Ketalar - Par Health USA, LLC

KETALAR 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 KETALAR.

Emergency airway equipment must be immediately available.

KETALAR is a 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.

Do not administer the 100 mg/mL concentration of KETALAR 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 KETALAR.  KETALAR is not recommended for use in patients who have not followed nil per os guidelines.

Due to the potential for salivation during KETALAR administration, administer an antisialagogue prior to induction of anesthesia.

The KETALAR 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: The 100 mg/mL concentration of KETALAR must be diluted prior to intravenous administration. Dilute the 100 mg/mL concentration of KETALAR 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. The 10 mg/mL and 50 mg/mL concentrations of KETALAR may be administered intravenously for induction of anesthesia without dilution. The 100 mg/mL concentration of KETALAR may be administered intramuscularly for induction of anesthesia without 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, KETALAR can be added to a 250 mL infusion as described above to provide a KETALAR concentration of 2 mg/mL. The 10 mg/mL concentration of KETALAR may be administered intravenously for maintenance of anesthesia without dilution. 

Transient increases in blood pressure, heart rate, and cardiac index are frequently observed following administration of KETALAR. Decreases in blood pressure and heart rate, arrhythmias, and cardiac decompensation have also been observed. Monitor vital signs and cardiac function during KETALAR administration. KETALAR is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard [see Contraindications (4)].

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 KETALAR 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 KETALAR 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.

Respiratory depression may occur with overdosage or a rapid rate of administration of KETALAR. Maintain adequate oxygenation and ventilation.

KETALAR does not suppress pharyngeal and laryngeal reflexes. Avoid KETALAR 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.

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.

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.

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.

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.

Theophylline or Aminophylline: Concomitant administration of KETALAR and theophylline or aminophylline may lower the seizure threshold [see Drug Interactions (7.1)]. Consider using an alternative to KETALAR 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 KETALAR 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 KETALR and opioid analgesics, benzodiazepines, or other CNS depressants are co-administered. Consider dose adjustment individualized to the patient’s clinical situation.

Concomitant administration of KETALAR and theophylline or aminophylline may lower the seizure threshold. Consider using an alternative to KETALAR in patients receiving theophylline or aminophylline.

Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine. Closely monitor vital signs when KETALAR and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patient’s clinical situation.

Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.9 )].

Opioid analgesics administered concomitantly with KETALAR may prolong time to complete recovery from anesthesia.

Risk Summary

Published literature describe the presence of ketamine and its metabolite in human milk. There are no data on the effects on the breastfed infants; however, infants should be monitored for sedation, respiratory depression, and increased muscle tone and spasms. There are no data on the effects of ketamine on milk production. Due to the potential for developmental neurotoxicity of ketamine in newborns and infants [ see subsection ( 8.4 )], KETALAR treatment in lactating women should be limited to anesthesia. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ketamine and any potential adverse effects on the breastfed child from ketamine or from the underlying maternal condition.

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 KETALAR, 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 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 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)].

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.

KETALAR contains ketamine, a Schedule III controlled substance under the Controlled Substance Act.

Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of KETALAR. Abuse is the intentional, non-therapeutic use of a drug, even once, for its psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed.

In a context of drug abuse, KETALAR may produce a 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. Long-term ketamine use or abuse may be associated with hepatobiliary complications including hepatobiliary dysfunction (cholestatic pattern with elevated alkaline phosphatase and gamma-glutamyl transferase), biliary duct dilatation and strictures, sclerosing cholangitis, and urological complications including cystitis, reduced bladder capacity, ureteral stenosis and obstruction, and hydronephrosis [see Warnings and Precautions (5.6, 5.7) and Adverse Reactions (6)]. 

Physical dependence has been reported with prolonged use of ketamine. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of a 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 a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

KETALAR, 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.

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 3 years of age in humans.

In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 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). A no-effect level for neuronal vacuolation was 20 mg/kg intraperitoneal (0.3 times a human dose of 10 mg/kg on a 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.