Ketamine Hydrochloride

Dosage and Administration ( 2.1 , 2.3 ) 03/2026 Warnings and Precautions ( 5.6 , 5.7 ) 03/2026 Adverse Reactions ( 6 ) 03/2026

1 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. • 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 the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation ( 1 ) • for the induction of anesthesia prior to the administration of other general anesthetic agents ( 1 ) • as a supplement to other anesthetic agents ( 1 ).

DOSAGE AND ADMINISTRATION 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 do …

3 DOSAGE FORMS AND STRENGTHS Ketamine Hydrochloride Injection, USP is a clear, colorless, sterile solution available in multiple-dose vials containing either 50 mg ketamine base/mL (equivalent to 57.7 mg ketamine hydrochloride) or 100 mg ketamine base/mL (equivalent to 115.3 mg ketamine hydrochloride). • 500 mg/10 mL (50 mg/mL) • 500 mg/5 mL (100 mg/mL) Injection: 500 mg/10 mL (50 mg/mL) and 500 mg/5 mL (100 mg/mL) multiple-dose vials. ( 3 )

4 CONTRAINDICATIONS • Ketamine Hydrochloride Injection is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard [see Warnings and Precautions (5.1) ] . • Ketamine Hydrochloride Injection is contraindicated in patients with known hypersensitivity to ketamine or to any excipient [see Adverse Reactions (6) ] . • In patients for whom a significant elevation of blood pressure would be a serious hazard. ( 4 ) • Known hypersensitivity to ketamine or to any excipient. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hemodynamic Instability [see Warnings and Precautions (5.1) ] • Emergence Reactions [see Warnings and Precautions (5.2) ] • Respiratory Depression [see Warnings and Precautions (5.3) ] • Pediatric Neurotoxicity [see Warnings and Precautions (5.5) ] • Drug-Induced Liver Injury [see Warnings and Precautions (5.6) ] 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, biliary duct stricture and/or stenosis with or without evidence of biliary obstruction; secondary sclerosing cholangitis [see Warnings and Precautions (5.6) ] . Administration site disorders : Local pain and exanthema at the injection site. Immune system disorders : Anaphylaxis. Neurologic disorders : Emergence reactions (post-operative delirium), [see Warnings and Precautions (5.2) ] . 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 a history of long-term ketamine use or abuse, urinary tract complications related to cystitis, reduced bladder capacity, ureteral stenosis (strictures), ureteral obstruction, and hydronephrosis have been reported [see Warnings and Precautions (5.7) ] . Cystitis (including cystitis non-infective, cystitis interstitial, cystitis ulcerative, cystitis erosive and cystitis hemorrhagic) and reduced bladder capacity may present with genitourinary pain, dysuria, increased urinary frequency, urgency, urge incontinence, and hematuria. Ureteral stenosis (strictures), ureteral obstruction, and hydronephrosis may present with flank and/or pelvic pain, recurrent urinary tract infections, hematuria, nausea and vomiting, and acute kidney injury. 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. ( 6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

7 DRUG INTERACTIONS • Theophylline or Aminophylline : Do not co-administer with Ketamine Hydrochloride Injection as concomitant use may lower the seizure threshold. ( 7.1 ) • Sympathomimetics and Vasopressin : Closely monitor vital signs when co-administered with Ketamine Hydrochloride Injection. Consider dose adjustment individualized to the patient's clinical situation. ( 7.2 ) • Benzodiazepines, Opioid Analgesics, or Other CNS Depressants : Concomitant use may result in profound sedation, respiratory depression, coma, or death. Concomitant use of opioid analgesics may prolong recovery time. ( 7.3 ) 7.1 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. 7.2 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. 7.3 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 [see Warnings and Precautions (5.9) ] . Opioid analgesics administered concomitantly with Ketamine Hydrochloride Injection may prolong time to complete recovery from anesthesia.

8 USE IN SPECIFIC POPULATIONS • Pregnancy : Animal data show that Ketamine Hydrochloride Injection may cause harm to the fetus; avoid use during pregnancy, labor, and delivery. ( 8.1 ) 8.1 Pregnancy Risk Summary Available data on the use of ketamine in pregnant women mostly describe its use at the time of cesarean section and have not identified a drug-associated risk of adverse maternal or fetal outcomes. The data are limited by retrospective collection, small sample sizes, and a lack of long-term follow-up. There are no available data on ketamine use during other stages of pregnancy to allow for an evaluation of drug-associated risk of major birth defects or miscarriage. 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 clinical significance of these nonclinical findings is not known, and the benefits of appropriate anesthesia in pregnant women who require procedures should be balanced with the potential risks suggested by the nonclinical data. 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 2 to 4% and 15 to 20%, respectively. Data Animal Data Pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days 6 to 10 or Gestation Days 11 to 15. Ketamine treatment produced an increased incidence of hypoplastic skull, phalanges, and sternebrae in the pups. Pregnant rabbits were treated intramuscularly with 20 mg/kg ketamine (0.6 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days 6 to 10 or Gestation Days 11 to 15. An increase in resorptions and skeletal hypoplasia of the fetuses were noted. Additional pregnant rabbits were treated intramuscularly with a single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg IM based on body surface area) on Gestation Day 6 only. Skeletal hypoplasia was reported in the fetuses. In a study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) from Gestation Day 18 to 21. 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 (3) pregnant beagle dogs were treated intramuscularly with 25 mg/kg ketamine (1.3 times the human dose of 10 mg/kg IM 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 …

12.1 Mechanism of Action Ketamine Hydrochloride Injection, a racemic mixture of ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The major circulating metabolite of ketamine (norketamine) demonstrated activity at the same receptor with less affinity. Norketamine is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat.

11 DESCRIPTION Ketamine Hydrochloride Injection, USP for intravenous or intramuscular use, contains ketamine, a nonbarbiturate general anesthetic. Ketamine hydrochloride, USP is a white crystalline powder and has a molecular formula of C 13 H 16 ClNO∙HCl and a molecular weight of 274.19. The chemical name for ketamine hydrochloride is (±)-2-( o -Chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride. The chemical structure of ketamine hydrochloride is: It is formulated as a slightly acidic (pH 3.5 to 5.5) sterile solution for intravenous or intramuscular injection. Each milliliter (mL) of the multiple-dose vials contain either 50 mg ketamine base (equivalent to 57.7 mg ketamine hydrochloride) or 100 mg ketamine base (equivalent to 115.3 mg ketamine hydrochloride) and not more than 0.10 mg/mL benzethonium chloride added as a preservative in water for injection. Chemical Structure

10 OVERDOSAGE 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.

HOW SUPPLIED Ketamine Hydrochloride Injection, USP is supplied as the hydrochloride in concentrations equivalent to ketamine base. 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 a precipitate appears. Store between 20° to 25°C (68° to 77°F). (See USP Controlled Room Temperature.) Protect from light. Product repackaged by: Henry Schein, Inc., Bastian, VA 24314 From Original Manufacturer/Distributor's NDC and Unit of Sale To Henry Schein Repackaged Product NDC and Unit of Sale Total Strength/Total Volume (Concentration) per unit NDC 0409-2053-10 Box of 10 10 mL Multiple-dose Fliptop Vial NDC 0404-9882-10 1 10 mL Multiple-dose Fliptop vial in a bag (Vial bears NDC 0409-2053-20) 500 mg/10 mL (50 mg/mL) Image1.jpg