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Ketamine: Drug information

Ketamine: Drug information
2024© UpToDate, Inc. and its affiliates and/or licensors. All Rights Reserved.
For additional information see "Ketamine: Patient drug information" and "Ketamine: Pediatric drug information"

For abbreviations, symbols, and age group definitions show table
Brand Names: US
  • Ketalar
Brand Names: Canada
  • Ketalar
Pharmacologic Category
  • Antidepressant;
  • General Anesthetic
Dosing: Adult

Dosage guidance:

Safety: To decrease risk of respiratory depression and apnea, administer IV bolus doses over >30 to 60 seconds (Ref).

Agitation, acute/severe or refractory

Agitation, acute/severe or refractory (adjunct) (off-label use): Note: May be used when benzodiazepines and/or antipsychotics have failed (Ref).

IV: Initial: 1 to 2 mg/kg once over 30 to 60 seconds; if initial sedation is inadequate, may repeat dose once 5 to 10 minutes after the initial dose using 0.5 to 1 mg/kg; however, this is not common if using the upper end of the initial dose range (Ref). Some experts use an initial dose of 0.5 to 1 mg/kg in the emergency department with concomitant sedatives (Ref).

IM: Initial: 4 to 6 mg/kg once; if initial sedation is inadequate, may repeat dose once 10 to 25 minutes after the initial dose using 2 to 3 mg/kg; however, this is not common if using the upper end of the initial dose range (Ref). Some experts use an initial dose of 2 mg/kg in the emergency department with concomitant sedatives (Ref).

Analgesia, subanesthetic dosing

Analgesia, subanesthetic dosing (off-label use):

Acute pain:

Note: Prior to use, consult with a pain specialist or service experienced with ketamine use in this setting. Optimal doses and regimens have not been identified; refer to institutional protocols. Recommendations provided below are examples of regimens. May be useful for moderately to severely painful procedures and conditions that do not respond optimally to standard analgesics (eg, postoperative, burn, trauma, sickle cell disease vaso-occlusive pain).

IV: Initial: 0.25 to 0.5 mg/kg bolus (maximum bolus: 35 mg), followed by 0.05 to 0.25 mg/kg/hour continuous infusion in patients who need a longer duration of analgesia; titrate to pain goal and tolerability; usual dosing range: 0.05 to 1 mg/kg/hour; may need to use doses at the higher range in patients who are opioid-tolerant or with opioid-induced hyperalgesia; duration of infusion: 48 to 72 hours (Ref).

Intranasal (off-label route): 0.2 to 1 mg/kg by administering half dose in each nostril (using 100 mg/mL solution); if necessary, may repeat after 10 to 15 minutes with 0.25 to 0.5 mg/kg; titrate to pain goal and tolerability. Doses up to 40 mg may be reliably administered intranasally; for doses >40 mg, part of the dose will be delivered to the oropharynx and ingested orally due to volume limitations, which may decrease effectiveness (Ref).

Chronic pain, intractable:

Note: Prior to use, consult with a pain specialist or service experienced with ketamine use in this setting. Optimal regimens, doses, and duration have not been identified; refer to institutional protocols. Long-term safety, efficacy, and timing of repeated ketamine treatments are not well established. Recommendations provided below are examples of regimens. May be used in refractory chronic pain (eg, complex regional pain syndrome, end-stage illness, neuropathies). May need to use doses at the higher range in opioid-tolerant patients (Ref). Reduce baseline opioids by 25% to 50% when used concomitantly with ketamine (Ref).

IV intermittent infusion: Initial: 0.25 to 0.6 mg/kg (usual maximum dose: 60 mg) as a 4- to 6-hour infusion; titrate to pain goal and tolerability; repeat daily for up to 2 to 10 days as needed (Ref).

IV continuous infusion: Initial: 0.05 to 0.15 mg/kg/hour for 1 day outpatient or for 2 to 5 days inpatient; titrate to pain goal and tolerability; usual dosing range: 0.02 to 1 mg/kg/hour (maximum dose: 30 mg/hour; not well established) (Ref).

SubQ: Initial: 0.1 to 0.6 mg/kg (usual 2.5 to 25 mg) as needed; titrate to pain goal and tolerability. In patients who need a longer duration of analgesia, follow with continuous SubQ infusion at 0.1 to 1.2 mg/kg/hour (maximum daily dose: 500 mg) (Ref).

Oral: Note: Used in refractory chronic pain (eg, advanced illness or palliative care) in a hospitalized patient when other regimens have failed.

Initial: 0.5 mg/kg/day administered in 3 to 4 divided doses as needed; then increase dose in increments of ~5 mg/dose based on pain goal and tolerability; maximum daily escalation dose: 15 to 20 mg; maximum dose: 800 mg/day (Ref). Note: May administer dose as the undiluted injectable or mixed with an appropriate flavoring agent (eg, simple syrup).

