Ketamine Hydrochloride

CLINICAL PHARMACOLOGY

Ketamine hydrochloride injection 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 depression.

A patent airway is maintained partly by virtue of unimpaired pharyngeal and laryngeal reflexes. (See WARNINGS AND PRECAUTIONS Sections.)

The biotransformation of ketamine hydrochloride injection 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.

The anesthetic state produced by ketamine hydrochloride injection 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 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 Section).

Ketamine has a 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 injection 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 injection 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 pharnyx, 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 dilation 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 a second method of evaluation, the anesthesia was rated "adequate" in at least 90% and "inadequate" in 10% or less of the procedures.

KETAMINE HYDROCHLORIDE INDICATIONS AND USAGE

Ketamine Hydrochloride Injection, USP is indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. Ketamine Hydrochloride Injection, USP is best suited for short procedures but it can be used, with additional doses, for longer procedures.

Ketamine Hydrochloride Injection, USP is indicated for the induction of anesthesia prior to the administration of other general anesthetic agents.

Ketamine Hydrochloride Injection, USP is indicated to supplement low-potency agents, such as nitrous oxide.

Specific areas of application are described in the CLINICAL PHARMACOLOGY Section.

KETAMINE HYDROCHLORIDE CONTRAINDICATIONS

Ketamine hydrochloride 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.

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 a rate of administration of ketamine hydrochloride injection, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to administration of analeptics.

PRECAUTIONS

General

Ketamine hydrochloride injection 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 injection 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 injection is used alone. Muscle relaxants, with proper attention to respiration, may be required in both of these instances.

Resuscitative equipment should be ready for use.

The incidence of emergence reactions may be reduced if verbal and tactile stimulation of the patient is minimized during the recovery period. This does not preclude the monitoring of vital signs (see Special Note).

The intravenous dose should be administered over a period of 60 seconds. More rapid administration may result in respiratory depression or apnea and enhanced pressor response.

In surgical procedures involving visceral pain pathways, ketamine hydrochloride injection 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.

Information for Patients

As appropriate, especially in cases where early discharge is possible, the duration of ketamine hydrochloride injection 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 injection and consideration of other drugs employed) after anesthesia.

Drug Interactions

Prolonged recovery time may occur if barbiturates and/or narcotics are used concurrently with ketamine hydrochloride injection.

Ketamine hydrochloride injection 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).

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 16 have not been established.

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.

KETAMINE HYDROCHLORIDE ADVERSE REACTIONS

Cardiovascular

Blood pressure and pulse rate are frequently elevated following administration of ketamine hydrochloride injection 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 injection anesthesia.

Eye

Diplopia and nystagmus have been noted following ketamine hydrochloride injection administration. It also may cause a slight elevation in intraocular pressure measurement.

Genitourinary

Severe irritative and inflammatory urinary tract and bladder symptoms including cystitis have been reported in individuals with history of chronic ketamine use or abuse.

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 your adverse reactions, contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Mylan Institutional at 1-877-446-3679 (1-877-4-INFO-RX) or MEDWATCH at 1-800-FDA-1088 (1-800-332-1088) or http://www.fda.gov/medwatch/.

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.

OVERDOSAGE

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

KETAMINE HYDROCHLORIDE 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 a supported position during administration.

The onset of action of ketamine hydrochloride injection 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 effects.

Intramuscular doses, in a range of 9 to 13 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.

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 patient's requirements.

Induction

Intravenous Route

The initial dose of ketamine hydrochloride injection 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 (base) 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.

Rate of Administration

It is recommended that ketamine hydrochloride injection 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 hydrochloride injection 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 anesthesia.

Maintenance of Anesthesia

The maintenance dose should be adjusted according to the patient's 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 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 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 a dose of 0.1 to 0.5 mg/minute ketamine (base), 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 program.

