KETAMINE: 7,993 Adverse Event Reports & Safety Profile
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Drug Class: General Anesthesia [PE] · Route: INTRAMUSCULAR · Manufacturer: Eugia US LLC · FDA Application: 016812 · HUMAN PRESCRIPTION DRUG · FDA Label: Available
First Report: 1981 · Latest Report: 20250825
What Are the Most Common KETAMINE Side Effects?
All KETAMINE Side Effects by Frequency
| Side Effect | Reports | % of Total | Deaths | Hosp. |
|---|---|---|---|---|
| Drug ineffective | 1,458 | 18.2% | 119 | 726 |
| Off label use | 992 | 12.4% | 79 | 430 |
| Drug abuse | 748 | 9.4% | 161 | 356 |
| Anaphylactic shock | 568 | 7.1% | 19 | 150 |
| Hyperhidrosis | 496 | 6.2% | 1 | 16 |
| Hypotension | 468 | 5.9% | 40 | 237 |
| Product use in unapproved indication | 457 | 5.7% | 27 | 97 |
| Toxicity to various agents | 420 | 5.3% | 254 | 179 |
| Sedation | 395 | 4.9% | 15 | 43 |
| Agitation | 344 | 4.3% | 13 | 105 |
| Nausea | 341 | 4.3% | 9 | 51 |
| Nightmare | 325 | 4.1% | 0 | 3 |
| Hallucination | 311 | 3.9% | 5 | 79 |
| Vomiting | 283 | 3.5% | 20 | 79 |
| Fatigue | 271 | 3.4% | 4 | 77 |
| Rash | 270 | 3.4% | 26 | 74 |
| Drug ineffective for unapproved indication | 259 | 3.2% | 43 | 190 |
| Anxiety | 251 | 3.1% | 4 | 51 |
| Dizziness | 247 | 3.1% | 3 | 32 |
| Nephrolithiasis | 240 | 3.0% | 0 | 5 |
Who Reports KETAMINE Side Effects? Age & Gender Data
Gender: 46.7% female, 53.3% male. Average age: 41.0 years. Most reports from: US. View detailed demographics →
Is KETAMINE Getting Safer? Reports by Year
| Year | Reports | Deaths | Hosp. |
|---|---|---|---|
| 2000 | 3 | 1 | 2 |
| 2001 | 22 | 0 | 15 |
| 2002 | 5 | 1 | 4 |
| 2003 | 4 | 0 | 1 |
| 2004 | 1 | 0 | 1 |
| 2005 | 7 | 1 | 5 |
| 2006 | 5 | 1 | 2 |
| 2007 | 9 | 3 | 1 |
| 2008 | 4 | 4 | 0 |
| 2009 | 5 | 0 | 4 |
| 2010 | 23 | 7 | 12 |
| 2011 | 9 | 3 | 5 |
| 2012 | 35 | 2 | 27 |
| 2013 | 59 | 13 | 34 |
| 2014 | 82 | 19 | 38 |
| 2015 | 106 | 6 | 58 |
| 2016 | 145 | 32 | 78 |
| 2017 | 178 | 32 | 64 |
| 2018 | 308 | 48 | 124 |
| 2019 | 322 | 43 | 141 |
| 2020 | 238 | 33 | 111 |
| 2021 | 240 | 65 | 103 |
| 2022 | 307 | 49 | 113 |
| 2023 | 420 | 53 | 171 |
| 2024 | 315 | 18 | 117 |
| 2025 | 168 | 2 | 63 |
What Is KETAMINE Used For?
| Indication | Reports |
|---|---|
| Product used for unknown indication | 1,671 |
| Anaesthesia | 727 |
| General anaesthesia | 711 |
| Status epilepticus | 452 |
| Induction of anaesthesia | 345 |
| Migraine | 309 |
| Pain | 309 |
| Sedation | 283 |
| Sedative therapy | 197 |
| Complex regional pain syndrome | 179 |
KETAMINE vs Alternatives: Which Is Safer?
