ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Cardiovascular: Blood pressure and pulse rate are frequently elevated following administration of ketamine hydrochloride alone. However, hypotension and bradycardia have been observed. Arrhythmia has also occurred. Respiration: Although respiration is frequently stimulated, severe depression of respiration or apnea may occur following rapid intravenous administration of high doses of ketamine hydrochloride injection. Laryngospasms and other forms of airway obstruction have occurred during ketamine hydrochloride anesthesia. Eye: Diplopia and nystagmus have been noted following ketamine hydrochloride administration. It also may cause slight elevation in intraocular pressure measurement. Genitourinary: 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 section). 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) as well as hydronephrosis and reduced bladder capacity. Psychological: (See SPECIAL NOTE.) Neurological: In some patients, enhanced skeletal muscle tone may be manifested by tonic and clonic movements sometimes resembling seizures (see DOSAGE AND ADMINISTRATION section). Gastrointestinal: Anorexia, nausea and vomiting have been observed; however, this is not usually severe and allows the great majority of patients to take liquids by mouth shortly after regaining consciousness (see DOSAGE AND ADMINISTRATION section). General: Anaphylaxis. Local pain and exanthema at the injection site have infrequently been reported. Transient erythema and/or morbilliform rash have also been reported. For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact AuroMedics Pharma LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

ANIMAL PHARMACOLOGY AND TOXICOLOGY. Published studies in animals demonstrate that the use of anesthetic agents 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 through the first several months of life, but may extend out to approximately years of age in humans. In primates, exposure to hours of an anesthetic regimen that produced light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but 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 neonates and young children who require procedures against the potential risks suggested by the nonclinical data (see WARNINGS: Pediatric Neurotoxicity, PRECAUTIONS: Pregnancy, and PRECAUTIONS: Pediatric Use). In published studies, intraperitoneal administration of ketamine at doses greater than 40 mg/kg induced vacuolation in neuronal cells of the posterior cingulate and retrosplenial cortices in adult rats, similar to what has been reported in rodents administered other NMDA receptor antagonists. These vacuoles were demonstrated to be reversible and did not progress to degeneration or neuronal death up to doses of 80 mg/kg (1.2 times the human dose of 10 mg/kg based on body surface area). no-effect level for neuronal vacuolation was 20 mg/kg intraperitoneal (0.3 times human dose of 10 mg/kg on body surface area basis). The window of vulnerability to these changes is believed to correlate with exposures in humans from the onset of puberty through adulthood. The relevance of this finding to humans is unknown. Distributed by: AuroMedics Pharma LLC 279 Princeton-Hightstown Rd.E. Windsor, NJ 08520 Manufactured by: Mylan Institutional Galway, Ireland Revised: October 2021.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Ketamine hydrochloride is rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally transient and minimal respiratory depression. The mechanism of action is primarily due to antagonism of N-methyl-D-aspartate (NMDA receptors) in the central nervous system. patent airway is maintained partly by virtue of unimpaired pharyngeal and laryngeal reflexes (see WARNINGS and PRECAUTIONS sections). The biotransformation of ketamine hydrochloride includes N-dealkylation (metabolite I), 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). Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug. The anesthetic action is terminated by combination of redistribution from the CNS to slower equilibrating peripheral tissues and by hepatic biotransformation to metabolite I. This metabolite is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat. The later half-life of ketamine (beta phase) is 2.5 hours. The anesthetic state produced by ketamine hydrochloride has been termed dissociative anesthesia in that it appears to selectively interrupt association pathways of the brain before producing somatesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems). Elevation of blood pressure begins shortly after injection, reaches maximum within few minutes and usually returns to preanesthetic values within 15 minutes after injection. In the majority of cases, the systolic and diastolic blood pressure peaks from 10% to 50% above preanesthetic levels shortly after induction of anesthesia, but the elevation can be higher or longer in individual cases (see CONTRAINDICATIONS section). Ketamine has wide margin of safety; several instances of unintentional administration of overdoses of ketamine hydrochloride injection (up to ten times that usually required) have been followed by prolonged but complete recovery. Ketamine hydrochloride has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients from 105 separate studies. During the course of these studies ketamine hydrochloride was administered as the sole agent, as induction for other general agents, or to supplement low-potency agents. Specific areas of application have included the following: 1. debridement, painful dressings, and skin grafting in burn patients, as well as other superficial surgical procedures. 2. neurodiagnostic procedures such as pneumonencephalograms, ventriculograms, myelograms, and lumbar punctures. See also Precaution concerning increased intracranial pressure. 3. diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental extractions. 4. diagnostic and operative procedures of the pharynx, larynx, or bronchial tree. NOTE: Muscle relaxants, with proper attention to respiration, may be required (see PRECAUTIONS section). 5. sigmoidoscopy and minor surgery of the anus and rectum, and circumcision. 6. extraperitoneal procedures used in gynecology such as dilatation and curettage. 7. orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies. 8. as an anesthetic in poor-risk patients with depression of vital functions. 9. in procedures where the intramuscular route of administration is preferred. 10. in cardiac catheterization procedures. In these studies, the anesthesia was rated either excellent or good by the anesthesiologist and the surgeon at 90% and 93%, respectively; rated fair at 6% and 4%, respectively; and rated poor at 4% and 3%, respectively. In second method of evaluation, the anesthesia was rated adequate in at least 90%, and inadequate in 10% or less of the procedures.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Ketamine hydrochloride is contraindicated in those in whom significant elevation of blood pressure would constitute serious hazard and in those who have shown hypersensitivity to the drug.

