ketamine hydrochloride injection, solution, concentrate Hospira, Inc.
Ketamine Hydrochloride Injection, USP
EMERGENCE REACTIONS HAVE OCCURRED IN APPROXIMATELY 12 PERCENT
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 A FEW PATIENTS RECALL AS AN UNPLEASANT EXPERIENCE. THE DURATION
ORDINARILY IS NO MORE THAN A FEW HOURS; IN A 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.
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.
INCIDENCE OF PSYCHOLOGICAL MANIFESTATIONS DURING EMERGENCE, PARTICULARLY DREAM-LIKE
OBSERVATIONS AND EMERGENCE DELIRIUM, MAY BE REDUCED BY USING LOWER RECOMMENDED
DOSAGES OF KETAMINE IN CONJUNCTION WITH INTRAVENOUS DIAZEPAM DURING INDUCTION
AND MAINTENANCE OF ANESTHESIA. (See DOSAGE AND ADMINISTRATION.) 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.
ORDER TO TERMINATE A SEVERE EMERGENCE REACTION THE USE OF A SMALL HYPNOTIC
DOSE OF A SHORT-ACTING OR ULTRASHORT-ACTING BARBITURATE MAY BE REQUIRED.
WHEN KETAMINE IS USED ON AN OUTPATIENT BASIS, THE PATIENT
SHOULD NOT BE RELEASED UNTIL RECOVERY FROM ANESTHESIA IS COMPLETE AND THEN
SHOULD BE ACCOMPANIED BY A RESPONSIBLE ADULT.
Ketamine hydrochloride is a nonbarbiturate anesthetic chemically
cyclohexanone hydrochloride. It is formulated as a slightly acid (pH 3.5 to
5.5) sterile solution for intravenous or intramuscular injection in concentrations
containing the equivalent of either 50 or 100 mg ketamine base per milliliter
and contains not more than 0.1 mg/mL benzethonium chloride added as a preservative.
Ketamine hydrochloride has a molecular formula of C13H16ClNO• HCl, a molecular weight of 274.19 and the following structural
Ketamine is a 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 a transient and minimal respiratory
A patent airway is maintained partly by
virtue of unimpaired pharyngeal and laryngeal reflexes. (See WARNINGS and PRECAUTIONS.)
biotransformation of ketamine 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 a 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 a 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.
anesthetic state produced by ketamine has been termed “dissociative
anesthesia” in that it appears to selectively interrupt association
pathways of the brain before producing somesthetic sensory blockade. It may
selectively depress the thalamoneocortical system before significantly obtunding
the more ancient cerebral centers and pathways (reticular-activating and limbic
Elevation of blood pressure begins shortly
after injection, reaches a maximum within a 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).
Ketamine has a 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 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.
of application have included the following:
debridement, painful dressings, and skin grafting in burn
patients, 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, and
extraperitoneal procedures used in gynecology such as dilatation
orthopedic procedures such as closed reductions, manipulations,
femoral pinning, amputations, and biopsies.
as an anesthetic in poor-risk patients with depression of
in procedures where the intramuscular route of administration
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 a second method
of evaluation, the anesthesia was rated “adequate” in at least
90% and “inadequate” in 10% or less of the procedures.
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
Ketamine hydrochloride injection is indicated
for the induction of anesthesia prior to the administration of other general
Ketamine hydrochloride injection
is indicated to supplement low-potency agents, such as nitrous oxide.
areas of application are described in the CLINICAL
Ketamine is contraindicated in those in whom a significant
elevation of blood pressure would constitute a serious hazard and in those
who have shown hypersensitivity to the drug.
Cardiac function should be continually monitored during the
procedure in patients found to have hypertension or cardiac decompensation.
confusional states may occur during the recovery period. (See SPECIAL
Respiratory depression may occur with
overdosage or too rapid a rate of administration of ketamine, in which case
supportive ventilation should be employed. Mechanical support of respiration
is preferred to administration of analeptics.
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.
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.
equipment should be ready for use.
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.
surgical procedures involving visceral pain pathways, ketamine should be supplemented
with an agent which obtunds visceral pain.
caution in the chronic alcoholic and the acutely alcohol-intoxicated patient.
increase in cerebrospinal fluid pressure has been reported following administration
of ketamine. Use with extreme caution in patients with preanesthetic elevated
cerebrospinal fluid pressure.
Information for Patients
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.
Prolonged recovery time may occur if barbiturates and/or
narcotics are used concurrently with ketamine.
is clinically compatible with the commonly used general and local anesthetic
agents when an adequate respiratory exchange is maintained.
Usage in Pregnancy
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, Reproduction).
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.
Safety and effectiveness in pediatric patients below the
age of 16 have not been established.
pressure and pulse rate are frequently elevated following administration of
ketamine alone. However, hypotension and bradycardia have been observed. Arrhythmia
has also occurred.