Other Drugs in Same Class: General Anesthesia [PE]
Official FDA Label for KETAMINE
Official prescribing information from the FDA-approved drug label.
Drug Description
Ketamine hydrochloride injection, USP for intravenous or intramuscular use, contains ketamine, a nonbarbiturate general anesthetic. Ketamine hydrochloride, USP is a white or almost white, crystalline powder and has a molecular formula of C 13 H 16 ClNO•HCl and a molecular weight of 274.19. The chemical name for ketamine hydrochloride is 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride. The chemical structure of ketamine hydrochloride is: It is formulated as a slightly acidic (pH 3.5-5.5) sterile solution for intravenous or intramuscular injection. Each milliliter (mL) of the multiple-dose vials contain either 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride), 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) or 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride) and not more than 0.10 mg/mL benzethonium chloride added as a preservative in water for injection.
The
10 mg/mL solution has been made isotonic with 6.60 mg sodium chloride. Ketamine-SPL-Structure
FDA Approved Uses (Indications)
AND USAGE Ketamine Hydrochloride Injection is indicated:
- as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.
- for the induction of anesthesia prior to the administration of other general anesthetic agents.
- as a supplement to other anesthetic agents.
Ketamine Hydrochloride
Injection is a general anesthetic indicated:
- as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation ( 1 )
- for the induction of anesthesia prior to the administration of other general anesthetic agents ( 1 )
- as a supplement to other anesthetic agents. ( 1 )
Dosage & Administration
AND ADMINISTRATION
- See Full Prescribing Information for important dosage and administration instructions. ( 2 )
- Induction of anesthesia: -- Intravenous route : Initially, 1 to 4.5 mg/kg administered slowly (over a period of 60 seconds). Alternatively, administer a dose of 1 to 2 mg/kg at a rate of 0.5 mg/kg/min. ( 2 2 ) -- Intramuscular route : Initially, 6.5 to 13 mg/kg. ( 2.2 )
- Maintenance of anesthesia: Increments of one-half to the full induction dose may be repeated as needed (2.2). Adjust the dose according to the patient's anesthetic needs and whether an additional anesthetic agent is employed. ( 2.2 )
- Supplement to other anesthetic agents: The regimen of a reduced dose of Ketamine Hydrochloride Injection supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents. ( 2.2 )
2.1 Important Dosage and Administration Information Ketamine Hydrochloride Injection should be administered by or under the direction of physicians experienced in the administration of general anesthetics, maintenance of a patent airway, and oxygenation and ventilation. Continuously monitor vital signs in patients receiving Ketamine Hydrochloride Injection. Emergency airway equipment must be immediately available. Do not administer the 100 mg/mL concentration of Ketamine Hydrochloride Injection intravenously without proper dilution <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Must be used immediately after dilution. While some degree of airway protection may be afforded due to active laryngeal-pharyngeal reflexes, vomiting and aspiration may occur with Ketamine Hydrochloride Injection.
Ketamine Hydrochloride
Injection is not recommended for use in patients who have not followed nil per os guidelines. Due to the potential for salivation during Ketamine Hydrochloride Injection administration, administer an antisialagogue prior to induction of anesthesia. In individuals with a history of chronic ketamine use for off-label indications, there have been case reports of genitourinary pain that may be related to the ketamine treatment, not the underlying condition [see Adverse Reactions (6) ] . Consider cessation of ketamine if genitourinary pain continues in the setting of other genitourinary symptoms.
2.2 Recommended Dosage and Administration The Ketamine Hydrochloride Injection dosage must be individualized and titrated to the desired clinical effect. If a longer duration of effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia. However, a higher total dose will result in a longer time to complete recovery. Induction of Anesthesia Intravenous Route: The initial dose of Ketamine Hydrochloride Injection administered intravenously may range from 1 mg/kg to 4.5 mg/kg. The average amount required to produce 5 to 10 minutes of surgical anesthesia within 30 seconds following injection is 2 mg/kg.