DESCRIPTION SECTION.

DESCRIPTION. Ketamine hydrochloride injection, USP is nonbarbiturate general anesthetic chemically designated dl 2-(o-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride. It is formulated as slightly acid (pH 3.5 to 5.5) sterile solution for intravenous or intramuscular injection in concentrations containing the equivalent of either 10 mg, 50 mg or 100 mg ketamine base per milliliter and contains not more than 0.1 mg/mL benzethonium chloride added as preservative. The 10 mg/mL solution has been made isotonic with sodium chloride. Molecular Weight: 274.19 C13H16ClNO.HCl. ketamine-structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Note: Barbiturates and ketamine hydrochloride injection, being chemically incompatible because of precipitate formation, should not be injected from the same syringe. If the ketamine hydrochloride injection dose is augmented with diazepam, the two drugs must be given separately. Do not mix ketamine hydrochloride injection and diazepam in syringe or infusion flask. For additional information on the use of diazepam, refer to the WARNINGS and DOSAGE AND ADMINISTRATION sections of the diazepam insert. Preoperative Preparations: 1. While vomiting has been reported following ketamine hydrochloride injection administration, some airway protection may be afforded because of active laryngeal-pharyngeal reflexes. However, since aspiration may occur with ketamine hydrochloride injection and since protective reflexes may also be diminished by supplementary anesthetics and muscle relaxants, the possibility of aspiration must be considered. Ketamine hydrochloride injection is recommended for use in the patient whose stomach is not empty when, in the judgment of the practitioner, the benefits of the drug outweigh the possible risks.2. Atropine, scopolamine, or another drying agent should be given at an appropriate interval prior to induction. Onset and Duration: Because of rapid induction following the initial intravenous injection, the patient should be in supported position during administration. The onset of action of ketamine hydrochloride injection is rapid; an intravenous dose of mg/kg of body weight usually produces surgical anesthesia within 30 seconds after injection, with the anesthetic effect usually lasting five to ten minutes. If longer effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia without producing significant cumulative effects. Intramuscular doses, in range of mg/kg to 13 mg/kg usually produce surgical anesthesia within to minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes. Dosage: As with other general anesthetic agents, the individual response to ketamine hydrochloride injection is somewhat varied depending on the dose, route of administration, and age of patient, so that dosage recommendation cannot be absolutely fixed. The drug should be titrated against the patients requirements. In individuals with 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 section). Consider cessation of ketamine if genitourinary pain continues in the setting of other genitourinary symptoms. Induction: Intravenous Route: The initial dose of ketamine hydrochloride injection administered intravenously may range from mg/kg to 4.5 mg/kg. The average amount required to produce five to ten minutes of surgical anesthesia has been mg/kg. Alternatively, in adult patients an induction dose of mg to mg/kg intravenous ketamine at rate of 0.5 mg/kg/min may be used for induction of anesthesia. In addition, diazepam in mg to mg doses, administered in separate syringe over 60 seconds, may be used. In most cases, 15 mg of intravenous diazepam or less will suffice. The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by this induction dosage program. Note: The 100 mg/mL concentration of ketamine hydrochloride injection should not be injected intravenously without proper dilution. It is recommended the drug be diluted with an equal volume of either Sterile Water for injection, USP, Normal Saline, or 5% Dextrose in Water. Rate of Administration: It is recommended that ketamine hydrochloride injection be administered slowly (over period of 60 seconds). More rapid administration may result in respiratory depression and enhanced pressor response. Intramuscular Route: The initial dose of ketamine