PRECAUTIONS SECTION.

PRECAUTIONS. General. Ketamine should be used by or under the direction of physiciansexperienced in administering general anesthetics and in maintenance of anairway and in the control of respiration.Because pharyngealand laryngeal reflexes are usually active, ketamine should not be used alonein 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.Resuscitativeequipment should be ready for use.The incidenceof emergence reactions may be reduced if verbal and tactile stimulationof the patient is minimized during the recovery period. This does not precludethe monitoring of vital signs (see SPECIAL NOTE).The intravenous dose should be administeredover period of 60 seconds. More rapid administration may result in respiratorydepression or apnea and enhanced pressor response.Insurgical procedures involving visceral pain pathways, ketamine should be supplementedwith an agent which obtunds visceral pain.Use withcaution in the chronic alcoholic and the acutely alcohol-intoxicated patient.Anincrease in cerebrospinal fluid pressure has been reported following administrationof ketamine. Use with extreme caution in patients with preanesthetic elevatedcerebrospinal fluid pressure.. Information for Patients. As appropriate, especially in cases where early dischargeis possible, the duration of ketamine and other drugs employed during theconduct of anesthesia should be considered. The patients should be cautionedthat driving an automobile, operating hazardous machinery or engaging in hazardousactivities should not be undertaken for 24 hours or more (depending upon thedosage of ketamine and consideration of other drugs employed) after anesthesia.. Drug Interactions. Prolonged recovery time may occur if barbiturates and/ornarcotics are used concurrently with ketamine.Ketamineis clinically compatible with the commonly used general and local anestheticagents when an adequate respiratory exchange is maintained.. Usage in Pregnancy. Since the safe use in pregnancy, including obstetrics (eithervaginal or abdominal delivery), has not been established, such use is notrecommended (see ANIMAL PHARMACOLOGY AND TOXICOLOGY, Reproduction).. Geriatric Use. Clinical studies of ketamine hydrochloride did not includesufficient numbers of subjects aged 65 and over to determine whether theyrespond differently from younger subjects. Other reported clinical experiencehas not identified differences in responses between the elderly and youngerpatients. In general, dose selection for an elderly patient should be cautious,usually starting at the low end of the dosing range, reflecting the greaterfrequency of decreased hepatic, renal, or cardiac function, and of concomitantdisease or other drug therapy.. Pediatric Use. Safety and effectiveness in pediatric patients below theage of 16 have not been established.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. CardiovascularBloodpressure and pulse rate are frequently elevated following administration ofketamine alone. However, hypotension and bradycardia have been observed. Arrhythmiahas also occurred.RespirationAlthough respiration is frequently stimulated,severe depression of respiration or apnea may occur following rapid intravenousadministration of high doses of ketamine. Laryngospasms and other forms ofairway obstruction have occurred during ketamine anesthesia.EyeDiplopia and nystagmushave been noted following ketamine administration. It also may cause slightelevation in intraocular pressure measurement.Psychological: (See SPECIAL NOTE.)NeurologicalIn some patients,enhanced skeletal muscle tone may be manifested by tonic and clonic movementssometimes resembling seizures (see DOSAGE AND ADMINISTRATION section).GastrointestinalAnorexia, nausea and vomiting have beenobserved; however, this is not usually severe and allows the great majorityof patients to take liquids by mouth shortly after regaining consciousness(see DOSAGE AND ADMINISTRATION section).General: AnaphylaxisLocalpain and exanthema at the injection site have infrequently been reported.Transient erythema and/or morbilliform rash have also been reported.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Ketamine is rapid-acting general anesthetic producing ananesthetic state characterized by profound analgesia, normal pharyngeal-laryngealreflexes, normal or slightly enhanced skeletal muscle tone, cardiovascularand respiratory stimulation, and occasionally transient and minimal respiratorydepression.A patent airway is maintained partly byvirtue of unimpaired pharyngeal and laryngeal reflexes. (See WARNINGS and PRECAUTIONS.)Thebiotransformation of ketamine includes N-dealkylation (metabolite I), hydroxylationof the cyclohexone ring (metabolites III and IV), conjugation with glucuronicacid and dehydration of the hydroxylated metabolites to form the cyclohexenederivative (metabolite II).Following intravenous administration,the ketamine concentration has an initial slope (alpha phase) lasting about45 minutes with half-life of 10 to 15 minutes. This first phase correspondsclinically to the anesthetic effect of the drug. The anesthetic action isterminated by