Administer Ketamine Hydrochloride
Injection slowly (i.e., over a period of 60 seconds). Rapid administration may result in respiratory depression and enhanced vasopressor response. The induction dose may be administered as an intravenous infusion at a rate of 0.5 mg/kg/min.
Intramuscular
Route : The initial dose of Ketamine Hydrochloride Injection administered intramuscularly may range from 6.5 to 13 mg/kg. A dose of 9 to 13 mg/kg usually produces surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes. Administer a benzodiazepine, if clinically indicated, for the prevention of neuropsychological manifestations during emergence from anesthesia. Maintenance of Anesthesia Adjust the maintenance dose according to the patient's anesthetic needs and whether an additional anesthetic agent is administered. Repeat increments of one-half to the full induction dose as needed for maintenance of anesthesia. Purposeless and tonic-clonic movements of extremities may occur during the course of ketamine anesthesia. These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic.
Ketamine Hydrochloride
Injection given by slow microdrip infusion technique at a dose of 0.1 to 0.5 mg/minute will maintain general anesthesia in adult patients induced with Ketamine Hydrochloride Injection.
Augment Ketamine Hydrochloride
Injection with an intravenous benzodiazepine for the prevention of neuropsychological manifestations during emergence. Supplement to Other Anesthetic Agents Ketamine Hydrochloride Injection can be administered to supplement other general and local anesthetic agents. Continuously monitor patients for changes in respiratory and hemodynamic parameters. A reduced dose of Ketamine Hydrochloride Injection can be used to produce balanced anesthesia when used in combination with other anesthetic agents.
2.3 Preparation of Dilution Ketamine Hydrochloride Injection is a clear, colorless to slightly yellowish sterile solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if product is discolored or contains particulate matter. Induction of Anesthesia : Do not intravenously inject the 100 mg/mL concentration of Ketamine Hydrochloride Injection without proper dilution.
Dilute Ketamine Hydrochloride
Injection with an equal volume of either Sterile Water for injection, USP, 0.9% Sodium Chloride Injection, USP (Normal Saline), or 5% Dextrose in Water. Use immediately after dilution. Maintenance of Anesthesia : To prepare a dilute solution containing 1 mg of ketamine per mL, aseptically transfer 10 mL from a 50 mg per mL vial or 5 mL from a 100 mg per mL vial to 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (Normal Saline) and mix well. The resultant solution will contain 1 mg of ketamine per mL. Use immediately after dilution. When fluid restriction is required, Ketamine Hydrochloride Injection can be added to a 250 mL infusion as described above to provide a Ketamine Hydrochloride Injection concentration of 2 mg/mL.
2.1 Important Dosage and Administration Information Ketamine Hydrochloride Injection should be administered by or under the direction of physicians experienced in the administration of general anesthetics, maintenance of a patent airway, and oxygenation and ventilation. Continuously monitor vital signs in patients receiving Ketamine Hydrochloride Injection. Emergency airway equipment must be immediately available. Do not administer the 100 mg/mL concentration of Ketamine Hydrochloride Injection intravenously without proper dilution <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Must be used immediately after dilution. While some degree of airway protection may be afforded due to active laryngeal-pharyngeal reflexes, vomiting and aspiration may occur with Ketamine Hydrochloride Injection.
Ketamine Hydrochloride
Injection is not recommended for use in patients who have not followed nil per os guidelines. Due to the potential for salivation during Ketamine Hydrochloride Injection administration, administer an antisialagogue prior to induction of anesthesia. In individuals with a history of chronic ketamine use for off-label indications, there have been case reports of genitourinary pain that may be related to the ketamine treatment, not the underlying condition [see Adverse Reactions (6) ] . Consider cessation of ketamine if genitourinary pain continues in the setting of other genitourinary symptoms.
