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Ketalar (Ketamine Hydrochloride) - Description and Clinical Pharmacology

 
 



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 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 KETALAR.

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 KETALAR IN CONJUCTION WITH INTRAVENOUS DIAZEPAM DURING INDUCTION AND MAINTENANCE OF ANESTHESIA. (See DOSAGE AND ADMINISTRATION Section.) ALSO, THESE REACTIONS MAY BE REDUCED IF 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 A SEVERE EMERGENCE REACTION, THE USE OF A SMALL HYPNOTIC DOSE OF A SHORT-ACTING OR ULTRA SHORT-ACTING BARBITURATE MAY BE REQUIRED.

WHEN KETALAR 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.

DESCRIPTION

Ketalar is a nonbarbiturate anesthetic chemically designated dl 2-(0-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride. It is formulated as a slightly acid (pH 3.5-5.5) sterile solution for intravenous or intramuscular injection in concentrations containing the equivalent of either 10, 50 or 100 mg ketamine base per milliliter and contains not more than 0.1 mg/mL Phemerol® (benzethonium chloride) added as a preservative. The 10 mg/mL solution has been made isotonic with sodium chloride.

CLINICAL PHARMACOLOGY

Ketalar 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 Ketalar 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. The 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 Ketalar has been termed "dissociative anesthesia" in that it appears to selectively interrupt association pathyways 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 Ketalar (up to ten times that usually required) have been followed by prolonged but complete recovery.

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

ANIMAL PHARMACOLOGY AND TOXICOLOGY

Toxicity: The acute toxicity of Ketalar 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 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.

Interaction with Other Drugs Commonly Used for Preanesthetic Medication: Large 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 Ketalar 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 Ketalar 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 Ketalar 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 Ketalar 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 norepineprhine. The pressor response to Ketalar is reduced or blocked by chlorpromazine (central depressant and peripheral a-adrenergic blockade), by b-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 Ketalar or Starling dog heart-lung preparations at a Ketalar concentration of 50 mg/kg of HLP. These observations support the hypothesis that the hypertension produced by Ketalar 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 Ketalar appears to have a weak antiarrhythmic activity.

Metabolic Disposition: Ketalar is rapidly absorbed following parenteral administration. Animal experiments indicated that Ketalar 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 Ketalar.

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 Ketalar 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 ug/mL, and CSF levels were about 0.2 ug/mL, 1 hour after dosing.

Ketalar 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 Ketalar. The unconjugated demethyl cyclohexanone derivative was found to be less than one-tenth as potent as Ketalar. Repeated doses of Ketalar 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 Ketalar 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 Ketalar on Day 6 of pregnancy to stimulate 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 Ketalar on the perinatal and postnatal period, pregnant rats were given twice the average human intramuscular dose during Days 18 and 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.

Prescribing Information as of June 2011.

JHP Pharmaceuticals

Manufactured and Distributed by:

JHP Pharmaceuticals, LLC

Rochester, MI 48307

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