Depressive episode associated with major depressive disorder

Depressive episode (severe, treatment resistant) associated with major depressive disorder (unipolar) (off-label use): Note: Avoid or use with caution in patients with substance use disorder.

IV: Initial: 0.5 mg/kg administered over 40 minutes; may repeat at a frequency of 1 to 3 times weekly; may increase dose to 0.75 to 1 mg/kg based on response and tolerability. Treatment up to 6 weeks has been studied, although optimal duration of therapy is unknown (Ref). In those who respond to short-term ketamine infusions (eg, 1 to 4 weeks), some experts recommend transitioning to maintenance treatment with antidepressants and/or psychotherapy instead of prolonged ketamine treatment (Ref).

General anesthesia

General anesthesia (alternative agent):

Induction of anesthesia:

Note: Useful in hypotensive patients or patients likely to develop hypotension during induction; lower doses may be used if concomitant anesthesia/sedatives (eg, midazolam) are administered (Ref).

IV: 0.5 to 2 mg/kg or 0.5 to 1 mg/kg in patients with shock (Ref).

IM (use only if IV access is not available): 4 to 6 mg/kg (Ref).

Maintenance of anesthesia (adjunct with total intravenous anesthesia): Note: Adjunct to reduce requirements of other anesthetic agents. Typically reserved for opioid-tolerant patients in order to avoid or limit opioid requirements (Ref); concurrent use of nitrous oxide reduces ketamine requirements (Ref).

IV: 0.25 to 0.35 mg/kg, followed by continuous infusion up to 1 mg/kg/hour (Ref).

Mechanically ventilated patients in the ICU, analgesia/sedation/agitation

Mechanically ventilated patients in the ICU, analgesia/sedation/agitation (adjunct or alternative agent) (off-label use):

Note: Used as part of a multimodal strategy and adjunct for the reduction of opioid and sedative requirements and/or for the management of opioid-induced hyperalgesia in patients with acute/chronic pain or postsurgical pain. Pain should be monitored using validated scales (eg, behavioral pain scale, critical-care pain observation tool) in patients who are unable to self-report. If used for sedation, titrate to a light level of sedation (eg, Richmond Agitation Sedation Scale 0 to −2), unless deeper sedation is clinically indicated (Ref). Refer to institutional policies and procedures.

IV: Initial: 0.1 to 0.5 mg/kg bolus, followed by a 0.2 to 0.5 mg/kg/hour continuous infusion; titrate dose to pain and/or sedation goal (dosing range: 0.04 to 2.5 mg/kg/hour) (Ref). Note: Higher initial bolus doses (eg, 1 to 2 mg/kg) can be used to manage severely agitated patients (Ref).

Procedural sedation

Procedural sedation (off-label use): Note: Although rarely needed, may consider using midazolam to decrease risk or to treat emergence reactions. However, premedication may significantly prolong recovery time (Ref).

IV: Initial: 1 to 2 mg/kg over 1 to 2 minutes; if initial sedation is inadequate or for longer procedures, repeat dose (0.5 to 1 mg/kg) every 5 to 10 minutes; use lower doses (0.25 to 0.5 mg/kg) depending on concomitant sedation and clinical status (Ref). Alternatively, may consider an initial dose of 0.375 to 0.75 mg/kg when combined with propofol (as a 1:1 mixture); if needed, repeat with one-half of the initial dose (Ref).

IM: Note: Onset of sedation will be delayed ~5 minutes with this route.

Initial: 4 to 5 mg/kg as a single dose; if sedation is inadequate after 5 to 10 minutes, repeat dose (2 to 5 mg/kg) (Ref).

Rapid sequence intubation outside the operating room, induction

Rapid sequence intubation outside the operating room, induction (off-label use): Note: Consider in patients with bronchospasm and/or hemodynamic compromise (Ref).

IV: Initial: 1 to 2 mg/kg once over 1 minute; in patients with shock, reduce initial dose by half (eg, 0.5 to 1 mg/kg) (Ref).

Intraosseous (use only if IV access is not available): Initial: 100 mg once (Ref).

Status epilepticus, refractory

Status epilepticus, refractory (off-label use): Note: Used as an alternative or adjunct to midazolam, propofol, or barbiturates after conventional intermittent antiseizure therapies have failed. Mechanical ventilation and hemodynamic support generally required; continuous EEG is recommended; titrate doses to cessation of electrographic seizures or burst suppression (Ref). Optimal regimen and dose are uncertain; refer to institutional protocol.

IV:

Loading dose: Initial: 1.5 mg/kg or 0.5 to 3 mg/kg; repeat loading dose of 0.5 mg/kg every 3 to 5 minutes as needed for electrographic/burst suppression, followed by continuous infusion (Ref).

Continuous infusion: After initial loading dose and electrographic suppression, begin at a rate of 0.1 to 4 mg/kg/hour; titrate as needed for electrographic/burst suppression; maximum dose: 15 mg/kg/hour (Ref).