2.2 Recommended Dosage and Administration The Ketamine Hydrochloride Injection dosage must be individualized and titrated to the desired clinical effect. If a longer duration of effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia. However, a higher total dose will result in a longer time to complete recovery. Induction of Anesthesia Intravenous Route: The initial dose of Ketamine Hydrochloride Injection administered intravenously may range from 1 mg/kg to 4.5 mg/kg. The average amount required to produce 5 to 10 minutes of surgical anesthesia within 30 seconds following injection is 2 mg/kg.
Administer Ketamine Hydrochloride
Injection slowly (i.e., over a period of 60 seconds). Rapid administration may result in respiratory depression and enhanced vasopressor response. The induction dose may be administered as an intravenous infusion at a rate of 0.5 mg/kg/min.
Intramuscular
Route : The initial dose of Ketamine Hydrochloride Injection administered intramuscularly may range from 6.5 to 13 mg/kg. A dose of 9 to 13 mg/kg usually produces surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes. Administer a benzodiazepine, if clinically indicated, for the prevention of neuropsychological manifestations during emergence from anesthesia. Maintenance of Anesthesia Adjust the maintenance dose according to the patient's anesthetic needs and whether an additional anesthetic agent is administered. Repeat increments of one-half to the full induction dose as needed for maintenance of anesthesia. Purposeless and tonic-clonic movements of extremities may occur during the course of ketamine anesthesia. These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic.
Ketamine Hydrochloride
Injection given by slow microdrip infusion technique at a dose of 0.1 to 0.5 mg/minute will maintain general anesthesia in adult patients induced with Ketamine Hydrochloride Injection.
Augment Ketamine Hydrochloride
Injection with an intravenous benzodiazepine for the prevention of neuropsychological manifestations during emergence. Supplement to Other Anesthetic Agents Ketamine Hydrochloride Injection can be administered to supplement other general and local anesthetic agents. Continuously monitor patients for changes in respiratory and hemodynamic parameters. A reduced dose of Ketamine Hydrochloride Injection can be used to produce balanced anesthesia when used in combination with other anesthetic agents.
2.3 Preparation of Dilution Ketamine Hydrochloride Injection is a clear, colorless to slightly yellowish sterile solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if product is discolored or contains particulate matter. Induction of Anesthesia : Do not intravenously inject the 100 mg/mL concentration of Ketamine Hydrochloride Injection without proper dilution.
Dilute Ketamine Hydrochloride
Injection with an equal volume of either Sterile Water for injection, USP, 0.9% Sodium Chloride Injection, USP (Normal Saline), or 5% Dextrose in Water. Use immediately after dilution. Maintenance of Anesthesia : To prepare a dilute solution containing 1 mg of ketamine per mL, aseptically transfer 10 mL from a 50 mg per mL vial or 5 mL from a 100 mg per mL vial to 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (Normal Saline) and mix well. The resultant solution will contain 1 mg of ketamine per mL. Use immediately after dilution. When fluid restriction is required, Ketamine Hydrochloride Injection can be added to a 250 mL infusion as described above to provide a Ketamine Hydrochloride Injection concentration of 2 mg/mL.
Contraindications
4 CONTRAINDICATIONS
- Ketamine Hydrochloride Injection is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard [see Warnings and Precautions (5.1) ] .
- Ketamine Hydrochloride Injection is contraindicated in patients with known hypersensitivity to ketamine or to any excipient [see Adverse Reactions (6) ] .
