Ketamine Drug Information

• Ketamine hydrochloride injection is indicated:
• As the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.
• For the induction of anesthesia prior to the administration of other general anesthetic agents.
• As a supplement to other anesthetic agents. Ketamine hydrochloride injection is a general anesthetic indicated:
• As a supplement to other anesthetic agents.

Important Dosage and Administration Information

Ketamine hydrochloride injection should be administered by or under the direction of physicians experienced in the administration of general anesthetics, maintenance of a patent airway, and oxygenation and ventilation. Continuously monitor vital signs in patients receiving ketamine hydrochloride injection. Emergency airway equipment must be immediately available.

While some degree of airway protection may be afforded due to active laryngeal-pharyngeal reflexes, vomiting and aspiration may occur with ketamine hydrochloride injection. Ketamine hydrochloride injection is not recommended for use in patients who have not followed nil per os guidelines. Due to the potential for salivation during ketamine hydrochloride injection administration, administer an antisialagogue prior to induction of anesthesia.

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. Consider cessation of ketamine if genitourinary pain continues in the setting of other genitourinary symptoms.

Recommended Dosage and Administration

The ketamine hydrochloride injection dosage must be individualized and titrated to the desired clinical effect. If a longer duration of effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia. However, a higher total dose will result in a longer time to complete recovery.

Induction of Anesthesia Intravenous Route: The initial dose of ketamine hydrochloride injection administered intravenously may range from 1 mg/kg to 4.5 mg/kg. Administer ketamine hydrochloride injection slowly (i.e., over a period of 60 seconds). Rapid administration may result in respiratory depression and enhanced vasopressor response.

The induction dose may be administered as an intravenous infusion at a rate of 0.5 mg/kg/min. Intramuscular Route: The initial dose of ketamine hydrochloride injection administered intramuscularly may range from 6.5 mg/kg to 13 mg/kg. Administer a benzodiazepine, if clinically indicated, for the prevention of neuropsychological manifestations during emergence from anesthesia.

Maintenance of Anesthesia Adjust the maintenance dose according to the patient's anesthetic needs and whether an additional anesthetic agent is administered. Repeat increments of one-half to the full induction dose as needed for maintenance of anesthesia. Purposeless and tonic-clonic movements of extremities may occur during the course of ketamine anesthesia.

These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic. Ketamine hydrochloride injection given by slow microdrip infusion technique at a dose of 0.1 mg/minutes to 0.5 mg/minute will maintain general anesthesia in adult patients induced with ketamine hydrochloride injection. Augment ketamine hydrochloride injection with an intravenous benzodiazepine for the prevention of neuropsychological manifestations during emergence.

Supplement to Other Anesthetic Agents Ketamine hydrochloride injection can be administered to supplement other general and local anesthetic agents. Continuously monitor patients for changes in respiratory and hemodynamic parameters. A reduced dose of ketamine hydrochloride injection can be used to produce balanced anesthesia when used in combination with other anesthetic agents.

Preparation of Dilution

Ketamine hydrochloride injection is a clear, colorless sterile solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if product is discolored or contains particulate matter.

Ketamine hydrochloride injection 10 mg/mL single-dose prefilled syringes are not recommended for dilution.

Instructions for Use of Prefilled Syringe CAUTION: Assure that the needle or Needleless Luer Access Device (NLAD) is securely attached before beginning the injection. Visually inspect the syringe-needle or syringe-NLAD connection before and during drug administration. Administration Technique Figure 1 • 10 mL – Pre-filled Syringe Ketamine injection may be administered intravenously or intramuscularly. 1.

Inspect the outer packaging and the syringe label by verifying: - drug name - drug strength - fill volume - route of administration - expiration date to be sure that the drug has not expired Do not use if package has been damaged 2. Open the outer packaging and remove the syringe from carton. 3. Visually inspect syringe for syringe damage, particulate matter, and discoloration. 4.

Push plunger rod slightly while tip cap is still on to break the stopper loose. 5. Remove tip cap by pulling it off. (See Figure 2) Figure 2 6. Discard the tip cap. 7.

Expel air bubble. 8. Connect the syringe to an appropriate injection connection depending on the route of administration. - Before injection, ensure that the syringe is securely attached to the needle or NLAD. 9. Depress plunger rod to deliver the required dose of medication.

Ensure that pressure is maintained on the plunger rod during the entire administration. Waste residual medication per institutional policy. 10. Remove syringe from NLAD (if applicable) and discard into appropriate receptacle.