Note: Generally, a period of at least 24 hours of electrographic suppression is suggested prior to down-titrating the continuous infusion; withdraw gradually by decreasing the dose by 20% every 3 hours while continuing conventional antiseizure therapies (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Obesity: Adult

The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.

Class 1 and 2 obesity (BMI 30 to 39 kg/m2):

IV, IM, Intranasal, Oral, SUBQ: Use actual body weight for weight-based dosing, then titrate to clinical effect, if needed (Ref). Refer to adult dosing for indication-specific doses.

Class 3 obesity (BMI ≥40 kg/m2):

IV, IM, Intranasal, Oral, SUBQ: Use either adjusted body weight or ideal body weight for initial weight-based dose calculations, then titrate to clinical effect (Ref). If rapid sedation or clinical effect is needed, use adjusted body weight for initial weight-based dose calculations, then titrate to clinical effect (Ref). Clinicians should not change dosing weight from one weight metric to another during therapy (ie, actual body weight to/from adjusted body weight or ideal body weight) (Ref). Refer to adult dosing for indication-specific doses.

Rationale for recommendations: Ketamine, a short-acting IV induction anesthetic, has a large Vd (2.1 to 3.1 L/kg), with peak anesthetic effects occurring within minutes and a rapid loss of effect related to redistribution (Ref). There are limited data on the influence of obesity on ketamine dosing or pharmacokinetics. A variety of studies have been performed in the past decade for acute pain and depression in patients with obesity or severe obesity using lean body weight, ideal body weight, and actual body weight; however, no consistency between dosing weight and clinical effect has been demonstrated (Ref). This inconsistency (even within indication) in specific weights used for dosing limits definition of a universal weight-based dosing strategy. Due to ketamine's active metabolite, prolonged use may contribute to the risk of accumulation and toxicity, especially in patients with BMI ≥40 kg/m2 (Ref).

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Ketamine: Pediatric drug information")

Dosage guidance:

Safety: 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 (Ref).

Dosing: Individualize dose and titrate to effect. May be used in combination with anticholinergic agents to decrease hypersalivation.

Analgesia, acute pain

Analgesia, acute pain (low dose; sub-dissociative): Very limited data available: Optimal dose not established: Note: Use of mucosal atomizer device is recommended:

Children ≥3 years and Adolescents: Intranasal: Usual: 1 mg/kg/dose, may repeat once; range: 0.5 to 1.5 mg/kg/dose; maximum dose: 100 mg/dose (Ref). Dosing based on 2 double-blind, randomized, controlled studies (n=80 in ketamine treatment group, age range: 3 to 17 years) comparing intranasal ketamine to intranasal fentanyl in the treatment of acute pain due to isolated limb injury or suspected single extremity fracture in the emergency department; pain relief was similar between both treatment groups; no serious adverse effects were reported (Ref).

Anesthesia

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 (Ref).

Children <2 years: 3 to 5 mg/kg/dose (half dose per nostril) administered at least 15 minutes prior to mask induction (Ref).

Children 2 to 7 years: 3 to 6 mg/kg/dose (half dose per nostril) administered 15 to 40 minutes prior to induction (Ref).

Oral: Children ≤8 years: 6 to 8 mg/kg/dose 20 to 30 minutes prior to surgery. Dosing based on 2 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 (Ref). 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 (Ref).

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) (Ref). 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 (Ref).

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 (Ref).

IV: 1 to 3 mg/kg has been reported and suggested by experts (Ref).

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

Endotracheal intubation: Limited data available: Infants, Children, and Adolescents: IV: 1 to 2 mg/kg as part of rapid sequence sedation (Ref).

Sedation/analgesia, procedural

Sedation/analgesia, procedural: Limited data available:

Ketamine without propofol: Infants ≥3 months, Children, and Adolescents:

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 (Ref). Some have recommended smaller doses (2 to 2.5 mg/kg) for minor procedures (eg, wound suture with local anesthetic) (Ref).

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 (Ref).

Intranasal: Note: Use of mucosal atomizer device is recommended:

Infants ≥3 months and Children: 3 to 6 mg/kg (half dose per nostril), doses up to 9 mg/kg have been described (Ref).

Oral: Children and Adolescents: 5 mg/kg with oral midazolam given 30 to 45 minutes before the procedure. Dosing based on 2 prospective, randomized, blinded studies involving patients aged 1 to 10 years with either laceration repair or burn wound care (Ref). 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) (Ref). 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) (Ref).

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 2 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 (Ref). 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) (Ref). 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 (Ref).

Sedation/analgesia, critically ill patients

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 (Ref); doses as high as 60 mcg/kg/minute (3.6 mg/kg/hour) have been reported in patients with refractory bronchospasm (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Adverse Reactions (Significant): Considerations
Airway complications

When used for procedural sedation for major procedures involving the posterior pharynx (eg, endoscopy) or in patients with an active pulmonary infection or disease (including upper respiratory disease or asthma), the use of ketamine increases the risk of laryngospasm (rare and typically transient) (Ref). 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.