combination of redistribution from the CNS to slower equilibratingperipheral tissues and by hepatic biotransformation to metabolite I. Thismetabolite 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.Theanesthetic state produced by ketamine has been termed dissociativeanesthesia in that it appears to selectively interrupt associationpathways of the brain before producing somesthetic sensory blockade. It mayselectively depress the thalamoneocortical system before significantly obtundingthe more ancient cerebral centers and pathways (reticular-activating and limbicsystems).Elevation of blood pressure begins shortlyafter injection, reaches maximum within few minutes and usually returnsto preanesthetic values within 15 minutes after injection. In the majorityof cases, the systolic and diastolic blood pressure peaks from 10% to 50%above preanesthetic levels shortly after induction of anesthesia, but theelevation can be higher or longer in individual cases (see CONTRAINDICATIONS).Ketamine has wide margin of safety;several instances of unintentional administration of overdoses of ketamine(up to ten times that usually required) have been followed by prolonged butcomplete recovery.Ketamine has been studied in over12,000 operative and diagnostic procedures, involving over 10,000 patientsfrom 105 separate studies. During the course of these studies ketamine hydrochloridewas administered as the sole agent, as induction for other general agents,or to supplement low-potency agents.Specific areasof application have included the following:debridement, painful dressings, and skin grafting in burnpatients, as well as other superficial surgical procedures.neurodiagnostic procedures such as pneumonencephalograms,ventriculograms, myelograms, and lumbar punctures. See also PRECAUTION concerning increased intracranial pressure.diagnostic and operative procedures of the eye, ear, nose,and mouth, including dental extractions. 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).sigmoidoscopy and minor surgery of the anus and rectum, andcircumcision.extraperitoneal procedures used in gynecology such as dilatationand curettage.orthopedic procedures such as closed reductions, manipulations,femoral pinning, amputations, and biopsies.as an anesthetic in poor-risk patients with depression ofvital functions.in procedures where the intramuscular route of administrationis preferred.in cardiac catheterization procedures.In these studies, the anesthesia was rated either excellentor good by the anesthesiologist and the surgeon at 90% and93%, respectively; rated fair at 6% and 4%, respectively;and rated poor at 4% and 3%, respectively. In second methodof evaluation, the anesthesia was rated adequate in at least90% and inadequate in 10% or less of the procedures.. debridement, painful dressings, and skin grafting in burnpatients, as well as other superficial surgical procedures.. neurodiagnostic procedures such as pneumonencephalograms,ventriculograms, myelograms, and lumbar punctures. See also PRECAUTION concerning increased intracranial pressure.. diagnostic and operative procedures of the eye, ear, nose,and mouth, including dental extractions. 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).. sigmoidoscopy and minor surgery of the anus and rectum, andcircumcision.. extraperitoneal procedures used in gynecology such as dilatationand curettage.. orthopedic procedures such as closed reductions, manipulations,femoral pinning, amputations, and biopsies.. as an anesthetic in poor-risk patients with depression ofvital functions.. in procedures where the intramuscular route of administrationis preferred.. in cardiac catheterization procedures.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Parenteral drug products should be inspected visually forparticulate matter and discoloration prior to administration, whenever solutionand container permit.Note: Barbiturates and ketamine, being chemically incompatible becauseof precipitate formation, should not beinjected from the same syringe.If the ketamine doseis augmented with diazepam, the two drugs must be given separately. Do notmix ketamine hydrochloride and diazepam in syringe or infusion flask. Foradditional information on the use of diazepam, refer to the WARNINGS and DOSAGE AND ADMINISTRATION sectionsof the diazepam insert.PreoperativePreparationsWhile vomiting has been reported following ketamine administration,some airway protection may be afforded because of active laryngeal-pharyngealreflexes. However, since aspiration may occur with ketamine and since protectivereflexes may also be diminished by supplementary anesthetics and muscle relaxants,the possibility of aspiration must be considered. Ketamine is recommendedfor use in the patient whose stomach is not empty when, in the judgment ofthe practitioner, the benefits of the drug outweigh the possible risks.Atropine, scopolamine, or another drying agent should begiven at an appropriate interval prior to induction.Onset and DurationBecauseof rapid induction following the initial intravenous injection, the patientshould be in supported position during administration.Theonset of action