hydrochloride injection administered intramuscularly may range from 6.5 mg/kg to 13 mg/kg. dose of 10 mg/kg will usually produce 12 to 25 minutes of surgical anesthesia. Maintenance of Anesthesia: The maintenance dose should be adjusted according to the patients anesthetic needs and whether an additional anesthetic agent is employed. Increments of one-half to the full induction dose may be repeated as needed for maintenance of anesthesia. However, it should be noted that purposeless and tonic-clonic movements of extremities may occur during the course of anesthesia. These movements do not imply light plane and are not indicative of the need for additional doses of the anesthetic. It should be recognized that the larger the total dose of ketamine hydrochloride injection administered, the longer will be the time to complete recovery. Adult patients induced with ketamine hydrochloride injection augmented with intravenous diazepam may be maintained on ketamine hydrochloride injection given by slow microdrip infusion technique at dose of 0.1 mg/minute to 0.5 mg/minute, augmented with diazepam mg to mg administered intravenously as needed. In many cases 20 mg or less of intravenous diazepam total for combined induction and maintenance will suffice. However, slightly more diazepam may be required depending on the nature and duration of the operation, physical status of the patient, and other factors. The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by this maintenance dosage program. Dilution: To prepare dilute solution containing mg of ketamine per mL, aseptically transfer 10 mL from 50 mg per mL vial or mL from 100 mg per mL vial to 500 mL of 5% Dextrose Injection, USP or Sodium Chloride (0.9%) Injection, USP (Normal Saline) and mix well. The resultant solution will contain mg of ketamine per mL. The fluid requirements of the patient and duration of anesthesia must be considered when selecting the appropriate dilution of ketamine hydrochloride injection. If fluid restriction is required, ketamine hydrochloride injection can be added to 250 mL infusion as described above to provide ketamine hydrochloride injection concentration of mg/mL. Ketamine hydrochloride injection 10 mg/mL vials are not recommended for dilution. Supplementary Agents: Ketamine hydrochloride injection is clinically compatible with the commonly used general and local anesthetic agents when an adequate respiratory exchange is maintained. The regimen of reduced dose of ketamine hydrochloride injection supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents such as nitrous oxide and oxygen. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. Ketamine has been reported being used as drug of abuse. Reports suggest that ketamine produces variety of symptoms including, but not limited to anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations, and psychotic episodes. Ketamine dependence and tolerance are possible following prolonged administration. withdrawal syndrome with psychotic features has been described following discontinuation of long-term ketamine use. Therefore, ketamine should be prescribed and administered with caution.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Ketamine Hydrochloride Injection, USP is supplied as the hydrochloride in concentrations equivalent to ketamine base. NDC 55150-438-10 carton containing 10, 20 mL multiple-dose vials with 10 mg/mL NDC 55150-439-10 carton containing 10, 10 mL multiple-dose vials with 50 mg/mL NDC 55150-440-10 carton containing 10, 10 mL multiple-dose vials with 100 mg/mL Store at 20o to 25oC (68o to 77oF) [see USP Controlled Room Temperature]. Protect from light. Retain in carton until time of use. The vial stopper is not made with natural rubber latex.

INDICATIONS & USAGE SECTION.

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. Ketamine hydrochloride injection is best suited for short procedures but it can be used, with additional doses, for longer procedures. Ketamine hydrochloride injection is indicated for the induction of anesthesia prior to the administration of other general anesthetic agents. Ketamine hydrochloride injection is indicated to supplement low-potency agents, such as nitrous oxide. Specific areas of application are described in the CLINICAL PHARMACOLOGY section.

OVERDOSAGE SECTION.

