KETAMINE HYDROCHLORIDE

KETAMINE HYDROCHLORIDE- ketamine hydrochloride injection, solution
General Injectables and Vaccines, Inc.

200 mg/20mL (10 mg/mL), 500 mg/10mL (50 mg/mL) and 1,000 mg/10 mL (100 mg/mL)

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 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 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 A SEVERE EMERGENCE RECTION, THE USE OF A SMALL HYPNOTIC DOSE OF A 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 A RESPONSIBLE ADULT.

DESCRIPTION:

Ketamine hydrochloride injection, USP is a nonbarbiturate general anesthetic chemically designated dl 2-(o-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 benzethonium chloride added as a preservative. The 10 mg/mL solution has been made isotonic with sodium chloride.

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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. The mechanism of action is primarily due to antagonism of N-methyl-D-aspartate (NMDA receptors) in the central nervous system.

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 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.

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.

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.

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 3 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 a 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.

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