When a needle is connected to the syringe, to prevent needle-stick injuries, do not recap needles. NOTES: • All steps must be performed sequentially • Do not autoclave syringe • Do not use this product on a sterile field • Do not introduce any other fluid into the syringe at any time • This product is for single dose only; discard unused portion image1-syringe-10ml image2-syringe-instruction

• The following clinically significant adverse reactions are described elsewhere in the labeling:
• Hemodynamic Instability
• Emergence Reactions
• Respiratory Depression
• Pediatric Neurotoxicity
• Drug-Induced Liver Injury The following adverse reactions associated with the use of ketamine hydrochloride injection were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular disorders: Elevated blood pressure, heart rate, and cardiac index; decreases in blood pressure and heart rate; arrhythmias; cardiac decompensation (in patients with suspected catecholamine depletion). Eye disorders: Diplopia, nystagmus, elevation in intraocular pressure. Gastrointestinal disorders: Anorexia, nausea, vomiting, hepatobiliary dysfunction. Biliary duct dilatation with or without evidence of biliary obstruction has been reported with recurrent use (e.g., misuse/abuse or medically supervised unapproved indications). Administration site disorders: Local pain and exanthema at the injection site. Immune system disorders: Anaphylaxis. Neurologic disorders: Emergence reactions (post-operative delirium),. During administration, enhanced muscle tone and spasms (resembling a partial motor or generalized motor seizure). Psychiatric disorders: Adverse psychiatric events have occurred and/or persisted days to weeks after ketamine exposure. Renal and urinary disorders: 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. 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. Respiratory disorders: Respiratory depression and apnea following rapid intravenous administration of high doses of ketamine hydrochloride injection; laryngospasm, and airway obstruction. Skin and subcutaneous tissue disorders: Transient erythema and/or morbilliform rash The most common adverse reactions are emergence reactions and elevated blood pressure and pulse. To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-877-725-2747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Theophylline or Aminophylline

Concomitant administration of ketamine hydrochloride injection and theophylline or aminophylline may lower the seizure threshold. Consider using an alternative to ketamine hydrochloride injection in patients receiving theophylline or aminophylline.

Sympathomimetics and Vasopressin Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine. Closely monitor vital signs when ketamine hydrochloride injection and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patient’s clinical situation.

Benzodiazepines, Opioid Analgesics, Or Other CNS Depressants

Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Opioid analgesics administered concomitantly with ketamine hydrochloride injection may prolong time to complete recovery from anesthesia.

Pregnancy Risk Summary There are no adequate and well-controlled studies of ketamine hydrochloride injection in pregnant women. In animal reproduction studies in rats developmental delays (hypoplasia of skeletal tissues) were noted at 0.3 times the human intramuscular dose of 10 mg/kg. In rabbits, developmental delays and increased fetal resorptions were noted at 0.6 times the human dose.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Ketamine hydrochloride injection use in pregnancy, including obstetrics (either vaginal or abdominal delivery), is not recommended because safe use has not been established.

Ketamine treatment produced an increased incidence of hypoplastic skull, phalanges, and sternebrae in the pups. An increase in resorptions and skeletal hypoplasia of the fetuses were noted. Skeletal hypoplasia was reported in the fetuses.

There was a slight increase in incidence of delayed parturition by one day in treated dams of this group. No adverse effects on the litters or pups were noted; however, learning and memory assessments were not completed. Three pregnant beagle dogs were treated intramuscularly with 25 mg/kg ketamine (1.3 times the human dose of 10 mg/kg intramuscular based on body surface area) 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.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits.

Pediatric Use Safety and effectiveness in pediatric patients below the age of 16 have not been established. Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as ketamine hydrochloride injection, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, 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 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures with the potential risks suggested by the nonclinical data.

• Ketamine hydrochloride injection is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard.
• Ketamine hydrochloride injection is contraindicated in patients with known hypersensitivity to ketamine or to any excipient.
• In patients for whom a significant elevation of blood pressure would be a serious hazard.
• Known hypersensitivity to ketamine or to any excipient.

Changes in heart rate and blood pressure, respiratory depression, and apnea may occur with overdosage or by a rapid rate of administration of ketamine hydrochloride injection. Monitor patients for clinically relevant changes in heart rate and blood pressure. Assisted ventilation, including mechanical ventilation, may be required.

In cases of unintentional overdose of ketamine hydrochloride injection (up to ten times that usually required), patients had a prolonged but complete recovery.