KETAMINE HYDROCHLORIDE

Ketamine hydrochloride 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 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 formula: Formula1.jpg

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.

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. Preoperative Preparations 1. 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. 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 is rapid; an intravenous dose of 2 mg/kg 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 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 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. In individuals with a history of chronic ketamine use for off-label indications, there have been case reports of genitourinary pain that may be related to the ketamine treatment, not the underlying condition (see ADVERSE REACTIONS Section). Consider cessation of ketamine if genitourinary pain continues in the setting of other genitourinary symptoms. Induction Intravenous Route The initial dose of ketamine administered intravenously may range from 1 mg/kg to 4.5 mg/kg. The average amount required to produce five to ten minutes of surgical anesthesia has been 2 mg/kg. 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, USP, Normal Saline, or 5% Dextrose in Water. Rate 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. A dose of 10 mg/kg 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 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 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 concentration of 2 mg/mL. Supplementary Agents 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 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.

Cardiovascular: Blood pressure and pulse rate are frequently elevated following administration of ketamine 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. Laryngospasms and other forms of airway obstruction have occurred during ketamine anesthesia. Eye: Diplopia and nystagmus have been noted following ketamine administration. It also may cause a slight elevation in intraocular pressure measurement. Genitourinary: In individuals with history of chronic ketamine use or abuse, lower urinary tract and bladder symptoms including dysuria, increased urinary frequency, urgency, urge incontinence, and hematuria have been reported (see DOSAGE AND ADMINISTRATION Section). In addition, diagnostic studies performed to assess the cause of these symptoms have reported cystitis (including cystitis non-infective, cystitis interstitial, cystitis ulcerative, cystitis erosive and cystitis hemorrhagic) as well as hydronephrosis and reduced bladder capacity. 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 adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.