OVERDOSAGE. Respiratory depression may occur with overdosage or too rapid rate of administration of ketamine hydrochloride in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to administration of analeptics.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL- 200 mg/20 mL (10 mg/mL) Container Label. NDC 55150-438-01Rx onlyKetamine CIIIHydrochlorideInjection, USP200 mg/20 mL(10 mg/mL)For Intramuscular orSlow Intravenous Use20 mL Multiple-Dose VialAUROMEDICS. ketamine-figure-1.

PRECAUTIONS SECTION.

PRECAUTIONS. General: Ketamine hydrochloride 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 hydrochloride 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 hydrochloride 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 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 hydrochloride 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 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 with 10 mg/kg ketamine IV (0.8 times the average human induction dose of mg/kg IV based on body surface area) on Days 11, 10, and prior to mating. No impact on fertility was noted; however, this study design does not adequately characterize the impact of drug on fertility endpoints. Pregnancy: Risk Summary: There are no adequate and well-controlled studies of ketamine hydrochloride 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 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 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 to 4% and 15 to 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 dose of 10 mg/kg IM based on body surface area) on either Gestation Days 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 dose of 10 mg/kg IM based on body surface area) on either Gestation Days 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 single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg IM based on body surface area) on Gestation Day only. Skeletal hypoplasia was reported in the fetuses. In study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) from Gestation Day 18 to 21. There was 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 dose of 10 mg/kg IM 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 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 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, PRECAUTIONS: 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 hydrochloride 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 hydrochloride 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 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 hydrochloride. Ketamine hydrochloride 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 hydrochloride 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 years of age in humans. In primates, exposure to hours of ketamine that produced light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 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 and PRECAUTIONS: Pregnancy).

SPL UNCLASSIFIED SECTION.

Rx only For intravenous and intramuscular use SPECIAL NOTE: EMERGENCE REACTIONS HAVE OCCURRED IN APPROXIMATELY 12 PERCENT OF PATIENTS. THE PSYCHOLOGICAL 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 FEW PATIENTS RECALL AS AN UNPLEASANT EXPERIENCE. THE DURATION ORDINARILY IS NO MORE THAN FEW HOURS; IN FEW CASES, HOWEVER, RECURRENCES HAVE TAKEN PLACE UP TO 24 HOURS POSTOPERATIVELY. NO RESIDUAL PSYCHOLOGICAL EFFECTS ARE KNOWN TO HAVE RESULTED FROM USE OF KETAMINE HYDROCHLORIDE INJECTION. THE INCIDENCE OF THESE EMERGENCE PHENOMENA IS LEAST IN THE ELDERLY (OVER 65 YEARS OF AGE) PATIENT. ALSO, THEY ARE LESS FREQUENT WHEN THE DRUG IS GIVEN INTRAMUSCULARLY AND THE INCIDENCE IS REDUCED AS EXPERIENCE WITH THE DRUG IS GAINED. 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 INTRAVENOUS DIAZEPAM DURING INDUCTION AND MAINTENANCE OF ANESTHESIA (see DOSAGE AND ADMINISTRATION section). 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. IN ORDER TO TERMINATE SEVERE EMERGENCE REACTION, THE USE OF SMALL HYPNOTIC DOSE OF SHORT-ACTING OR ULTRA SHORT-ACTING BARBITURATE MAY BE REQUIRED. WHEN KETAMINE HYDROCHLORIDE INJECTION IS USED ON AN OUTPATIENT BASIS, THE PATIENT SHOULD NOT BE RELEASED UNTIL RECOVERY FROM ANESTHESIA IS COMPLETE AND THEN SHOULD BE ACCOMPANIED BY RESPONSIBLE ADULT.

WARNINGS SECTION.

WARNINGS. Cardiac function should be continually monitored during the procedure in patients found to have hypertension or cardiac decompensation. Postoperative confusional states may occur during the recovery period (see SPECIAL NOTE). Respiratory depression may occur with overdosage or too rapid rate of administration of ketamine hydrochloride in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to administration of analeptics. 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 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 (see PRECAUTIONS: Pregnancy). 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 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.

ABUSE SECTION.