of ketamine is rapid; an intravenous dose of mg/kg (1 mg/lb)of body weight usually produces surgical anesthesia within 30 seconds afterinjection, with the anesthetic effect usually lasting five to ten minutes.If longer effect is desired, additional increments can be administered intravenouslyor intramuscularly to maintain anesthesia without producing significant cumulativeeffects.Intramuscular doses, in range of to13 mg/kg(4 to mg/lb) usually produce surgical anesthesia within to minutesfollowing injection, with the anesthetic effect usually lasting 12 to 25 minutes.DosageAs with other generalanesthetic agents, the individual response to ketamine is somewhat varieddepending on the dose, route of administration, and age of patient, so thatdosage recommendation cannot be absolutely fixed. The drug should be titratedagainst the patients requirements.InductionIntravenousRoute: The initial dose of ketamine administered intravenously mayrange from mg/kg to 4.5 mg/kg (0.5 to mg/lb). The average amountrequired to produce five to ten minutes of surgical anesthesia has been 2mg/kg (1 mg/lb).Alternatively, in adult patients aninduction dose of mg to mg/kg intravenous ketamine at rate of 0.5 mg/kg/minmay be used for induction of anesthesia. In addition, diazepam in mg to5 mg doses, administered in separate syringe over 60 seconds, may beused. In most cases, 15 mg of intravenous diazepam orless will suffice. The incidence of psychological manifestationsduring emergence, particularly dream-like observations and emergence delirium,may be reduced by this induction dosage program.Note: The 100 mg/mL concentration of ketamine should not be injected intravenously withoutproper dilution. It is recommended the drug be diluted with an equal volumeof either Sterile Water for Injection, Sodium Chloride Injection, 0.9% orDextrose Injection, 5%.Rateof Administration: It is recommended that ketamine be administeredslowly (over period of 60 seconds). More rapid administration may resultin respiratory depression and enhanced pressor response.Intramuscular Route: The initial dose of ketamineadministered intramuscularly may range from 6.5 to 13 mg/kg (3 to mg/lb).A dose of 10 mg/kg (5 mg/lb) will usually produce 12 to 25 minutes of surgicalanesthesia.Maintenance ofAnesthesiaThe maintenance dose should beadjusted according to the patients anesthetic needs and whether anadditional anesthetic agent is employed.Incrementsof one-half to the full induction dose may be repeated as needed for maintenanceof anesthesia. However, it should be noted that purposeless and tonic-clonicmovements of extremities may occur during the course of anesthesia. Thesemovements do not imply light plane and are not indicative of the need foradditional doses of the anesthetic.It should be recognizedthat the larger the total dose of ketamine administered, the longer will bethe time to complete recovery.Adult patients inducedwith ketamine augmented with intravenous diazepam may be maintained on ketaminegiven by slow microdrip infusion technique at dose of 0.1 to 0.5 mg/minute,augmented with diazepam to mg administered intravenously as needed. Inmany cases 20 mg or less of intravenousdiazepam total for combined induction and maintenance will suffice. However,slightly more diazepam may be required depending on the nature and durationof the operation, physical status of the patient, and other factors. The incidenceof psychological manifestations during emergence, particularly dream-likeobservations and emergence delirium, may be reduced by this maintenance dosageprogram.Dilution: Toprepare dilute solution containing mg of ketamine per mL, asepticallytransfer 10 mL (50 mg per mL vial) or mL (100 mg per mL vial) to 500mL of Dextrose Injection, 5% or Sodium Chloride Injection, 0.9% and mix well.The resultant solution will contain mg of ketamine per mL.Thefluid requirements of the patient and duration of anesthesia must be consideredwhen selecting the appropriate dilution of ketamine hydrochloride injection.If fluid restriction is required, ketamine hydrochloride injection can beadded to 250 mL infusion as described above to provide ketamine concentrationof mg/mL.SupplementaryAgentsKetamine is clinically compatible withthe commonly used general and local anesthetic agents when an adequate respiratoryexchange is maintained.The regimen of reduced doseof ketamine supplemented with diazepam can be used to produce balanced anesthesiaby combination with other agents such as nitrous oxide and oxygen.. While vomiting has been reported following ketamine administration,some airway protection may be afforded because of active laryngeal-pharyngealreflexes. However, since aspiration may occur with ketamine and since protectivereflexes may also be diminished by supplementary anesthetics and muscle relaxants,the possibility of aspiration must be considered. Ketamine is recommendedfor use in the patient whose stomach is not empty when, in the judgment ofthe practitioner, the benefits of the drug outweigh the possible risks.. Atropine, scopolamine, or another drying agent should begiven at an appropriate interval prior to induction.