- In patients for whom a significant elevation of blood pressure would be a serious hazard. ( 4 )
- Known hypersensitivity to ketamine or to any excipient. ( 4 )
Known Adverse Reactions
REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemodynamic Instability [see Warnings and Precautions ( 5.1 )]
Emergence
Reactions [see Warnings and Precautions ( 5.2 )]
Respiratory
Depression [see Warnings and Precautions ( 5.3 )]
Pediatric
Neurotoxicity [see Warnings and Precautions ( 5.5 )] Drug-Induced Liver Injury [see Warnings and Precautions ( 5.6 )] The following adverse reactions associated with the use of KETALAR were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular disorders : Elevated blood pressure, heart rate, and cardiac index; decreases in blood pressure and heart rate; arrhythmias; cardiac decompensation (in patients with suspected catecholamine depletion). Eye disorders : Diplopia, nystagmus, elevation in intraocular pressure. Gastrointestinal disorders : Anorexia, nausea, vomiting, hepatobiliary dysfunction. Biliary duct dilatation and/or biliary duct stricture and/or stenosis with or without evidence of biliary obstruction and secondary sclerosing cholangitis has been reported with recurrent use (e.g., misuse/abuse or medically supervised unapproved indications). Administration site disorders : Local pain and exanthema at the injection site. Immune system disorders : Anaphylaxis. Neurologic disorders : Emergence reactions (post-operative delirium), [see Warnings and Precautions ( 5.2 )]. During administration, enhanced muscle tone and spasms (resembling a partial motor or generalized motor seizure). Psychiatric disorders : Adverse psychiatric events have occurred and/or persisted days to weeks after ketamine exposure. Renal and urinary disorders: In individuals with history of chronic ketamine use or abuse, lower urinary tract and bladder symptoms including dysuria, increased urinary frequency, urgency, urge incontinence, and hematuria have been reported [see Dosage and Administration ( 2.1 )] . In addition, diagnostic studies performed to assess the cause of these symptoms have reported cystitis (including cystitis non-infective, cystitis interstitial, cystitis ulcerative, cystitis erosive and cystitis hemorrhagic), ureteric stenosis (strictures), ureteric obstruction as well as hydronephrosis and reduced bladder capacity. Respiratory disorders : Respiratory depression and apnea following rapid intravenous administration of high doses of KETALAR; laryngospasm, and airway obstruction. Skin and subcutaneous tissue disorders : Transient erythema and/or morbilliform rash The most common adverse reactions are emergence reactions and elevated blood pressure and pulse ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Par Health at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Warnings
AND PRECAUTIONS
- Hemodynamic Instability: Monitor vital signs and cardiac function during Ketamine Hydrochloride Injection administration. ( 5.1 )
- Emergence Reactions: Postoperative confusional states may occur during the recovery period. Reduce by minimizing verbal, tactile, and visual stimulation of the patient. ( 5.2 )
- Risk of Respiratory Depression: May occur with overdosage or too rapid a rate of administration. Maintain adequate oxygenation and ventilation. ( 5.3 )
- Risks of Ketamine Hydrochloride Injection alone for Procedures of the Pharynx, Larynx, or Bronchial Tree: Pharyngeal and laryngeal reflexes are not suppressed with Ketamine Hydrochloride Injection when it is used alone. Avoid use as a sole anesthetic agent in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree. Muscle relaxants may be required. ( 5.4 )
- Pediatric Neurotoxicity: Long-term cognitive deficits may occur when used for longer than 3 hours in children ≤3 years ( 5.5 )
5.1 Hemodynamic Instability Transient increases in blood pressure, heart rate, and cardiac index are frequently observed following administration of Ketamine Hydrochloride Injection. Decreases in blood pressure and heart rate, arrhythmias, and cardiac decompensation have also been observed. Monitor vital signs and cardiac function during Ketamine Hydrochloride Injection administration.
Ketamine Hydrochloride
Injection is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard [see Contraindications (4) ] .
