DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Ketamine Hydrochloride Injection, USP is clear, colorless, sterile solution available in single-dose pre-filled syringe containing 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride).o100 mg/10 mL (10 mg/mL). o100 mg/10 mL (10 mg/mL). Injection: 100 mg/10 mL (10 mg/mL) single-dose pre-filled syringe (3).

ABUSE SECTION.

9.2 Abuse Individuals with history of drug abuse or dependence may be at greater risk for abuse and misuse of ketamine hydrochloride injection. Abuse is the intentional, non-therapeutic use of drug, even once, for its psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed.In context of drug abuse, ketamine hydrochloride injection may produce variety of symptoms including anxiety, dysphoria, disorientation, insomnia, flashback, hallucinations, and feelings of floating, detachment and being spaced out.Recurrent high-dose ketamine misuse or abuse may be associated with memory and/or attention impairment.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:oHemodynamic Instability [see Warnings and Precautions (5.1)]oEmergence Reactions [see Warnings and Precautions (5.2)]oRespiratory Depression [see Warnings and Precautions (5.3)]oPediatric Neurotoxicity [see Warnings and Precautions (5.5)]oDrug-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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 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. oHemodynamic Instability [see Warnings and Precautions (5.1)]. oEmergence Reactions [see Warnings and Precautions (5.2)]. oRespiratory Depression [see Warnings and Precautions (5.3)]. oPediatric Neurotoxicity [see Warnings and Precautions (5.5)]. oDrug-Induced Liver Injury [see Warnings and Precautions (5.6)]. 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics DistributionFollowing intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug.EliminationMetabolismKetamine is metabolized via N-dealkylation to the active metabolite norketamine primarily by CYP2B6 and CYP3A4 and to lesser extent by other CYP enzymes. Norketamine undergoes hydroxylation of the cyclohexone ring to form hydroxynorketamine compounds via CYP-dependent pathways, which are conjugated with glucuronic acid and subsequently undergo dehydration of the hydroxylated metabolites to form the cyclohexene derivative dehydroxynorketamine.ExcretionFollowing intravenous administration, the ketamine concentration decreases due to combination of redistribution from the CNS to slower equilibrating peripheral tissues and hepatic biotransformation to norketamine. The redistribution half-life of ketamine from the CNS to slower equilibrating peripheral tissues (beta phase) is 2.5 hours.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology Published studies in animals demonstrate that the use of anesthetic agents 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 through the first several months of life, but may extend out to approximately years of age in humans.In primates, exposure to hours of an anesthetic regimen that produced light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but 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 against the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.5), Use in Specific Populations (8.1,8.4)].In published studies, intraperitoneal administration of ketamine at doses greater than 40 mg/kg induced vacuolation in neuronal cells of the posterior cingulate and retrosplenial cortices in adult rats, similar to what has been reported in rodents administered other NMDA receptor antagonists. These vacuoles were demonstrated to be reversible and did not progress to degeneration or neuronal death up to doses of 80 mg/kg (1.2 times the human dose of 10 mg/kg based on body surface area). no-effect level for neuronal vacuolation was 20 mg/kg intraperitoneal (0.3 times human dose of 10 mg/kg on body surface area basis). The window of vulnerability to these changes is believed to correlate with exposures in humans from the onset of puberty through adulthood. The relevance of this finding to humans is unknown.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisLong-term animal studies have not been conducted to evaluate the carcinogenic potential of ketamine.MutagenesisIn published report, ketamine was clastogenic in the in vitro chromosomal aberration assay.Impairment of FertilityAdequate studies to evaluate the impact of ketamine on male or female fertility have not been conducted. Male and female rats were treated with 10 mg/kg ketamine intravenous (0.8 times the average human induction dose of mg/kg intravenous based on body surface area) on Days 11, 10, and prior to mating. No impact on fertility was noted; however, this study design does not adequately characterize the impact of drug on fertility endpoints.