9.2 Abuse. Individuals with history of drug abuse or dependence may be at greater risk for abuse and misuse of ketamine hydrochloride. Abuse is the intentional, non-therapeutic use of drug, even once, for its psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. In context of drug abuse, ketamine hydrochloride may produce variety of symptoms including anxiety, dysphoria, disorientation, insomnia, flashback, hallucinations, and feelings of floating, detachment and being spaced out Recurrent high-dose ketamine misuse or abuse may be associated with memory and/or attention impairment.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis Long-term animal studies have not been conducted to evaluate the carcinogenic potential of ketamine. Mutagenesis In 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 with 10 mg/kg ketamine IV (0.8 times the average human induction dose of mg/kg IV based on body surface area) on Days 11, 10, and prior to mating. No impact on fertility was noted; however, this study design does not adequately characterize the impact of drug on fertility endpoints.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Ketamine hydrochloride has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients in 105 separate studies. During the course of these studies, ketamine hydrochloride was administered as the sole general anesthetic, as an induction agent prior to administration of other general anesthetics, or to supplement other anesthetic agents. Ketamine hydrochloride has been evaluated during the following procedures:debridement, dressing changes, and skin grafting in burn patients, as well as other superficial surgical procedures.neurodiagnostic procedures such as myelograms and lumbar punctures.diagnostic and operative procedures of the ear, nose, and mouth, including dental extractions.sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.extraperitoneal procedures, such as dilatation and curettage.orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.cardiac catheterization procedures.. debridement, dressing changes, and skin grafting in burn patients, as well as other superficial surgical procedures.. neurodiagnostic procedures such as myelograms and lumbar punctures.. diagnostic and operative procedures of the ear, nose, and mouth, including dental extractions.. sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.. extraperitoneal procedures, such as dilatation and curettage.. orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.. cardiac catheterization procedures.

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance. Ketamine hydrochloride contains ketamine, Schedule III controlled substance under the Controlled Substance Act.

DEPENDENCE SECTION.

9.3 Dependence. Physical dependence has been reported with prolonged use of ketamine. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of drug. Withdrawal symptoms have been reported after the discontinuation of frequently used (more than weekly), large doses of ketamine for long periods of time. Reported symptoms of withdrawal associated with daily intake of large doses of ketamine include craving, fatigue, poor appetite, and anxiety. Tolerance has been reported with prolonged use of ketamine. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Ketamine hydrochloride injection, USP is clear, colorless, sterile solution available in multiple-dose vials containing 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).200 mg/20 mL (10 mg/mL)500 mg/10 mL (50 mg/mL)1,000 mg/10 mL (100 mg/mL). 200 mg/20 mL (10 mg/mL). 500 mg/10 mL (50 mg/mL). 1,000 mg/10 mL (100 mg/mL). Injection: 200 mg/20 mL (10 mg/mL), 500 mg/10 mL (50 mg/mL), and 1,000 mg/10 mL (100 mg/mL) multiple-dose vials (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Theophylline or Aminophylline: Do not co-administer with ketamine hydrochloride as concomitant use may lower the seizure threshold (7.1). Sympathomimetics and Vasopressin: Closely monitor vital signs when co-administered with ketamine hydrochloride. Consider dose adjustment individualized to the patients 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).. 7.1 Theophylline or Aminophylline. Concomitant administration of ketamine hydrochloride and theophylline or aminophylline may lower the seizure threshold. Consider using an alternative to ketamine hydrochloride in patients receiving theophylline or aminophylline.. 7.2 Sympathomimetics and Vasopressin. Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine. Closely monitor vital signs when ketamine hydrochloride and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patients clinical situation.. 7.3 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 [see Warnings and Precautions (5.8)]. Opioid analgesics administered concomitantly with ketamine hydrochloride may prolong time to complete recovery from anesthesia.

GERIATRIC USE SECTION.

