) pressure elevation: Use with caution in patients with CSF pressure elevation; an increase in CSF pressure may be associated with use.
• Ethanol use: Use with caution in the chronic alcoholic or acutely alcohol-intoxicated.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric neurotoxicity: In pediatric and neonatal patients <3 years and patients in third trimester of pregnancy (ie, times of rapid brain growth and synaptogenesis), the repeated or lengthy exposure to sedatives or anesthetics during surgery/procedures may have detrimental effects on child or fetal brain development and may contribute to various cognitive and behavioral problems. Epidemiological studies in humans have reported various cognitive and behavioral problems, including neurodevelopmental delay (and related diagnoses), learning disabilities, and ADHD. Human clinical data suggest that single, relatively short exposures are not likely to have similar negative effects. No specific anesthetic/sedative has been found to be safer. For elective procedures, risk versus benefits should be evaluated and discussed with parents/caregivers/patients; critical surgeries should not be delayed (FDA 2016).

Other warnings/precautions:

• Experienced personnel: Use requires careful patient monitoring, should only be used by experienced personnel who are not actively engaged in the procedure or surgery. If used in a nonintubated and/or nonmechanically ventilated patient, qualified personnel and appropriate equipment for rapid institution of respiratory and/or cardiovascular support must be immediately available. Use to induce moderate (conscious) sedation in patients warrants monitoring equivalent to that seen with deep anesthesia. Consult local regulations and individual institutional policies and procedures.

Monitoring Parameters

Heart rate, blood pressure, respiratory rate, transcutaneous O₂ saturation, emergence reactions; cardiac function should be continuously monitored in patients with increased blood pressure or cardiac decompensation

Pregnancy

Pregnancy Considerations

Ketamine crosses the placenta (Ellingson 1977; Little 1972).

Ketamine produces dose dependent increases in uterine contractions; effects may vary by trimester. The plasma clearance of ketamine is reduced during pregnancy. Dose related neonatal depression and decreased Apgar scores have been reported with large doses administered at delivery (Little 1972; Neuman 2013; White 1982).

Based on animal data, repeated or prolonged use of general anesthetic and sedation medications that block N-methyl-D-aspartate (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity may affect brain development. Evaluate benefits and potential risks of fetal exposure to ketamine when duration of surgery is expected to be >3 hours (Olutoye 2018).

Although obstetric use is not recommended by the manufacturer, ketamine has been evaluated for use during cesarean and vaginal delivery (ACOG 209 2019; Akamatsu 1974; Galbert 1973). Ketamine may be considered as an alternative induction agent in females requiring general anesthesia for cesarean delivery who are hemodynamically unstable (Devroe 2015). Use of ketamine as an adjunctive analgesic in cesarean section has also been evaluated; however, use for this purpose may require additional studies (Carvalho 2017; Heesen 2015). When sedation and analgesia is needed for other procedures during pregnancy, low doses of ketamine may be used, but other agents are preferred (Neuman 2013; Schwenk 2018). Use of ketamine infusion for the treatment of refractory status epilepticus in a pregnant patient has been noted in a case report (Talahma 2018).

The ACOG recommends that pregnant women should not be denied medically necessary surgery, regardless of trimester. If the procedure is elective, it should be delayed until after delivery (ACOG 775 2019).

Patient Education

What is this drug used for?

• It is used to cause sleep during a procedure.
• It is used to put you to sleep for surgery.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Fatigue
• Lack of appetite
• Vomiting
• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe dizziness
• Passing out
• Difficulty breathing
• Slow breathing
• Shallow breathing
• Slow heartbeat
• Abnormal heartbeat
• Severe headache
• Confusion
• Sensing things that seem real but are not
• Behavioral changes
• Stiff muscles
• Seizures
• Vision changes
• Involuntary eye movements
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.