Dilution

To prepare a dilute solution containing 1 mg of ketamine per mL, aseptically transfer 10 mL from a 50 mg per mL vial or 5 mL from a 100 mg per mL vial to 500 mL of 5% Dextrose Injection, USP or Sodium Chloride (0.9%) Injection, USP (Normal Saline) and mix well. The resultant solution will contain 1 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 a 250 mL infusion as described above to provide a ketamine hydrochloride injection concentration of 2 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 a 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.

HOW SUPPLIED

Ketamine Hydrochloride Injection, USP is supplied as the hydrochloride in concentrations equivalent to ketamine base.

NDC 67457-181-20      carton containing 10, 20 mL multi-dose vials with 10 mg/mL
NDC 67457-001-10      carton containing 10, 10 mL multi-dose vials with 50 mg/mL
NDC 67457-108-10      carton containing 10, 10 mL multi-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.

ANIMAL PHARMACOLOGY AND TOXICOLOGY

Toxicity

The acute toxicity of ketamine hydrochloride injection 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 pediatric patients. Daily intravenous injections in rats of 5 times the average human intravenous dose and intramuscular injections in dogs at 4 times the average human intramuscular dose demonstrated excellent tolerance for as long as 6 weeks. Similarly, twice weekly anesthetic sessions of one, 3, or 6 hours' duration in monkeys over a 4- to 6-week period were well tolerated.

Interaction with Other Drugs Commonly Used for Preanesthetic Medication

Large doses (3 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 hydrochloride injection 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.

Blood Pressure

Blood pressure responses to ketamine hydrochloride injection 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.

Intravenous ketamine hydrochloride injection 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 hydrochloride injection 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 hydrochloride injection 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 hydrochloride injection or in Starling dog heart-lung preparations at a ketamine hydrochloride injection concentration of 50 mg/kg of HLP. These observations support the hypothesis that the hypertension produced by ketamine hydrochloride injection 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 hydrochloride injection appears to have a weak antiarrhythmic activity.

Metabolic Disposition

Ketamine hydrochloride injection is rapidly absorbed following parenteral administration. Animal experiments indicated that ketamine hydrochloride injection 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 hydrochloride injection.

Balance 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 hydrochloride injection 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, one hour after dosing.

Ketamine hydrochloride injection 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 hydrochloride injection. The unconjugated demethyl cyclohexanone derivative was found to be less than one-tenth as potent as ketamine hydrochloride injection. Repeated doses of ketamine hydrochloride injection administered to animals did not produce any detectable increase in microsomal enzyme activity.

Reproduction

Male and female rats, when given five times the average human intravenous dose of ketamine hydrochloride injection for 3 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 (6 times the average human dose) of ketamine hydrochloride injection 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.

To determine the effect of ketamine hydrochloride injection 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.

Manufactured for:
Mylan Institutional LLC
Rockford, IL 61103 U.S.A.

Manufactured by:
Mylan Institutional
Galway, Ireland

REVISED OCTOBER 2012
MI:KETAIJ:R3
0624L105

PRINCIPAL DISPLAY PANEL - 10 mg/mL Label

NDC 67457-181-20

Ketamine
Hydrochloride
Injection, USP

200 mg/20 mL*
(10 mg/mL)

CIII

For Intramuscular or Slow Intravenous Use

Rx only      10 x 20 mL Multi-Dose Vials

Sterile

*Each mL contains:

Ketamine hydrochloride equivalent to 10 mg of
ketamine with a pH range of 3.5 to 5.5. Also
contains not more than 0.1 mg/mL of
benzethonium chloride added as a preservative.

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 precipitate appears.

Warning: Keep this and all drugs out of the
reach of children.

Store at 20° to 25°C (68° to 77°F). [See USP
Controlled Room Temperature.]

Protect from light. Retain in carton until time of
use.

Usual Dosage: See accompanying prescribing
information.

Manufactured for:
Mylan Institutional LLC
Rockford, IL 61103 U.S.A.

Manufactured by:
Mylan Institutional
Galway, Ireland

MI:181:10C:R2

Mylan.com