8.5 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 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 and Precautions (5.5)]. Due to the residual anesthetic effects and the potential for drowsiness, advise patients not to drive an automobile, operate hazardous machinery, or engage in hazardous activities within 24 hours of receiving ketamine hydrochloride.Distributed by: AuroMedics Pharma LLC 279 Princeton-Hightstown Rd.E. Windsor, NJ 08520 Manufactured by: Mylan Institutional Galway, Ireland. Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 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 and Precautions (5.5)].. Due to the residual anesthetic effects and the potential for drowsiness, advise patients not to drive an automobile, operate hazardous machinery, or engage in hazardous activities within 24 hours of receiving ketamine hydrochloride.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Ketamine hydrochloride, racemic mixture of ketamine, is non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The major circulating metabolite of ketamine (norketamine) demonstrated activity at the same receptor with less affinity. Norketamine is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis Long-term animal studies have not been conducted to evaluate the carcinogenic potential of ketamine. Mutagenesis In 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 with 10 mg/kg ketamine IV (0.8 times the average human induction dose of mg/kg IV based on body surface area) on Days 11, 10, and prior to mating. No impact on fertility was noted; however, this study design does not adequately characterize the impact of drug on fertility endpoints.. 13.2 Animal Toxicology and/or Pharmacology. Published studies in animals demonstrate that the use of anesthetic agents 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 through the first several months of life, but may extend out to approximately years of age in humans. In primates, exposure to hours of an anesthetic regimen that produced light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but 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 neonates and young children who require procedures against the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.4)]. In published studies, intraperitoneal administration of ketamine at doses greater than 40 mg/kg induced vacuolation in neuronal cells of the posterior cingulate and retrosplenial cortices in adult rats, similar to what has been reported in rodents administered other NMDA receptor antagonists. These vacuoles were demonstrated to be reversible and did not progress to degeneration or neuronal death up to doses of 80 mg/kg (1.2 times the human dose of 10 mg/kg based on body surface area). no-effect level for neuronal vacuolation was 20 mg/kg intraperitoneal (0.3 times human dose of 10 mg/kg on body surface area basis). The window of vulnerability to these changes is believed to correlate with exposures in humans from the onset of puberty through adulthood. The relevance of this finding to humans is unknown.

PEDIATRIC USE SECTION.

8.4 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 hydrochloride, 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 years of age in humans. In primates, exposure to hours of ketamine that produced light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 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 neonates and young children who require procedures with the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.5), Use in Specific Populations (8.1), and Nonclinical Toxicology (13.2)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Nervous System Ketamine is rapidly-acting general anesthetic producing dissociative anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally transient and minimal respiratory depression. The mechanism of action is primarily due to antagonism of N-methyl-D-aspartate (NMDA receptors) in the central nervous system. Ketamine can produce nystagmus with pupillary dilation, salivation, lacrimation, and spontaneous limb movements with increased muscle tone through indirect sympathomimetic activity. Ketamine produces analgesia. Ketamine-induced emergence delirium can be reduced with benzodiazepines. Cardiovascular System Ketamine increases blood pressure, heart rate, and cardiac output. Cardiovascular effects of ketamine are indirect and believed to be mediated by inhibition of both central and peripheral catecholamine reuptake. Elevation of blood pressure reaches maximum within few minutes of injection and usually returns to preanesthetic values within 15 minutes. In the majority of cases, the systolic and diastolic blood pressure peaks from 10% to 50% above preanesthetic levels shortly after induction of anesthesia, but the elevation can be higher or longer in individual cases. Respiratory System Ketamine is potent bronchodilator suitable for anesthetizing patients at high risk for bronchospasm.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Distribution Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug. Elimination Metabolism Ketamine is metabolized via N-dealkylation to the active metabolite norketamine primarily by CYP2B6 and CYP3A4 and to lesser extent by other CYP enzymes. Norketamine undergoes hydroxylation of the cyclohexone ring to form hydroxynorketamine compounds via CYP-dependent pathways, which are conjugated with glucuronic acid and subsequently undergo dehydration of the hydroxylated metabolites to form the cyclohexene derivative dehydroxynorketamine. Excretion Following intravenous administration, the ketamine concentration decreases due to combination of redistribution from the CNS to slower equilibrating peripheral tissues and hepatic biotransformation to norketamine. The redistribution half-life of ketamine from the CNS to slower equilibrating peripheral tissues (beta phase) is 2.5 hours.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary There are no adequate and well-controlled studies of ketamine hydrochloride 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 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 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 to 4% and 15 to 20%, respectively. Clinical Considerations Ketamine hydrochloride use in pregnancy, including obstetrics (either vaginal or abdominal delivery), is not recommended because safe use has not been established [see Warnings and Precautions (5.5), Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)]. Data Animal Data Pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days 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 dose of 10 mg/kg IM based on body surface area) on either Gestation Days 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 single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg IM based on body surface area) on Gestation Day only. Skeletal hypoplasia was reported in the fetuses. In study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) from Gestation Day 18 to 21. There was 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 (3) pregnant beagle dogs were treated intramuscularly with 25 mg/kg ketamine (1.3 times the human dose of 10 mg/kg IM 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 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 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 and Precautions (5.5), Use in Specific Populations (8.4), and Nonclinical Toxicology (13.2)].

