Ketamine Hydrochloride

5 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). 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. 5.7 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. 5.8 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, 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 patient’s clinical situation.

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.

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. 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 Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .