ketamine 100 MG/ML Injectable Solution [Zetamine]

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 • 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 anesthesia. These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic. Ketamine Hydrochloride Injection given by slow microdrip infusion technique at a dose of 0.1 to 0.5 mg/minute will maintain general anesthesia in adult patients induced with Ketamine Hydrochloride Injection. Augment Ketamine Hydrochloride Injection with an intravenous benzodiazepine for the prevention of neuropsychological manifestations during emergence. Supplement to Other Anesthetic Agents Ketamine Hydrochloride Injection can be administered to supplement other general and local anesthetic agents. Continuously monitor patients for changes in respiratory and hemodynamic parameters. A reduced dose of Ketamine Hydrochloride Injection can be used to produce balanced anesthesia when used in combination with other anesthetic agents. 2.3 Preparation of Dilution Ketamine Hydrochloride Injection is a clear, colorless to slightly yellowish 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. Induction of Anesthesia : Do not intravenously inject the 100 mg/mL concentration of Ketamine Hydrochloride Injection without proper dilution. Dilute Ketamine Hydrochloride Injection with an equal volume of either Sterile Water for injection, USP, 0.9% Sodium Chloride Injection, USP (Normal Saline), or 5% Dextrose in Water. Use immediately after dilution. Maintenance of Anesthesia : To prepare a dilute solution containing 1 mg of ketamine per mL, aseptically transfer 10 mL from a 50 mg per mL vial or 5 mL from a 100 mg per mL vial to 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (Normal Saline) and mix well. The resultant solution will contain 1 mg of ketamine per mL. Use immediately after dilution. When fluid restriction is required, Ketamine Hydrochloride Injection can be added to a 250 mL infusion as described above to provide a Ketamine Hydrochloride Injection concentration of 2 mg/mL. 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

WARNINGS AND PRECAUTIONS • Hemodynamic Instability : Monitor vital signs and cardiac function during Ketamine Hydrochloride Injection administration. ( 5.1 ) • Emergence Reactions : Postoperative confusional states may occur during the recovery period. Reduce by minimizing verbal, tactile, and visual stimulation of the patient. ( 5.2 ) • Risk of Respiratory Depression : May occur with overdosage or too rapid a rate of administration. Maintain adequate oxygenation and ventilation. ( 5.3 ) • Risks 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 a sole anesthetic agent in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree. Muscle relaxants may be required. ( 5.4 ) • Pediatric Neurotoxicity : Long-term cognitive deficits may occur when used for longer than 3 hours in children ≤3 years. ( 5.5 ) 5.1 Hemodynamic 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 a significant elevation of blood pressure would constitute a serious hazard [see Contraindications (4) ] . 5.2 Emergence Reactions Emergence delirium (postoperative confusional states or agitation) has occurred in approximately 12% of patients during the recovery period, and the duration is generally a 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, excitement, 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 a 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. 5.3 Respiratory Depression Respiratory depression may occur with overdosage or a rapid rate of administration of Ketamine Hydrochloride Injection. Maintain adequate oxygenation and ventilation. 5.4 Risks 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 a 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. 5.5 Pediatric 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 3 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 a 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. 5.6 Drug-Induced Liver Injury Ketamine administration is associated with hepatobiliary dysfunction (most often a cholestatic pattern), with recurrent use (e.g., misuse/abuse or medically supervised unapproved indications). Biliary duct dilatation, stricture, stenosis, and obstructions have also been reported with recurrent use. Obtain baseline LFTs, including alkaline phosphatase and gamma glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing. Monitor those receiving recurrent ketamine at periodic intervals during treatment. Sclerosing cholangitis has been reported in patients on long term ketamine therapy. Ketamine-induced sclerosing cholangitis is potentially reversible with ketamine discontinuation. If signs or symptoms consistent with sclerosing cholangitis (e.g., a cholestatic pattern of increased liver function tests with grossly elevated gamma glutamyl transferase and alkaline phosphatase levels) are observed in a patient receiving ketamine, discontinue ketamine immediately and refer the patient to the appropriate specialist for evaluation. 5.7 Urological Complications Serious renal and urinary complications, including cystitis, reduced bladder capacity, ureteral stenosis, ureteral obstruction, and hydronephrosis have been reported with long-term ketamine use or abuse. Ureteral stenosis and ureteral obstruction can lead to hydronephrosis and renal impairment and may require emergency interventions such as nephrostomy tube placement, ureteral stenting, or surgical intervention. If signs or symptoms of urinary obstruction or severe lower urinary tract symptoms are observed, discontinue ketamine and refer for urgent urological evaluation. 5.8 Increase 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 a monitored setting with frequent neurologic assessments. 5.9 Drug 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 patient's clinical situation. Benzodiazepines, Opioid Analgesics, or Other CNS Depressants Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respirator

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 )

Clinical Pharmacology 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. 12.2 Pharmacodynamics Nervous System Ketamine is a rapidly-acting general anesthetic producing a dissociative anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a 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 System Ketamine 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 a maximum within a 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 System Ketamine is a potent bronchodilator suitable for anesthetizing patients at high risk for bronchospasm. 12.3 Pharmacokinetics Distribution Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug. Elimination Metabolism Ketamine is metabolized via N-dealkylation to the active metabolite norketamine primarily by CYP2B6 and CYP3A4 and to a 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. Excretion Following intravenous administration, the ketamine concentration decreases due to a 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.