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions (5.6) 06/2022.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Animal data show that ketamine hydrochloride may cause harm to the fetus; avoid use during pregnancy, labor, and delivery (8.1). 8.1 Pregnancy. Risk Summary There are no adequate and well-controlled studies of ketamine hydrochloride 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 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 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 to 4% and 15 to 20%, respectively. Clinical Considerations Ketamine hydrochloride use in pregnancy, including obstetrics (either vaginal or abdominal delivery), is not recommended because safe use has not been established [see Warnings and Precautions (5.5), Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)]. Data Animal Data Pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days 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 dose of 10 mg/kg IM based on body surface area) on either Gestation Days 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 single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg IM based on body surface area) on Gestation Day only. Skeletal hypoplasia was reported in the fetuses. In study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) from Gestation Day 18 to 21. There was 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 (3) pregnant beagle dogs were treated intramuscularly with 25 mg/kg ketamine (1.3 times the human dose of 10 mg/kg IM 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 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 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 and Precautions (5.5), Use in Specific Populations (8.4), and Nonclinical Toxicology (13.2)].. 8.4 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 hydrochloride, 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 years of age in humans. In primates, exposure to hours of ketamine that produced light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 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 neonates and young children who require procedures with the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.5), Use in Specific Populations (8.1), and Nonclinical Toxicology (13.2)].. 8.5 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hemodynamic Instability: Monitor vital signs and cardiac function during ketamine hydrochloride 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 rate of administration. Maintain adequate oxygenation and ventilation. (5.3) Risks of Ketamine Hydrochloride Alone for Procedures of the Pharynx, Larynx, or Bronchial Tree: Pharyngeal and laryngeal reflexes are not suppressed with ketamine hydrochloride when it is used alone. Avoid use as 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 hours in children <= years (5.5). Hemodynamic Instability: Monitor vital signs and cardiac function during ketamine hydrochloride 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 rate of administration. Maintain adequate oxygenation and ventilation. (5.3). Risks of Ketamine Hydrochloride Alone for Procedures of the Pharynx, Larynx, or Bronchial Tree: Pharyngeal and laryngeal reflexes are not suppressed with ketamine hydrochloride when it is used alone. Avoid use as 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 hours in children <= 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. Decreases in blood pressure and heart rate, arrhythmias, and cardiac decompensation have also been observed. Monitor vital signs and cardiac function during ketamine hydrochloride administration. Ketamine hydrochloride is contraindicated in patients for whom significant elevation of blood pressure would constitute 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 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, exctextent, and irrational behavior, which have been recalled as unpleasant experiences. No residual psychological effects are known to have resulted from use of ketamine hydrochloride during induction and maintenance of anesthesia. Intramuscular administration results in 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 in conjunction with an intravenous benzodiazepine during induction and maintenance of anesthesia [see Dosage and Administration (2.3)]. 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 rapid rate of administration of ketamine hydrochloride. Maintain adequate oxygenation and ventilation.. 5.4 Risks of Ketamine Hydrochloride Alone for Procedures of the Pharynx, Larynx, or Bronchial Tree. Ketamine hydrochloride does not suppress pharyngeal and laryngeal reflexes. Avoid ketamine hydrochloride administration as 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 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 [see Use in Specific Populations (8.1, 8.4), Nonclinical Toxicology (13.2)]. 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 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 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 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 monitored setting with frequent neurologic assessments.. 5.8 Drug Interactions. Theophylline or Aminophylline: Concomitant administration of ketamine hydrochloride and theophylline or aminophylline may lower the seizure threshold [see Drug Interactions (7.1)]. Consider using an alternative to ketamine hydrochloride in patients receiving theophylline or aminophylline. Sympathomimetics and Vasopressin: Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine [see Drug Interactions (7.2)]. Closely monitor vital signs when ketamine hydrochloride and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patients 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 [see Drug Interactions (7.3)]. Closely monitor neurological status and respiratory parameters, including respiratory rate and pulse oximetry, when ketamine hydrochloride and opioid analgesics, benzodiazepines, or other CNS depressants are co-administered. Consider dose adjustment individualized to the patients clinical situation.