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ketamine hydrochloride injection, racemic mixture of ketamine, is 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.. 12.2 Pharmacodynamics Nervous SystemKetamine is rapidly-acting general anesthetic producing dissociative anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally 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.Ketamine can produce nystagmus with pupillary dilation, salivation, lacrimation, and spontaneous limb movements with increased muscle tone through indirect sympathomimetic activity. Ketamine produces analgesia. Ketamine-induced emergence delirium can be reduced with benzodiazepines.Cardiovascular SystemKetamine increases blood pressure, heart rate, and cardiac output. Cardiovascular effects of ketamine are indirect and believed to be mediated by inhibition of both central and peripheral catecholamine reuptake. Elevation of blood pressure reaches maximum within few minutes of injection and usually returns to preanesthetic values within 15 minutes. 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.Respiratory SystemKetamine is potent bronchodilator suitable for anesthetizing patients at high risk for bronchospasm.. 12.3 Pharmacokinetics DistributionFollowing intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug.EliminationMetabolismKetamine is metabolized via N-dealkylation to the active metabolite norketamine primarily by CYP2B6 and CYP3A4 and to lesser extent by other CYP enzymes. Norketamine undergoes hydroxylation of the cyclohexone ring to form hydroxynorketamine compounds via CYP-dependent pathways, which are conjugated with glucuronic acid and subsequently undergo dehydration of the hydroxylated metabolites to form the cyclohexene derivative dehydroxynorketamine.ExcretionFollowing intravenous administration, the ketamine concentration decreases due to combination of redistribution from the CNS to slower equilibrating peripheral tissues and hepatic biotransformation to norketamine. The redistribution half-life of ketamine from the CNS to slower equilibrating peripheral tissues (beta phase) is 2.5 hours.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Ketamine hydrochloride injection has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients in 105 separate studies. During the course of these studies, ketamine hydrochloride injection was administered as the sole general anesthetic, as an induction agent prior to administration of other general anesthetics, or to supplement other anesthetic agents. Ketamine hydrochloride injection has been evaluated during the following procedures:1.debridement, dressing changes, and skin grafting in burn patients, as well as other superficial surgical procedures.2.neurodiagnostic procedures such as myelograms and lumbar punctures.3.diagnostic and operative procedures of the ear, nose, and mouth, including dental extractions.4.sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.5.extraperitoneal procedures, such as dilatation and curettage.6.orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.7. cardiac catheterization procedures.. 1.debridement, dressing changes, and skin grafting in burn patients, as well as other superficial surgical procedures.. 2.neurodiagnostic procedures such as myelograms and lumbar punctures.. 3.diagnostic and operative procedures of the ear, nose, and mouth, including dental extractions.. 4.sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.. 5.extraperitoneal procedures, such as dilatation and curettage.. 6.orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.. 7. cardiac catheterization procedures.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS oKetamine hydrochloride injection is contraindicated in patients for whom significant elevation of blood pressure would constitute serious hazard [see Warnings and Precautions (5.1)].oKetamine hydrochloride injection is contraindicated in patients with known hypersensitivity to ketamine or to any excipient [see Adverse Reactions (6)].. oKetamine hydrochloride injection is contraindicated in patients for whom significant elevation of blood pressure would constitute serious hazard [see Warnings and Precautions (5.1)].. oKetamine hydrochloride injection is contraindicated in patients with known hypersensitivity to ketamine or to any excipient [see Adverse Reactions (6)].. oIn patients for whom significant elevation of blood pressure would be serious hazard (4).oKnown hypersensitivity to ketamine or to any excipient (4).. oIn patients for whom significant elevation of blood pressure would be serious hazard (4).. oKnown hypersensitivity to ketamine or to any excipient (4).