Mechanism: Dose-related; ketamine does not suppress pharyngeal and laryngeal reflexes. Laryngospasm may occur secondary to stimulation of the vocal cords by instrumentation and/or ketamine-induced increased salivary secretions (Ref).

Risk factors:

• Higher IV doses (Ref)

• IM administration (and higher doses) (Ref)

• Pediatric patients <2 years or ≥13 years of age (Ref)

• Active pulmonary infection or disease, including upper respiratory disease or asthma (Ref)

• History of airway instability, tracheal surgery, or tracheal stenosis (Ref)

Cardiovascular effects

Ketamine causes increased blood pressure, increased heart rate, and increased cardiac output, thereby increasing myocardial oxygen demand; cardiac arrhythmia, cardiac decompensation, decreased blood pressure, and decreased heart rate have also been reported (Ref). 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) (Ref). Resolution of increased blood pressure usually occurs within 15 minutes after the peak.

Mechanism: Ketamine has both central sympathetic stimulation and inhibition of catecholamine uptake and direct negative inotropic effects. Central sympathetic stimulation results in increased blood pressure, heart rate, cardiac output, and therefore, increased myocardial oxygen demand (Ref). Direct negative inotropic effects may predominate in patients with heart failure and contribute to decompensation (Ref).

Onset: Rapid; a peak in blood pressure occurs within a few minutes of administration.

Risk factors:

• Known or suspected coronary artery disease, angina, hypertension (Ref)

• Older adults with risk factors for coronary artery disease (Ref)

• Heart failure (Ref)

• Catecholamine depletion (hypotension) (Ref)

Dependence

Ketamine may cause drug dependence (withdrawal symptoms on discontinuation) and drug tolerance with prolonged use (Ref). Multiple case reports of ketamine misuse have been described (Ref). A withdrawal syndrome following discontinuation may include symptoms such as shaking, sweating, palpitations, fatigue, decreased appetite, chills, autonomic arousal, lacrimation, restlessness, cravings, dysphoria, anxiety, depressed mood, nightmares, paranoia, delusions, and hallucinations (Ref). Typical duration of withdrawal symptoms is ~3 days, with some cases persisting for 2 weeks (Ref).

Mechanism: Dose- and time-related; development of dependence may be related to the psychological effects of ketamine and tolerance. Ketamine is structurally similar to phencyclidine and the psychological effects contributing to dependence may include euphoria, perceptual changes, dissociation, and hallucinations. Tolerance most likely occurs due to auto-induction of metabolism (Ref). Dependence may also be related to N-methyl-D-aspartate (NMDA) glutamate receptor blockade, producing alcohol-like subjective effects, as well as opioid effects (Ref).

Onset: Dependence: Delayed; from isolated case reports, dependence may evolve over weeks to years (Ref). Withdrawal syndrome: Rapid; symptoms usually occur within 24 hours of discontinuation (Ref).

Risk factors:

• Long-term high-dose use (Ref)

• Rapid dose escalation (Ref)

• History of multiple substance use disorders (eg, alcohol, cannabis, opioids) (Ref)

• Ease of access (Ref)

Emergence reactions

Prolonged emergence from anesthesia, which can manifest as vivid dreams, hallucinations, and/or frank delirium commonly occur in all ages (Ref).

Mechanism: Dose-related; may occur due to depression of auditory and visual relay nuclei, leading to misperception and/or misinterpretation of auditory and visual stimuli (Ref).

Onset: Rapid; emergence reactions may occur up to 24 hours postoperatively.

Risk factors:

• Higher doses (Ref)

• Rapid IV administration (Ref)

• Age >16 years (Ref)

• Females (Ref)

• Excessive noise or stimulation during recovery (Ref)

• People who normally dream or have a history of a personality disorder (Ref)

• Ketamine monotherapy (concurrent use with a benzodiazepine may reduce risk) (Ref)

Genitourinary effects

Lower urinary tract and bladder symptoms, including dysuria, urinary frequency, urinary urgency, urinary incontinence, hematuria, and nocturia, 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 bladder dysfunction (reduced capacity) (Ref). Reversibility of symptoms depends on time to diagnosis and intervention (Ref).

Mechanism: Not clearly established; several proposed mechanisms, including direct effects of ketamine and the active metabolite, norketamine/hydroxynorketamine on bladder mucosa (Ref).

Onset: Delayed; case reports range from 1 month to 4.5 years (Ref).