Although respiration is frequently stimulated,
severe depression of respiration or apnea may occur following rapid intravenous
administration of high doses of ketamine. Laryngospasms and other forms of
airway obstruction have occurred during ketamine anesthesia.
Diplopia and nystagmus
have been noted following ketamine administration. It also may cause a slight
elevation in intraocular pressure measurement.
Psychological: (See SPECIAL NOTE.)
In some patients,
enhanced skeletal muscle tone may be manifested by tonic and clonic movements
sometimes resembling seizures (see DOSAGE AND ADMINISTRATION section).
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).
pain and exanthema at the injection site have infrequently been reported.
Transient erythema and/or morbilliform rash have also been reported.
DRUG ABUSE AND DEPENDENCE
Ketamine has been reported being used as a drug of abuse.
Reports suggest that ketamine produces a 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. A withdrawal syndrome with psychotic features has
been described following discontinuation of long-term ketamine use. Therefore,
ketamine should be prescribed and administered with caution.
Respiratory depression may occur with overdosage or too rapid
a rate of administration of ketamine, in which case supportive ventilation
should be employed. Mechanical support of respiration is preferred to administration
DOSAGE AND ADMINISTRATION
Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration, whenever solution
and container permit.
Note: Barbiturates and ketamine, being chemically incompatible because
of precipitate formation, should not be
injected from the same syringe.
If the ketamine dose
is augmented with diazepam, the two drugs must be given separately. Do not
mix ketamine hydrochloride 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.
While vomiting has been reported following ketamine administration,
some airway protection may be afforded because of active laryngeal-pharyngeal
reflexes. However, since aspiration may occur with ketamine and since protective
reflexes may also be diminished by supplementary anesthetics and muscle relaxants,
the possibility of aspiration must be considered. Ketamine 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.
Atropine, scopolamine, or another drying agent should be
given at an appropriate interval prior to induction.
Onset and Duration
of rapid induction following the initial intravenous injection, the patient
should be in a supported position during administration.
onset of action of ketamine is rapid; an intravenous dose of 2 mg/kg (1 mg/lb)
of body weight usually produces surgical anesthesia within 30 seconds after
injection, with the anesthetic effect usually lasting five to ten minutes.
If a longer effect is desired, additional increments can be administered intravenously
or intramuscularly to maintain anesthesia without producing significant cumulative
Intramuscular doses, in a range of 9 to13 mg/kg
(4 to 6 mg/lb) usually produce surgical anesthesia within 3 to 4 minutes
following injection, with the anesthetic effect usually lasting 12 to 25 minutes.
As with other general
anesthetic agents, the individual response to ketamine 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 patient’s requirements.
Route: The initial dose of ketamine administered intravenously may
range from 1 mg/kg to 4.5 mg/kg (0.5 to 2 mg/lb). The average amount
required to produce five to ten minutes of surgical anesthesia has been 2
mg/kg (1 mg/lb).
Alternatively, in adult patients an
induction dose of 1 mg to 2 mg/kg intravenous ketamine at a rate of 0.5 mg/kg/min
may be used for induction of anesthesia. In addition, diazepam in 2 mg to
5 mg doses, administered in a 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 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, Sodium Chloride Injection, 0.9% or
Dextrose Injection, 5%.
of Administration: It is recommended that ketamine be administered
slowly (over a period of 60 seconds). More rapid administration may result
in respiratory depression and enhanced pressor response.
Intramuscular Route: The initial dose of ketamine
administered intramuscularly may range from 6.5 to 13 mg/kg (3 to 6 mg/lb).
A dose of 10 mg/kg (5 mg/lb) will usually produce 12 to 25 minutes of surgical
The maintenance dose should be
adjusted according to the patient’s anesthetic needs and whether an
additional anesthetic agent is employed.
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 a 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 administered, the longer will be
the time to complete recovery.
Adult patients induced
with ketamine augmented with intravenous diazepam may be maintained on ketamine
given by slow microdrip infusion technique at a dose of 0.1 to 0.5 mg/minute,
augmented with diazepam 2 to 5 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
prepare a dilute solution containing 1 mg of ketamine per mL, aseptically
transfer 10 mL (50 mg per mL vial) or 5 mL (100 mg per mL vial) to 500
mL of Dextrose Injection, 5% or Sodium Chloride Injection, 0.9% and mix well.
The resultant solution will contain 1 mg of ketamine per mL.
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 a 250 mL infusion as described above to provide a ketamine concentration
of 2 mg/mL.
Ketamine is clinically compatible with
the commonly used general and local anesthetic agents when an adequate respiratory
exchange is maintained.
The regimen of a reduced dose
of ketamine supplemented with diazepam can be used to produce balanced anesthesia
by combination with other agents such as nitrous oxide and oxygen.
Ketamine Hydrochloride Injection, USP is supplied as the
hydrochloride in concentrations equivalent to ketamine base.