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance Ketamine hydrochloride injection contains ketamine, Schedule III controlled substance under the Controlled Substance Act.

DEPENDENCE SECTION.

9.3 Dependence Physical dependence has been reported with prolonged use of ketamine. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of drug. Withdrawal symptoms have been reported after the discontinuation of frequently used (more than weekly), large doses of ketamine for long periods of time. Reported symptoms of withdrawal associated with daily intake of large doses of ketamine include craving, fatigue, poor appetite, and anxiety.Tolerance has been reported with prolonged use of ketamine. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose).

DESCRIPTION SECTION.

11 DESCRIPTION Ketamine Hydrochloride Injection, USP, for intravenous or intramuscular use, contains ketamine, nonbarbiturate general anesthetic. Ketamine hydrochloride, USP is white crystalline powder and has molecular formula of C13H16ClNOoHCl and molecular weight of 274.19 g/mol. 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 slightly acidic (pH 3.5-5.5) sterile solution for intravenous or intramuscular injection. Each milliliter (mL) of the single-dose pre-filled syringe contain 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride) in water for injection. The 10 mg/mL solution has been made isotonic with 6.60 mg sodium chloride.. image3-structural-formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oSee Full Prescribing Information for important dosage and administration instructions. (2)oInduction of anesthesia: --Intravenous route: Initially, mg/kg to 4.5 mg/kg administered slowly (over period of 60 seconds). Alternatively, administer dose of mg/kg to mg/kg at rate of 0.5 mg/kg/min. (2.2) --Intramuscular route: Initially, 6.5 mg/kg to 13 mg/kg. (2.2)oMaintenance of anesthesia: Increments of one-half to the full induction dose may be repeated as needed (2.2). Adjust the dose according to the patients anesthetic needs and whether an additional anesthetic agent is employed. (2.2)oSupplement to other anesthetic agents: The regimen of reduced dose of ketamine hydrochloride injection supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents. (2.2). oSee Full Prescribing Information for important dosage and administration instructions. (2). oInduction of anesthesia:. --Intravenous route: Initially, mg/kg to 4.5 mg/kg administered slowly (over period of 60 seconds). Alternatively, administer dose of mg/kg to mg/kg at rate of 0.5 mg/kg/min. (2.2). --Intramuscular route: Initially, 6.5 mg/kg to 13 mg/kg. (2.2). oMaintenance of anesthesia: Increments of one-half to the full induction dose may be repeated as needed (2.2). Adjust the dose according to the patients anesthetic needs and whether an additional anesthetic agent is employed. (2.2). oSupplement to other anesthetic agents: The regimen of reduced dose of ketamine hydrochloride injection supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents. (2.2). 2.1Important 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 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 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.. 2.2Recommended Dosage and Administration The ketamine hydrochloride injection dosage must be individualized and titrated to the desired clinical effect.If longer duration of effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia. However, higher total dose will result in longer time to complete recovery.Induction of AnesthesiaIntravenous Route: The initial dose of ketamine hydrochloride injection administered intravenously may range from mg/kg to 4.5 mg/kg. The average amount required to produce minutes to 10 minutes of surgical anesthesia within 30 seconds following injection is mg/kg. Administer ketamine hydrochloride injection slowly (i.e., over 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 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. dose of mg/kg to 13 mg/kg usually produces surgical anesthesia within minutes to minutes following injection, with the anesthetic effect usually lasting 12 minutes to 25 minutes. Administer benzodiazepine, if clinically indicated, for the prevention of neuropsychological manifestations during emergence from anesthesia.Maintenance of AnesthesiaAdjust the maintenance dose according to the patients 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 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 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 AgentsKetamine 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. 2.3Preparation of Dilution Ketamine hydrochloride injection is 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.. 2.4Instructions 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 TechniqueFigure 1o10 mL Pre-filled SyringeKetamine 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 expiredDo 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 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 needle is connected to the syringe, to prevent needle-stick injuries, do not recap needles.NOTES:oAll steps must be performed sequentiallyoDo not autoclave syringeoDo not use this product on sterile fieldoDo not introduce any other fluid into the syringe at any timeoThis product is for single dose only; discard unused portion. o10 mL Pre-filled Syringe. 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. 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) . 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 needle is connected to the syringe, to prevent needle-stick injuries, do not recap needles.. oAll steps must be performed sequentially. oDo not autoclave syringe. oDo not use this product on sterile field. oDo not introduce any other fluid into the syringe at any time. oThis product is for single dose only; discard unused portion. image1-syringe-10ml. image2-syringe-instruction.

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Ketamine hydrochloride injection contains ketamine, Schedule III controlled substance under the Controlled Substance Act.. 9.2 Abuse Individuals with history of drug abuse or dependence may be at greater risk for abuse and misuse of ketamine hydrochloride injection. Abuse is the intentional, non-therapeutic use of drug, even once, for its psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed.In context of drug abuse, ketamine hydrochloride injection may produce variety of symptoms including anxiety, dysphoria, disorientation, insomnia, flashback, hallucinations, and feelings of floating, detachment and being spaced out.Recurrent high-dose ketamine misuse or abuse may be associated with memory and/or attention impairment.. 9.3 Dependence Physical dependence has been reported with prolonged use of ketamine. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of drug. Withdrawal symptoms have been reported after the discontinuation of frequently used (more than weekly), large doses of ketamine for long periods of time. Reported symptoms of withdrawal associated with daily intake of large doses of ketamine include craving, fatigue, poor appetite, and anxiety.Tolerance has been reported with prolonged use of ketamine. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose).