Risk factors:

• Chronic use or abuse (Ref)

• Frequency of use of other drugs (eg, opiates, methamphetamine) (Ref)

• Female gender (Ref)

• History of urinary tract infections (Ref)

Neurodevelopmental effects in children

Animal studies have shown that prolonged or repeated exposure to medications for anesthesia or sedation cause adverse effects on brain maturation resulting in changes in behavior and learning. Some human studies have also suggested similar effects, including epidemiological studies in humans that have observed various cognitive and behavioral problems, including neurodevelopmental delay (and related diagnoses), learning disabilities, and attention deficit hyperactivity disorder. However, data are limited, inconclusive, and further studies are needed to fully characterize findings. Based on the potential risk, the FDA warned in 2016 that in neonates, infants, children <3 years, and patients in the third trimester of pregnancy (ie, times of rapid brain growth and synaptogenesis) undergoing repeated or lengthy exposure to sedatives or anesthetics during surgery/procedures/critical illness, there may be detrimental effects on the child's or fetus’ brain development which may lead to various cognitive and behavioral problems. Relatively short exposure (<3 hours) to sedatives or anesthetics during surgery or procedures is unlikely to adversely affect brain development (Ref).

Mechanism: Unknown; in juvenile animal studies, drugs that potentiate gamma-aminobutyric acid activity and/or block N-methyl-D aspartate receptors for >3 hours demonstrated widespread neuronal and oligodendrocyte cell loss along with alteration in synaptic morphology and neurogenesis (Ref).

Risk factors:

• Neonates, infants, children <3 years, and pregnant patients in their third trimester undergoing procedures lasting >3 hours or multiple procedures (Ref)

Respiratory depression

Ketamine may rarely cause respiratory depression or apnea, which are usually transient. These adverse reactions are most associated with rapid IV administration but have also been reported with IM administration (Ref). According to the manufacturer, overdose is also a risk factor for these adverse reactions; however, respiratory depression and apnea have been reported in the setting of slow sub-anesthetic IV infusion (Ref).

Onset: Rapid; typically, 1 to 2 minutes after IV administration or 4 to 5 minutes after IM administration (Ref). In the case of respiratory depression and apnea in the setting of slow sub-clinical IV infusion, onset occurred 25 minutes after the start of ketamine infusion (Ref).

Risk factors:

• Overdose

• Rapid IV administration (Ref)

• Concurrent use of other CNS depressants (eg, benzodiazepines, opioids)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

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

Frequency not defined:

Cardiovascular: Cardiac arrhythmia, cardiac decompensation, decreased blood pressure, decreased heart rate, increased blood pressure, increased heart rate

Dermatologic: Erythema of skin, morbilliform rash

Gastrointestinal: Anorexia, nausea, vomiting

Local: Pain at injection site, rash at injection site

Nervous system: Hypertonia (tonic-clonic movements sometimes resembling seizures), psychiatric disturbance

Ophthalmic: Diplopia, increased intraocular pressure, nystagmus disorder

Respiratory: Airway obstruction

Postmarketing:

Cardiovascular: Ventricular premature contractions (Cabbabe 1985)

Endocrine & metabolic: Central diabetes insipidus (Hatab 2014)

Gastrointestinal: Biliary tract disease (dilation; Cotter 2021), cholangitis (Cotter 2021), sialorrhea (Hatab 2014)

Genitourinary: Bladder dysfunction (reduced capacity) (Wei 2013), cystitis (including cystitis noninfective, cystitis interstitial, cystitis ulcerative, cystitis erosive, cystitis hemorrhagic) (Wei 2013), dysuria (Wei 2013), hematuria (Wei 2013), nocturia (Wei 2013), urinary frequency (Wei 2013), urinary incontinence (Wei 2013), urinary urgency (Wei 2013)

Hepatic: Abnormal hepatobiliary function (with recurrent or continuous use; including pericholeductal fibrosis) (Cotter 2021), hepatic cirrhosis (Cotter 2021), increased direct serum bilirubin (Cotter 2021), increased gamma-glutamyl transferase (Cotter 2021), increased liver enzymes (Cotter 2021), increased serum alanine aminotransferase (Cotter 2021), increased serum alkaline phosphatase (Cotter 2021), increased serum aspartate aminotransferase (Cotter 2021), increased serum bilirubin (Cotter 2021), jaundice (Cotter 2021)

Hypersensitivity: Anaphylaxis (Chow 2021)

Nervous system: Drug dependence (Pal 2002), increased cerebrospinal fluid pressure (List 1972), withdrawal syndrome (Cosci 2020)

Neuromuscular & skeletal: Laryngospasm (Green 2011)

Renal: Hydronephrosis (Wei 2013)

Respiratory: Apnea (Driver 2017; Gómez-Revuelta 2020), respiratory depression (Melendez 2009)

Miscellaneous: Drug tolerance

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

Warnings/Precautions

Concerns related to adverse effects:

• 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.

• 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; use caution, especially at higher doses (ACEP [Green 2011]; Cohen 2018). 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; Quibell 2015; 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).

• Liver injury: Recurrent use (eg, abuse/misuse, medically supervised unapproved use) may cause hepatobiliary dysfunction (usually a cholestatic pattern) and biliary duct dilatation with or without evidence of biliary obstruction.