5.2 Emergence Reactions Emergence delirium (postoperative confusional states or agitation) has occurred in approximately 12% of patients during the recovery period, and the duration is generally a few hours. The neuropsychological manifestations vary in severity between pleasant dream-like states, vivid imagery, hallucinations, and emergence delirium. In some cases, these states have been accompanied by confusion, excitement, and irrational behavior, which have been recalled as unpleasant experiences. No residual psychological effects are known to have resulted from use of Ketamine Hydrochloride Injection during induction and maintenance of anesthesia. Intramuscular administration results in a lower incidence of emergence reactions. The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by using lower recommended dosages of Ketamine Hydrochloride Injection in conjunction with an intravenous benzodiazepine during induction and maintenance of anesthesia <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Also, these reactions may be reduced if verbal, tactile, and visual stimulation of the patient is minimized during the recovery period. This does not preclude the monitoring of vital signs.
5.3 Respiratory Depression Respiratory depression may occur with overdosage or a rapid rate of administration of Ketamine Hydrochloride Injection. Maintain adequate oxygenation and ventilation.
5.4 Risks of Ketamine Hydrochloride Injection Alone for Procedures of the Pharynx, Larynx, or Bronchial Tree Ketamine Hydrochloride Injection does not suppress pharyngeal and laryngeal reflexes.
Avoid Ketamine Hydrochloride
Injection administration as a sole anesthetic agent during procedures of the pharynx, larynx, or bronchial tree, including mechanical stimulation of the pharynx. Muscle relaxants may be required for successful completion of procedures of the pharynx, larynx, or bronchial tree.
5.5 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.4 ), Nonclinical Toxicology (13.2) ]</span>. Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.
5.6 Drug-Induced Liver Injury Ketamine administration is associated with hepatobiliary dysfunction (most often a cholestatic pattern), with recurrent use (e.g., misuse/abuse or medically supervised unapproved indications). Biliary duct dilatation with or without evidence of biliary obstruction has also been reported with recurrent use. Obtain baseline LFTs, including alkaline phosphatase and gamma glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing. Monitor those receiving recurrent ketamine at periodic intervals during treatment.
5.7 Increase in Cerebrospinal Fluid Pressure An increase in intracranial pressure has been reported following administration of ketamine hydrochloride. Patients with elevated intracranial pressure should be in a monitored setting with frequent neurologic assessments.
5.8 Drug Interactions Theophylline or Aminophylline: Concomitant administration of Ketamine Hydrochloride Injection and theophylline or aminophylline may lower the seizure threshold <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> . Consider using an alternative to Ketamine Hydrochloride Injection in patients receiving theophylline or aminophylline. Sympathomimetics and Vasopressin: Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . Closely monitor vital signs when Ketamine Hydrochloride Injection and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patient’s clinical situation. Benzodiazepines, Opioid Analgesics, or Other CNS Depressants Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> . Closely monitor neurological status and respiratory parameters, including respiratory rate and pulse oximetry, when Ketamine Hydrochloride Injection and opioid analgesics, benzodiazepines, or other CNS depressants are co-administered. Consider dose adjustment individualized to the patient’s clinical situation.
5.1 Hemodynamic Instability Transient increases in blood pressure, heart rate, and cardiac index are frequently observed following administration of Ketamine Hydrochloride Injection. Decreases in blood pressure and heart rate, arrhythmias, and cardiac decompensation have also been observed. Monitor vital signs and cardiac function during Ketamine Hydrochloride Injection administration.
Ketamine Hydrochloride
Injection is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard [see Contraindications (4) ] .
5.2 Emergence Reactions Emergence delirium (postoperative confusional states or agitation) has occurred in approximately 12% of patients during the recovery period, and the duration is generally a few hours. The neuropsychological manifestations vary in severity between pleasant dream-like states, vivid imagery, hallucinations, and emergence delirium. In some cases, these states have been accompanied by confusion, excitement, and irrational behavior, which have been recalled as unpleasant experiences. No residual psychological effects are known to have resulted from use of Ketamine Hydrochloride Injection during induction and maintenance of anesthesia. Intramuscular administration results in a lower incidence of emergence reactions. The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by using lower recommended dosages of Ketamine Hydrochloride Injection in conjunction with an intravenous benzodiazepine during induction and maintenance of anesthesia <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Also, these reactions may be reduced if verbal, tactile, and visual stimulation of the patient is minimized during the recovery period. This does not preclude the monitoring of vital signs.