DRUG INTERACTIONS SECTION.

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 patients 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).. 7.1Theophylline 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.. 7.2Sympathomimetics 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 patients clinical situation.. 7.3Benzodiazepines, 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use Clinical studies of ketamine hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING How SuppliedKetamine Hydrochloride Injection, USP is clear, colorless solution supplied as the hydrochloride salt in concentrations equivalent to ketamine base, as follows:Unit of saleStrengthNDC 43066-117-05Unit of 05100 mg in 10 mL single-dose pre-filled syringe (10 mg/mL)10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride)Storage and HandlingKetamine hydrochloride injection, USP should be stored at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Protect from light.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Ketamine hydrochloride injection is indicated:oas the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.ofor the induction of anesthesia prior to the administration of other general anesthetic agents.oas supplement to other anesthetic agents.. oas the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.. ofor the induction of anesthesia prior to the administration of other general anesthetic agents.. oas supplement to other anesthetic agents.. Ketamine hydrochloride injection is general anesthetic indicated:oas the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation (1)ofor the induction of anesthesia prior to the administration of other general anesthetic agents (1)oas supplement to other anesthetic agents (1).. oas the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation (1). ofor the induction of anesthesia prior to the administration of other general anesthetic agents (1). oas supplement to other anesthetic agents (1).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Nervous SystemKetamine is rapidly-acting general anesthetic producing dissociative anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally 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.Ketamine can produce nystagmus with pupillary dilation, salivation, lacrimation, and spontaneous limb movements with increased muscle tone through indirect sympathomimetic activity. Ketamine produces analgesia. Ketamine-induced emergence delirium can be reduced with benzodiazepines.Cardiovascular SystemKetamine increases blood pressure, heart rate, and cardiac output. Cardiovascular effects of ketamine are indirect and believed to be mediated by inhibition of both central and peripheral catecholamine reuptake. Elevation of blood pressure reaches maximum within few minutes of injection and usually returns to preanesthetic values within 15 minutes. 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.Respiratory SystemKetamine is potent bronchodilator suitable for anesthetizing patients at high risk for bronchospasm.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION oStudies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs [see Warnings and Precautions (5.5)].oDue to the residual anesthetic effects and the potential for drowsiness, advise patients not to drive an automobile, operate hazardous machinery, or engage in hazardous activities within 24 hours of receiving ketamine hydrochloride injection.Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 USAManufactured by: Gland Pharma Limited,Survey No. 143 148, 150 151, Near Gandimaisamma Cross Roads, D. P. Pally, Dundigal Post, Dundigal Gandimaisamma Mandal, Medchal Malkajgiri District, Hyderabad, Telangana 500043, India (IND) Baxter is registered trademark of Baxter International Inc.Revised. 06/202507-19-00-7583. oStudies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs [see Warnings and Precautions (5.5)].. oDue to the residual anesthetic effects and the potential for drowsiness, advise patients not to drive an automobile, operate hazardous machinery, or engage in hazardous activities within 24 hours of receiving ketamine hydrochloride injection.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Ketamine hydrochloride injection, racemic mixture of ketamine, is 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisLong-term animal studies have not been conducted to evaluate the carcinogenic potential of ketamine.MutagenesisIn published report, ketamine was clastogenic in the in vitro chromosomal aberration assay.Impairment of FertilityAdequate studies to evaluate the impact of ketamine on male or female fertility have not been conducted. Male and female rats were treated with 10 mg/kg ketamine intravenous (0.8 times the average human induction dose of mg/kg intravenous based on body surface area) on Days 11, 10, and prior to mating. No impact on fertility was noted; however, this study design does not adequately characterize the impact of drug on fertility endpoints.. 13.2 Animal Toxicology and/or Pharmacology Published studies in animals demonstrate that the use of anesthetic agents 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 through the first several months of life, but may extend out to approximately years of age in humans.In primates, exposure to hours of an anesthetic regimen that produced light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but 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 against the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.5), Use in Specific Populations (8.1,8.4)].In published studies, intraperitoneal administration of ketamine at doses greater than 40 mg/kg induced vacuolation in neuronal cells of the posterior cingulate and retrosplenial cortices in adult rats, similar to what has been reported in rodents administered other NMDA receptor antagonists. These vacuoles were demonstrated to be reversible and did not progress to degeneration or neuronal death up to doses of 80 mg/kg (1.2 times the human dose of 10 mg/kg based on body surface area). no-effect level for neuronal vacuolation was 20 mg/kg intraperitoneal (0.3 times human dose of 10 mg/kg on body surface area basis). The window of vulnerability to these changes is believed to correlate with exposures in humans from the onset of puberty through adulthood. The relevance of this finding to humans is unknown.