• Porphyria: The ACEP considers the use of ketamine in patients with porphyria a relative contraindication due to enhanced sympathomimetic effect produced by ketamine (ACEP [Green 2011]).

• Thyroid disorders: The ACEP 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:

• Cerebrospinal fluid pressure elevation: Use with caution in patients with cerebrospinal fluid (CSF) pressure elevation; an increase in CSF pressure may be associated with use.

• Ethanol use: Use with caution in patients with chronic alcohol use disorder or who are acutely alcohol-intoxicated..

Special populations:

• Pediatric neurotoxicity: In pediatric and neonatal patients <3 years of age 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 attention deficit hyperactivity disorder. 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.

Warnings: Additional Pediatric Considerations

Postanesthetic emergence reactions may be minimized by limiting verbal, tactile, and visual patient stimulation during recovery, or by pretreatment with a benzodiazepine (using lower recommended doses of ketamine). Severe emergent reactions may require treatment with a small hypnotic dose of a short or ultrashort acting barbiturate.

Dosage Forms: US

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

Solution, Injection, as hydrochloride:

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)

Generic Equivalent Available: US

Yes

Pricing: US

Solution (Ketalar Injection)

10 mg/mL (per mL): $1.19

50 mg/mL (per mL): $0.84

100 mg/mL (per mL): $3.20

Solution (Ketamine HCl Injection)

10 mg/mL (per mL): $1.19 - $1.46

50 mg/mL (per mL): $0.43 - $1.19

100 mg/mL (per mL): $1.99 - $3.62

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

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

Solution, Injection, as hydrochloride:

Ketalar: 10 mg/mL (20 mL); 50 mg/mL (10 mL, 20 mL) [contains benzethonium chloride]

Generic: 10 mg/mL (2 mL, 20 mL); 50 mg/mL (2 mL, 10 mL)

Controlled Substance

C-III

Administration: Adult

Intranasal (off label): 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 (Ref).

Oral (off label): May administer undiluted or mix the appropriate dose (using the injectable solution) in a flavoring agent (eg, simple syrup), cola, or other beverage; administer immediately after preparation (Ref).

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 (Ref). When used for treatment refractory unipolar depression, administer over 40 minutes (Ref). May also be administered as a continuous infusion.

Rectal (off label): May use the 50 mg/mL solution undiluted or use the 100 mg/mL solution and further dilute prior to administration (Ref).

SubQ (off label): May administer as a subcutaneous continuous infusion (Ref).

Administration: Pediatric

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 (Ref). Administer dose in 1 nostril (for volumes ≤0.5 mL) or divide dose and administer half dose in each nostril using a mucosal atomizer device (preferred) or needleless syringe (Ref).

Oral (using parenteral dosage form): Use the 100 mg/mL IV solution and mix the appropriate dose in 0.2 to 0.4 mL/kg of cola, sour cherry juice, or other beverage (Ref).

Parenteral:

IV push: May administer the 10 mg/mL and 50 mg/mL undiluted. Administer slowly over 60 seconds, do not exceed 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 (Ref).

IV infusion: May be administered as a continuous IV 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 (Ref).

Use: Labeled Indications

Anesthesia: Induction and maintenance of general anesthesia.

Use: Off-Label: Adult

Agitation, acute/severe or refractory; Analgesia, subanesthetic dosing, acute and chronic pain; Depressive episode (severe, treatment resistant) associated with major depressive disorder (unipolar); Mechanically ventilated patients in the ICU, analgesia/sedation/agitation; Procedural sedation; Rapid sequence intubation outside the operating room, induction; Status epilepticus, refractory

Medication Safety Issues
Sound-alike/look-alike issues:

Ketalar may be confused with Kenalog, ketorolac

Ketamine may be confused with ketorolac

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (anesthetic agent, general, inhaled and IV; moderate and minimal sedation agent, oral, for children [using parenteral form]) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care and Community/Ambulatory Care Settings).

Older Adult: High-Risk Medication:

Ketamine is identified in the Screening Tool of Older Person's Prescriptions (STOPP) criteria as a potentially inappropriate medication in older adults (≥65 years of age) for the treatment of depression due to an increased risk of falls (O’Mahony 2023).

