ketamine hydrochloride

RECENT MAJOR CHANGES Warnings and Precautions ( 5.6 ) 8/2020

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 ).

2 DOSAGE AND ADMINISTRATION • See Full Prescribing Information for important dosage and administration instructions. ( 2 ) • Induction of anesthesia: -- Intravenous route : Initially, 1 to 4.5 mg/kg administered slowly (over a period of 60 seconds). Alternatively, administer a dose of 1 to 2 mg/kg at a rate of 0.5 mg/kg/min. ( 2 2 ) -- Intramuscular route : Initially, 6.5 to 13 mg/kg. ( 2.2 ) • Maintenance of anesthesia: Increments of one-half to the full induction dose may be repeated as needed (2.2). Adjust the dose according to the patient's anesthetic needs and whether an additional anesthetic agent is employed. ( 2.2 ) • Supplement to other anesthetic agents: The regimen of a reduced dose of Ketamine Hydrochloride Injection supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents. ( 2.2 ) 2.1 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. Do not administer the 100 mg/mL concentration of Ketamine Hydrochloride Injection intravenously without proper dilution [see Dosage and Administration (2.3) ] . Must be used immediately after dilution. 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 [see Adverse Reactions (6) ] . Consider cessation of ketamine if genitourinary pain continues in the setting of other genitourinary symptoms. 2.2 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. The average amount required to produce 5 to 10 minutes of surgical anesthesia within 30 seconds following injection is 2 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 to 13 mg/kg. A dose of 9 to 13 mg/kg usually produces surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes. 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 …

3 DOSAGE FORMS AND STRENGTHS Ketamine Hydrochloride Injection, USP is a clear, colorless to slightly yellow sterile solution available in multiple-dose vials containing either 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride) or 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) or 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride). 200 mg/20 mL (10 mg/mL) 500 mg/10 mL (50 mg/mL) 500 mg/5 mL (100 mg/mL) Injection: 200 mg/20 mL (10 mg/mL), 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 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), [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 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 (2.1) ] . 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 ( 6 ). 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.

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 coadministered 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 (5.8) ] . Opioid analgesics administered concomitantly with Ketamine Hydrochloride Injection may prolong time to complete recovery from anesthesia.

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 (5.8) ] . Opioid analgesics administered concomitantly with Ketamine Hydrochloride Injection may prolong time to complete recovery from anesthesia.

8 USE IN SPECIFIC POPULATIONS 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. Clinical Considerations Ketamine hydrochloride use in pregnancy, including obstetrics (either vaginal or abdominal delivery), is not recommended because safe use has not been established [see Warnings and Precautions (5.5) , Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2) ] . 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 a …

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 dl -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 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride), 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) or 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride) and not more than 0.10 mg/mL benzethonium chloride added as a preservative in water for injection. The 10 mg/mL solution has been made isotonic with 6.60 mg sodium chloride. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Ketamine Hydrochloride Injection, USP is a clear, colorless to slightly yellow solution supplied as the hydrochloride salt in concentrations equivalent to ketamine base, as follows: Product Code Unit of Sale Strength (Concentration) Unit of Use 180020 NDC 65219-184-20 Unit of 10 200 mg/20 mL (10 mg/mL) 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride) NDC 65219-184-01 20 mL multiple-dose vial 180610 NDC 65219-188-10 Unit of 10 500 mg/10 mL (50 mg/mL) 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) NDC 65219-188-01 10 mL multiple-dose vial 180605 NDC 65219-186-05 Unit of 10 500 mg/5 mL (100 mg/mL) 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride) NDC 65219-186-01 5 mL multiple-dose vial Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Protect from freezing. This container closure is not made with natural rubber latex.