OVERDOSAGE SECTION.

10 OVERDOSAGE Changes in heart rate and blood pressure, respiratory depression, and apnea may occur with overdosage or by 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 prolonged but complete recovery.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 43066-177-01Rx OnlyKetamine HCl Injection, USP CIII100 mg/10 mL 10 mg/mLFor Slow Intravenous or Intramuscular Use10 mL Single-Dose Pre-filled Syringe. Discard unused portion.Dosage: See full prescribing information.Store between 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Protect from light.Baxter07-26-00-1944Code: TN/Drugs/TN0000000Made in IndiaPSFIL-XXXXXX-XXNDC 43066-177-01Rx OnlyKetamine Hydrochloride Injection, USP CIII100 mg/10 mL 10 mg/mLFor Slow Intravenous or Intramuscular UseDiscard unused portion.1 10 mL Single-Dose Pre-filled Syringe. NDC 43066-177-05Rx OnlyKetamine Hydrochloride Injection, USP CIII100 mg/10 mL 10 mg/mLFor Slow Intravenous or Intramuscular UseDiscard unused portion.5 10 mL Single-Dose Pre-filled Syringe.. image4-container-label-10ml-pfs. image5-mono-carton-label-10ml-pfs. image6-outer-carton-label-10ml-pfs.

PEDIATRIC USE SECTION.

8.4 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 years of age in humans.In primates, exposure to hours of ketamine that produced light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 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 [see Warnings and Precautions (5.5), Use in Specific Populations (8.1), and Nonclinical Toxicology (13.2)].

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryThere 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 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 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 ConsiderationsKetamine hydrochloride injection 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)].DataAnimal DataPregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg intramuscular based on body surface area) on either Gestation Days 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 intramuscular based on body surface area) on either Gestation Days 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 single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg intramuscular based on body surface area) on Gestation Day only. Skeletal hypoplasia was reported in the fetuses.In study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg intramuscular based on body surface area) from Gestation Day 18 to 21. There was 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 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 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 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 [see Warnings and Precautions (5.5), Use in Specific Populations (8.4), and Nonclinical Toxicology (13.2)].

SPL UNCLASSIFIED SECTION.