Metabolism/Transport Effects

Substrate of CYP2B6 (major), CYP2C9 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

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

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

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

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

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

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

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: 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. Risk D: Consider therapy modification

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

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

CYP2B6 Inducers (Moderate): May decrease the serum concentration of Ketamine. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Ketamine. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ketamine. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ketamine. Risk C: Monitor therapy

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

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. Risk C: 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. Risk D: Consider therapy modification

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

Fexinidazole: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Management: Avoid concomitant use of fexinidazole and CYP2B6 substrates when possible. If combined, monitor for reduced efficacy of the CYP2B6 substrate. Risk D: Consider therapy modification

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Grapefruit Juice: May increase the serum concentration of Ketamine. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

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. Risk D: Consider therapy modification

Levothyroxine: May enhance the hypertensive effect of Ketamine. Levothyroxine may enhance the tachycardic effect of Ketamine. Risk C: Monitor therapy

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Loxapine: CNS Depressants may enhance the CNS depressant effect of Loxapine. Risk D: Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Memantine: NMDA Receptor Antagonists may enhance the adverse/toxic effect of Memantine. Risk C: 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 the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

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

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

Mivacurium: Ketamine may enhance the therapeutic effect of Mivacurium. Risk C: Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

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. Risk D: Consider therapy modification

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

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

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

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

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

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

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

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

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

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

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. Risk D: Consider therapy modification

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

Theophylline Derivatives: Ketamine may enhance the adverse/toxic effect of Theophylline Derivatives. Specifically, the risk for seizures may be increased. Risk C: Monitor therapy

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

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

Ticlopidine: May increase the serum concentration of Ketamine. Risk C: Monitor therapy

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

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification

Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification

Reproductive Considerations

When treating depression, evaluate pregnancy status prior to initiating treatment in patients who could become pregnant. Treatment should not be withheld, but pharmacologic management may vary based on reproductive status, severity of illness, and history of antidepressant response (ACOG 2023; WFSBP [Dodd 2018]). Patients effectively treated may continue their current medication when planning a pregnancy unless contraindications exist (BAP [McAllister-Williams 2017]). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]).

Pregnancy Considerations

Ketamine crosses the placenta (Ellingson 1977; Little 1972; Su 2010).

Ketamine produces dose-dependent increases in uterine contractions; effects may vary by trimester, with effects more common in early pregnancy. Dose-related neonatal depression and decreased Apgar scores have been reported with large doses administered at delivery; serum bilirubin may also be increased (Little 1972; Neuman 2013; White 1982). General hypotonia, resolving within 21 days, was observed in a newborn following maternal abuse of ketamine during pregnancy (Su 2010).

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).

Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of ketamine may be altered; clearance may be decreased (Little 1972).

Obstetric use is not recommended by the manufacturer; however, ketamine has been evaluated for anesthesia during cesarean and vaginal delivery and as an adjunctive analgesic in cesarean deliveries (ACOG 2019b; Corssen 1974; Heesen 2015; Wang 2020). When sedation and analgesia are needed for other procedures during pregnancy, low doses of ketamine may be used, but other agents are preferred (Neuman 2013; Schwenk 2018). The American College of Obstetricians and Gynecologists recommends that pregnant patients should not be denied medically necessary surgery, regardless of trimester. If the procedure is elective, it should be delayed until after delivery (ACOG 2019a).

Ketamine has been studied for the adjunctive treatment of depression (VA/DoD 2022). Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Untreated or undertreated depression is associated with preterm birth, low birth weight, preeclampsia, postpartum depression, and impaired infant attachment (associated with long-term developmental effects). Discontinuing effective medications during pregnancy increases the risk of relapse. Management should be made as part of a shared decision-making process (ACOG 2023). Patients effectively treated for depression prepregnancy may use the same medication during pregnancy unless contraindications exist (ACOG 2023; CANMAT [MacQueen 2016]; BAP [McAllister-Williams 2017]). Treatment should not be withheld or discontinued based only on pregnancy status. When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Monthly monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023). Studies are investigating the use of ketamine to prevent postpartum depression in patients undergoing cesarean delivery (Li 2022; Li 2024).

Ketamine infusion for the treatment of refractory status epilepticus in a pregnant patient has been noted in a case report (Talahma 2018).

Breastfeeding Considerations

Ketamine and its metabolites are present in breast milk.

Multiple case reports provide data related to the presence of ketamine in breast milk:

• Ketamine and the active metabolite norketamine were observed in the breast milk of 4 lactating patients evaluated between 1 and 23 months postpartum. All patients in this case series were administered intermittent ketamine infusions for the treatment of depression. Ketamine doses ranged from 0.607 to 4.167 mg/kg (49 to 378 mg). Patients provided breast milk samples prior to and at specified intervals for 24 hours following a dose. Maximum breast milk concentrations of ketamine and norketamine occurred 1 hour after the start of the infusion. Authors of the study calculated the estimated infant dose of ketamine via breast milk to be 0.003 mg/kg/day to 0.017 mg/kg/day providing a relative infant dose (RID) of 0.34% to 0.57% compared to the weight-adjusted maternal dose. The estimated infant dose of norketamine via breast milk was calculated to be 0.005 mg/kg/day to 0.018 mg/kg/day providing an RID of 0.29% to 0.95%. Participants did not observe adverse events in the breastfed infants during the study period (Majdinasab 2023).