5.3 Respiratory Depression Respiratory depression may occur with overdosage or a rapid rate of administration of Ketamine Hydrochloride Injection. Maintain adequate oxygenation and ventilation.
5.4 Risks of Ketamine Hydrochloride Injection Alone for Procedures of the Pharynx, Larynx, or Bronchial Tree Ketamine Hydrochloride Injection does not suppress pharyngeal and laryngeal reflexes.
Avoid Ketamine Hydrochloride
Injection administration as a sole anesthetic agent during procedures of the pharynx, larynx, or bronchial tree, including mechanical stimulation of the pharynx. Muscle relaxants may be required for successful completion of procedures of the pharynx, larynx, or bronchial tree.
5.5 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.4 ), Nonclinical Toxicology (13.2) ]</span>. Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.
5.6 Drug-Induced Liver Injury Ketamine administration is associated with hepatobiliary dysfunction (most often a cholestatic pattern), with recurrent use (e.g., misuse/abuse or medically supervised unapproved indications). Biliary duct dilatation with or without evidence of biliary obstruction has also been reported with recurrent use. Obtain baseline LFTs, including alkaline phosphatase and gamma glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing. Monitor those receiving recurrent ketamine at periodic intervals during treatment.
5.7 Increase in Cerebrospinal Fluid Pressure An increase in intracranial pressure has been reported following administration of ketamine hydrochloride. Patients with elevated intracranial pressure should be in a monitored setting with frequent neurologic assessments.
5.8 Drug Interactions Theophylline or Aminophylline: Concomitant administration of Ketamine Hydrochloride Injection and theophylline or aminophylline may lower the seizure threshold <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> . Consider using an alternative to Ketamine Hydrochloride Injection in patients receiving theophylline or aminophylline. Sympathomimetics and Vasopressin: Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . Closely monitor vital signs when Ketamine Hydrochloride Injection and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patient’s clinical situation. Benzodiazepines, Opioid Analgesics, or Other CNS Depressants Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> . Closely monitor neurological status and respiratory parameters, including respiratory rate and pulse oximetry, when Ketamine Hydrochloride Injection and opioid analgesics, benzodiazepines, or other CNS depressants are co-administered. Consider dose adjustment individualized to the patient’s clinical situation.
Precautions
PRECAUTIONS General Ketamine should be used by or under the direction of physicians experienced in administering general anesthetics and in maintenance of an airway and in the control of respiration. Because pharyngeal and laryngeal reflexes are usually active, ketamine should not be used alone in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree. Mechanical stimulation of the pharynx should be avoided, whenever possible, if ketamine is used alone. Muscle relaxants, with proper attention to respiration, may be required in both of these instances. Resuscitative equipment should be ready for use. The incidence of emergence reactions may be reduced if verbal and tactile stimulation of the patient is minimized during the recovery period. This does not preclude the monitoring of vital signs (see SPECIAL NOTE). The intravenous dose should be administered over a period of 60 seconds. More rapid administration may result in respiratory depression or apnea and enhanced pressor response. In surgical procedures involving visceral pain pathways, ketamine should be supplemented with an agent which obtunds visceral pain. Use with caution in the chronic alcoholic and the acutely alcohol-intoxicated patient. An increase in cerebrospinal fluid pressure has been reported following administration of ketamine hydrochloride. Use with extreme caution in patients with preanesthetic elevated cerebrospinal fluid pressure. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term animal studies have not been conducted to evaluate the carcinogenic potential of ketamine. Mutagenesis In a published report, ketamine was clastogenic in the in vitro chromosomal aberration assay. Impairment of Fertility Adequate studies to evaluate the impact of ketamine on male or female fertility have not been conducted. Male and female rats were treated intravenously with 10 mg/kg ketamine (0.8 times the average human intravenous induction dose of 2 mg/kg based on body surface area) on Days 11, 10, and 9 prior to mating. No impact on fertility was noted; however, this study design does not adequately characterize the impact of a drug on fertility endpoints.