Box of 10
Box of 10
Color of solution may vary from colorless to very slightly
yellowish and may darken upon prolonged exposure to light. This darkening
does not affect potency. Do not use if a precipitate appears.
at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]
ANIMAL PHARMACOLOGY AND TOXICOLOGY
acute toxicity of ketamine has been studied in several species. In mature
mice and rats, the intraperitoneal LD50 values are approximately
100 times the average human intravenous dose and approximately 20 times the
average human intramuscular dose. A slightly higher acute toxicity observed
in neonatal rats was not sufficiently elevated to suggest an increased hazard
when used in children. Daily intravenous injections in rats of five times
the average human intravenous dose and intramuscular injections in dogs at
four times the average human intramuscular dose demonstrated excellent tolerance
for as long as 6 weeks. Similarly, twice weekly anesthetic sessions of one,
three, or six hours’ duration in monkeys over a four- to six-week period
were well tolerated.
with other Drugs Commonly Used for Preanesthetic Medication
doses (three or more times the equivalent effective human dose) of morphine,
meperidine, and atropine increased the depth and prolonged the duration of
anesthesia produced by a standard anesthetizing dose of ketamine in Rhesus
monkeys. The prolonged duration was not of sufficient magnitude to contraindicate
the use of these drugs for preanesthetic medication in human clinical trials.
responses to ketamine vary with the laboratory species and experimental conditions.
Blood pressure is increased in normotensive and renal hypertensive rats with
and without adrenalectomy and under pentobarbital anesthesia.
ketamine produces a fall in arterial blood pressure in the Rhesus monkey and
a rise in arterial blood pressure in the dog. In this respect the dog mimics
the cardiovascular effect observed in man. The pressor response to ketamine
injected into intact, unanesthetized dogs is accompanied by a tachycardia,
rise in cardiac output and a fall in total peripheral resistance. It causes
a fall in perfusion pressure following a large dose injected into an artificially
perfused vascular bed (dog hindquarters), and it has little or no potentiating
effect upon vasoconstriction responses of epinephrine or norepinephrine. The
pressor response to ketamine is reduced or blocked by chlorpromazine (central
depressant and peripheral α-adrenergic blockade), by β-adrenergic
blockade, and by ganglionic blockade. The tachycardia and increase in myocardial
contractile force seen in intact animals does not appear in isolated hearts
(Langendorff) at a concentration of 0.1 mg of ketamine nor in Starling dog
heart-lung preparations at a ketamine concentration of 50 mg/kg of HLP. These
observations support the hypothesis that the hypertension produced by ketamine
is due to selective activation of central cardiac stimulating mechanisms leading
to an increase in cardiac output. The dog myocardium is not sensitized to
epinephrine and ketamine appears to have a weak antiarrhythmic activity.
is rapidly absorbed following parenteral administration. Animal experiments
indicated that ketamine was rapidly distributed into body tissues, with relatively
high concentrations appearing in body fat, liver, lung, and brain; lower concentrations
were found in the heart, skeletal muscle, and blood plasma. Placental transfer
of the drug was found to occur in pregnant dogs and monkeys. No significant
degree of binding to serum albumin was found with ketamine.
studies in rats, dogs, and monkeys resulted in the recovery of 85% to 95%
of the dose in the urine, mainly in the form of degradation products. Small
amounts of drug were also excreted in the bile and feces. Balance studies
with tritium-labeled ketamine in human subjects (1 mg/lb given intravenously)
resulted in the mean recovery of 91% of the dose in the urine and 3% in the
feces. Peak plasma levels averaged about 0.75 mcg/mL, and CSF levels were
about 0.2 mcg/mL, 1 hour after dosing.
undergoes N-demethylation and hydroxylation of the cyclohexanone ring, with
the formation of water-soluble conjugates which are excreted in the urine.
Further oxidation also occurs with the formation of a cyclohexanone derivative.
The unconjugated N-demethylated metabolite was found to be less than one-sixth
as potent as ketamine. The unconjugated demethyl cyclohexanone derivative
was found to be less than one-tenth as potent as ketamine. Repeated doses
of ketamine administered to animals did not produce any detectable increase
in microsomal enzyme activity.
Male and female rats, when given five times
the average human intravenous dose of ketamine for three consecutive days
about one week before mating, had a reproductive performance equivalent to
that of saline-injected controls. When given to pregnant rats and rabbits
intramuscularly at twice the average human intramuscular dose during the respective
periods of organogenesis, the litter characteristics were equivalent to those
of saline-injected controls. A small group of rabbits was given a single large
dose (six times the average human dose) of ketamine on Day 6 of pregnancy
to simulate the effect of an excessive clinical dose around the period of
nidation. The outcome of pregnancy was equivalent in control and treated groups.
determine the effect of ketamine on the perinatal and postnatal period, pregnant
rats were given twice the average human intramuscular dose during Days 18
to 21 of pregnancy. Litter characteristics at birth and through the weaning
period were equivalent to those of the control animals. There was a slight
increase in incidence of delayed parturition by one day in treated dams of
this group. Three groups each of mated beagle bitches were given 2.5 times
the average human intramuscular dose 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.