• Ketamine, norketamine, and dehydronorketamine were detected in breast milk following an infusion of ketamine 0.1 mg/kg/hour over 12 hours (maximum 8 mg/hour) to lactating patients ~6 months postpartum. Breast milk was sampled at 7 specified intervals between 2 and 20 hours after the start of the infusion. Ketamine concentrations in breast milk were greater than the metabolites at all time points. Using data from 1 patient, the highest ketamine concentration occurred at ~8 hours into the infusion. It was not noted if infants were breastfed (Shahane 2023).

• Data are available from 4 lactating patients following single injections of ketamine 0.5 mg/g IM and 1 mg/kg SUBQ. Patients were at least 3 months postpartum, doses were separated by 5 to 14 days, and breast milk was collected prior to and at 3-hour intervals after the dose. Ketamine, norketamine, dehydronorketamine, and hydroxynorketamine were detected in breast milk. Authors of the study calculated the mean estimated infant dose of ketamine and metabolites via breast milk to be 0.00766 mg/kg over 12 hours providing a RID of 0.766% compared to the 1 mg/kg weight-adjusted maternal dose. The RID calculated using the 0.5 mg/kg maternal dose was 0.65%. Infants did not receive breast milk in this study (Wolfson 2023).

• In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000); however, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Anderson 2021).

Adverse events, including clinically significant weight loss or jaundice, were not observed in infants of 298 mothers who received ketamine as an anesthetic for tubal ligation. Maternal doses of ketamine were ≤3.8 mg/kg, patients were between 1 and 6 days postpartum, and most infants were fully breastfed (Gilder 2021).

The Academy of Breastfeeding Medicine recommends postponing elective surgery until milk supply and breastfeeding are established. Milk should be expressed ahead of surgery when possible. In general, when the child is healthy and full term, breastfeeding may resume, or milk may be expressed once the mother is awake and in recovery. For children who are at risk for apnea, hypotension, or hypotonia, milk may be saved for later use when the child is at lower risk (ABM [Reece-Stremtan 2017]).

Small supplemental doses of ketamine used during cesarean delivery should not prevent breastfeeding once the mother is stable and alert; however, data are insufficient to recommend use for long-term pain control (ABM [Martin 2018]).

Patients effectively treated for depression during pregnancy may continue their medication postpartum unless contraindications to breastfeeding exist. The presence and concentration of the drug in breast milk, efficacy of maternal treatment, and infant age should be considered when initiating a medication for the first time postpartum (ABM [Sriraman 2015]; BAP [McAllister-Williams 2017]).

Monitoring Parameters

Heart rate, blood pressure, respiratory rate, transcutaneous O2 saturation, level of sedation, emergence reactions; cardiac function (continuously monitored in patients with increased blood pressure or cardiac decompensation); LFTs, alkaline phosphatase, and gamma glutamyl transferase (baseline and then at periodic intervals). When used for the treatment of pain, monitor pain control during therapy.

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 (Adult Data Unless Noted)

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

Duration:

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)

Distribution: Vdss: 2.1 to 3.1 L/kg (Clements 1981)

Protein binding: 27% (Brunton 2006)

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).

Bioavailability:

IM: 93%

Oral: 20% to 30% (Miller 2010)

Intranasal: Children, Adolescents, and Adults: Mean range: 35% to 50% (Malinovsky 1996; Miller 2010; Nielsen 2014)

Rectal: Children 2 to 9 years: 25% (Malinovsky 1996)

Half-life elimination: Alpha: 10 to 15 minutes; Beta: 2.5 hours

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)

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

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Ketalar;
  • (AR) Argentina: Inducmina;
  • (AT) Austria: Ketalar;
  • (AU) Australia: Ketamine interpharma;
  • (BD) Bangladesh: Kain;
  • (BE) Belgium: Ketalar;
  • (CH) Switzerland: Ketamin sintetica;
  • (CL) Chile: Ketalar;
  • (CZ) Czech Republic: Calypsol | Ketalar | Narkamon;
  • (DE) Germany: Ketamin curamed;
  • (EC) Ecuador: Ketalar;
  • (HU) Hungary: Ketanest;
  • (IL) Israel: Ketalar;
  • (JP) Japan: Ketalar;
  • (LT) Lithuania: Ketalar | Narkamon;
  • (LV) Latvia: Ketalar | Narkamon;
  • (NZ) New Zealand: Ketamine;
  • (PE) Peru: Ketalar;
  • (PK) Pakistan: Calypsol | Ketlar;
  • (PL) Poland: Ketalar | Ketamin Inresa | Narkamon;
  • (PR) Puerto Rico: Ketamine HCL;
  • (QA) Qatar: Tekam;
  • (RU) Russian Federation: Ketalar | Ketamin;
  • (SI) Slovenia: Ketanest;
  • (SK) Slovakia: Calypsol | Narkamon;
  • (TW) Taiwan: Ketalar | Ketomin;
  • (UA) Ukraine: Ketalar;
  • (VE) Venezuela, Bolivarian Republic of: Keiran;
  • (ZA) South Africa: Micro ketamine
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