Pregnancy Risk Summary
There are no adequate and well-controlled studies of ketamine in pregnant women. In animal reproduction studies in rats developmental delays (hypoplasia of skeletal tissues) were noted at 0.3 times the human intramuscular dose of 10 mg/kg. In rabbits, developmental delays and increased fetal resorptions were noted at 0.6 times the human dose. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations
Since the safe use in pregnancy, including obstetrics (either vaginal or abdominal delivery), has not been established, such use is not recommended (see ANIMAL PHARMACOLOGY AND TOXICOLOGY).
Data Animal Data
Pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human intramuscular dose of 10 mg/kg based on body surface area) on either Gestation Days 6 to 10 or Gestation Days 11 to 15. Ketamine treatment produced an increased incidence of hypoplastic skull, phalanges, and sternebrae in the pups. Pregnant rabbits were treated intramuscularly with 20 mg/kg ketamine (0.6 times the human intramuscular dose of 10 mg/kg based on body surface area) on either Gestation Days 6 to 10 or Gestation Days 11 to 15. An increase in resorptions and skeletal hypoplasia of the fetuses were noted. Additional pregnant rabbits were treated intramuscularly with a single dose 60 mg/kg (1.9 times the human intramuscular dose of 10 mg/kg based on body surface area) on Gestation Day 6 only. Skeletal hypoplasia was reported in the fetuses. In a study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human intramuscular dose of 10 mg/kg based on body surface area) from Gestation Day 18 to 21. There was a slight increase in incidence of delayed parturition by one day in treated dams of this group. No adverse effects on the litters or pups were noted; however, learning and memory assessments were not completed. Three pregnant beagle dogs were treated intramuscularly with 25 mg/kg ketamine (1.3 times the human intramuscular dose of 10 mg/kg based on body surface area) twice weekly for the three weeks of the first, second, and third trimesters of pregnancy, respectively, without the development of adverse effects in the pups. In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits. (See WARNINGS/Pediatric Neurotoxicity, Pediatric Use, and ANIMAL TOXICOLOGY AND PHARMACOLOGY). Information for Patients Risk of Drowsiness As appropriate, especially in cases where early discharge is possible, the duration of ketamine and other drugs employed during the conduct of anesthesia should be considered. The patients should be cautioned that driving an automobile, operating hazardous machinery or engaging in hazardous activities should not be undertaken for 24 hours or more (depending upon the dosage of ketamine and consideration of other drugs employed) after anesthesia. Effect of anesthetic and sedation drugs on early brain development Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs (See WARNINGS/Pediatric Neurotoxicity).
Drug Interactions
Prolonged recovery time may occur if barbiturates and/or narcotics are used concurrently with ketamine. Ketamine is clinically compatible with the commonly used general and local anesthetic agents when an adequate respiratory exchange is maintained.
Geriatric Use
Clinical studies of ketamine hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 16 have not been established. Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as ketamine, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans. In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data. (See WARNINGS/Pediatric Neurotoxicity, Pregnancy).
Drug Interactions
INTERACTIONS Theophylline or Aminophylline: Do not co-administer with Ketamine Hydrochloride Injection as concomitant use may lower the seizure threshold ( 7.1 ). Sympathomimetics and Vasopressin: Closely monitor vital signs when coadministered with Ketamine Hydrochloride Injection. Consider dose adjustment individualized to the patient’s clinical situation ( 7.2 ). Benzodiazepines, Opioid Analgesics, or other CNS Depressants: Concomitant use may result in profound sedation, respiratory depression, coma, or death. Concomitant use of opioid analgesics may prolong recovery time. ( 7.3 ).