2.1Important 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 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 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPregnancy: Animal data show that ketamine hydrochloride injection may cause harm to the fetus; avoid use during pregnancy, labor, and delivery (8.1). oPregnancy: 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 SummaryThere 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 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 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 ConsiderationsKetamine hydrochloride injection 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)].DataAnimal DataPregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg intramuscular based on body surface area) on either Gestation Days 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 intramuscular based on body surface area) on either Gestation Days 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 single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg intramuscular based on body surface area) on Gestation Day only. Skeletal hypoplasia was reported in the fetuses.In study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg intramuscular based on body surface area) from Gestation Day 18 to 21. There was 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 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 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 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 [see Warnings and Precautions (5.5), Use in Specific Populations (8.4), and Nonclinical Toxicology (13.2)].. 8.4 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 years of age in humans.In primates, exposure to hours of ketamine that produced light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 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 [see Warnings and Precautions (5.5), Use in Specific Populations (8.1), and Nonclinical Toxicology (13.2)].. 8.5 Geriatric Use Clinical studies of ketamine hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHemodynamic Instability: Monitor vital signs and cardiac function during ketamine hydrochloride injection administration. (5.1)oEmergence Reactions: Postoperative confusional states may occur during the recovery period. Reduce by minimizing verbal, tactile, and visual stimulation of the patient. (5.2)oRisk of Respiratory Depression: May occur with overdosage or too rapid rate of administration. Maintain adequate oxygenation and ventilation. (5.3)oRisks of ketamine hydrochloride injection alone for Procedures of the Pharynx, Larynx, or Bronchial Tree: Pharyngeal and laryngeal reflexes are not suppressed with ketamine hydrochloride injection when it is used alone. Avoid use as sole anesthetic agent in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree. Muscle relaxants may be required. (5.4)oPediatric Neurotoxicity: Long-term cognitive deficits may occur when used for longer than hours in children <=3 years (5.5). oHemodynamic Instability: Monitor vital signs and cardiac function during ketamine hydrochloride injection administration. (5.1). oEmergence Reactions: Postoperative confusional states may occur during the recovery period. Reduce by minimizing verbal, tactile, and visual stimulation of the patient. (5.2). oRisk of Respiratory Depression: May occur with overdosage or too rapid rate of administration. Maintain adequate oxygenation and ventilation. (5.3). oRisks of ketamine hydrochloride injection alone for Procedures of the Pharynx, Larynx, or Bronchial Tree: Pharyngeal and laryngeal reflexes are not suppressed with ketamine hydrochloride injection when it is used alone. Avoid use as sole anesthetic agent in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree. Muscle relaxants may be required. (5.4). oPediatric Neurotoxicity: Long-term cognitive deficits may occur when used for longer than hours in children <=3 years (5.5). 5.1Hemodynamic Instability Transient increases in blood pressure, heart rate, and cardiac index are frequently observed following administration of ketamine hydrochloride injection. Decreases in blood pressure and heart rate, arrhythmias, and cardiac decompensation have also been observed. Monitor vital signs and cardiac function during ketamine hydrochloride injection administration. Ketamine hydrochloride injection is contraindicated in patients for whom significant elevation of blood pressure would constitute serious hazard [see Contraindications (4)].. 5.2Emergence Reactions Emergence delirium (postoperative confusional states or agitation) has occurred in approximately 12% of patients during the recovery period, and the duration is generally few hours. The neuropsychological 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, exctextent, and irrational behavior, which have been recalled as unpleasant experiences. No residual psychological effects are known to have resulted from use of ketamine hydrochloride injection during induction and maintenance of anesthesia.Intramuscular administration results in lower incidence of emergence reactions.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 an intravenous benzodiazepine during induction and maintenance of anesthesia [see Dosage and Administration (2.3)]. 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.. 5.3Respiratory Depression Respiratory depression may occur with overdosage or rapid rate of administration of ketamine hydrochloride injection. Maintain adequate oxygenation and ventilation.. 5.4Risks of Ketamine Hydrochloride Injection Alone for Procedures of the Pharynx, Larynx, or Bronchial Tree Ketamine hydrochloride injection does not suppress pharyngeal and laryngeal reflexes. Avoid ketamine hydrochloride injection administration as sole anesthetic agent during procedures of the pharynx, larynx, or bronchial tree, including mechanical stimulation of the pharynx. Muscle relaxants may be required for successful completion of procedures of the pharynx, larynx, or bronchial tree.. 5.5Pediatric 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 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 Use in Specific Populations (8.1, 8.4), Nonclinical Toxicology (13.2)]. 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 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.. 5.6Drug-Induced Liver Injury Ketamine administration is associated with hepatobiliary dysfunction (most often cholestatic pattern), with recurrent use (e.g., misuse/abuse or medically supervised unapproved indications). Biliary duct dilatation with or without evidence of biliary obstruction has also been reported with recurrent use. Obtain baseline LFTs, including alkaline phosphatase and gamma glutamyl transferase, in patients receiving ketamine as part of treatment plan that utilizes recurrent dosing. Monitor those receiving recurrent ketamine at periodic intervals during treatment.. 5.7Increase in Cerebrospinal Fluid Pressure An increase in intracranial pressure has been reported following administration of ketamine hydrochloride. Patients with elevated intracranial pressure should be in monitored setting with frequent neurologic assessments.. 5.8Drug Interactions Theophylline or Aminophylline: Concomitant administration of ketamine hydrochloride injection and theophylline or aminophylline may lower the seizure threshold [see Drug Interactions (7.1)]. 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 [see Drug Interactions (7.2)]. Closely monitor vital signs when ketamine hydrochloride injection and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patients clinical situation.Benzodiazepines, Opioid Analgesics, or Other CNS DepressantsConcomitant 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 Drug Interactions (7.3)]. Closely monitor neurological status and respiratory parameters, including respiratory rate and pulse oximetry, when ketamine hydrochloride injection and opioid analgesics, benzodiazepines, or other CNS depressants are co-administered. Consider dose adjustment individualized to the patients clinical situation.