GENERAL PRECAUTIONS SECTION.

General. Ketamine should be used by or under the direction of physiciansexperienced in administering general anesthetics and in maintenance of anairway and in the control of respiration.Because pharyngealand laryngeal reflexes are usually active, ketamine should not be used alonein 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.Resuscitativeequipment should be ready for use.The incidenceof emergence reactions may be reduced if verbal and tactile stimulationof the patient is minimized during the recovery period. This does not precludethe monitoring of vital signs (see SPECIAL NOTE).The intravenous dose should be administeredover period of 60 seconds. More rapid administration may result in respiratorydepression or apnea and enhanced pressor response.Insurgical procedures involving visceral pain pathways, ketamine should be supplementedwith an agent which obtunds visceral pain.Use withcaution in the chronic alcoholic and the acutely alcohol-intoxicated patient.Anincrease in cerebrospinal fluid pressure has been reported following administrationof ketamine. Use with extreme caution in patients with preanesthetic elevatedcerebrospinal fluid pressure.

SPL UNCLASSIFIED SECTION.

CIIIRx onlySPECIAL NOTEEMERGENCE REACTIONS HAVE OCCURRED IN APPROXIMATELY 12 PERCENTOF PATIENTS.THEPSYCHOLOGICAL MANIFESTATIONS VARY IN SEVERITY BETWEEN PLEASANT DREAM-LIKESTATES, VIVID IMAGERY, HALLUCINATIONS, AND EMERGENCE DELIRIUM. IN SOME CASESTHESE STATES HAVE BEEN ACCOMPANIED BY CONFUSION, EXCITEMENT, AND IRRATIONALBEHAVIOR WHICH FEW PATIENTS RECALL AS AN UNPLEASANT EXPERIENCE. THE DURATIONORDINARILY IS NO MORE THAN FEW HOURS; IN FEW CASES, HOWEVER, RECURRENCESHAVE TAKEN PLACE UP TO 24 HOURS POSTOPERATIVELY. NO RESIDUAL PSYCHOLOGICALEFFECTS ARE KNOWN TO HAVE RESULTED FROM USE OF KETAMINE.THE INCIDENCE OF THESE EMERGENCE PHENOMENA IS LEAST IN THEELDERLY (OVER 65 YEARS OF AGE) PATIENT. ALSO, THEY ARE LESS FREQUENT WHENTHE DRUG IS GIVEN INTRAMUSCULARLY AND THE INCIDENCE IS REDUCED AS EXPERIENCEWITH THE DRUG IS GAINED.THEINCIDENCE OF PSYCHOLOGICAL MANIFESTATIONS DURING EMERGENCE, PARTICULARLY DREAM-LIKEOBSERVATIONS AND EMERGENCE DELIRIUM, MAY BE REDUCED BY USING LOWER RECOMMENDEDDOSAGES OF KETAMINE IN CONJUNCTION WITH INTRAVENOUS DIAZEPAM DURING INDUCTIONAND MAINTENANCE OF ANESTHESIA. (See DOSAGE AND ADMINISTRATION.) ALSO, THESEREACTIONS MAY BE REDUCED IF VERBAL, TACTILE AND VISUAL STIMULATION OF THEPATIENT IS MINIMIZED DURING THE RECOVERY PERIOD. THIS DOES NOT PRECLUDE THEMONITORING OF VITAL SIGNS.INORDER TO TERMINATE SEVERE EMERGENCE REACTION THE USE OF SMALL HYPNOTICDOSE OF SHORT-ACTING OR ULTRASHORT-ACTING BARBITURATE MAY BE REQUIRED.WHEN KETAMINE IS USED ON AN OUTPATIENT BASIS, THE PATIENTSHOULD NOT BE RELEASED UNTIL RECOVERY FROM ANESTHESIA IS COMPLETE AND THENSHOULD BE ACCOMPANIED BY RESPONSIBLE ADULT.