KETARAZ

Ketamine is an

NMDA receptor antagonist with a potent anesthetic effect.

It was developed in as a replacement for phencyclidine (PCP) by Calvin Stevens at Parke Davis Laboratories.

It started being used for veterinary purposes in Belgium and in was proven that compared to PCP, it produced minor hallucinogenic effects and shorter psychotomimetic effects.

It was

FDA approved in 1970, and from there, it has been used as an anesthetic for children or patients undergoing minor surgeries but mainly for veterinary purposes.

Ketamine is indicated as an anesthetic agent for recommended diagnostic and surgical procedures.

If skeletal muscle relaxation is needed, it should be combined with a muscle relaxant.

If the surgical procedure involves visceral pain, it should be supplemented with an agent that obtunds visceral pain.

Ketamine can be used for induction of anesthesia prior other general anesthetic agents and as a supplement of low potency agents. 15, Label Reports have indicated a potential use of ketamine as a therapeutic tool for the management of depression when administered in lower doses.

These reports have increased the interest for ketamine in this area and several clinical trials are launched for this indication. 16,

Ketamine is a rapid-acting general anesthetic producing an 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 anesthetic state produced by

Ketamine has been termed as "dissociative anesthesia" in that it appears to selectively interrupt association pathways of the brain before producing somesthetic sensory blockade.

It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems).

Ketamine enhances descending inhibiting serotoninergic pathways and can exert antidepressive effects.

These effects are seen in concentrations ten times lower than the needed concentration for anesthetic proposes.

The effect of ketamine can be described as analgesic by the prevention of central sensitization in dorsal horn neurons as well as by the inhibition on the synthesis of nitric oxide.

Glutamate receptor ionotropic, NMDA 3A Antagonist 5-hydroxytryptamine receptor 3A Potentiator Neuronal acetylcholine receptor subunit alpha-7 Antagonist + 2 more targets.

Ketamine absorption is very rapid and the bioavailability is around 93%.

After the first pass metabolism, only 17% of the administered dose is absorbed.

It distributes very rapidly and presents a distribution half-life of 1.95 min.

Cmax levels at peak reach 0.75 mcg/ml in plasma and 0.2 mcg/ml in cerebrospinal fluid.

The apparent volume of distribution of the central compartment and at steady-state are 371.3 ml/kg and 4060.3 ml/kg, respectively.

Ketamine presents a mainly hepatic metabolism and its major metabolite is norketamine.

The biotransformation of ketamine corresponds to

N-dealkylation, hydroxylation of the cyclohexone ring, conjugation to glucuronic acid and dehydration of the hydroxylated metabolites for the formation of cyclohexene derivatives.

Hover over products below to view reaction partners Ketamine Norketamine 6-Hydroxynorketamine 5-Hydroxynorketamine 4-Hydroxynorketamine 6-Hydroxyketamine 6-Hydroxynorketamine 5-Hydroxyketamine 5-Hydroxynorketamine 4-Hydroxyketamine 4-Hydroxynorketamine.

Pharmacokinetic studies have resulted in the recovery of 85-95% of the administered dose in urine mainly in the form of metabolites.

Some other routes of elimination of ketamine are bile and feces.

When administered

Intravenous the resultant recovery is distributed by 91% of the administered dose in urine and 3% in feces.

The reported half-life in preclinical studies for ketamine is 186 min.

The clearance rate of ketamine is high and of around 95 L/h/70 kg.

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Preclinical studies related to the blocking of NMDA receptors have shown an increase in apoptosis in the developing brain which results in cognitive deficits when used for longer than 3 hours.

Toxicity studies regarding carcinogenesis have not been performed.

Regarding mutagenesis and fertility, ketamine showed to be clastogenic and to not have effects on fertility.

is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard.

KETALAR is contraindicated in patients with known hypersensitivity to ketamine or to any excipient.

In patients for whom a significant elevation of blood pressure would be a serious hazard.

Known hypersensitivity to ketamine or to any excipient.

Information for important dosage and administration instructions.

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 to 2 mg/kg at a rate of 0.5 mg/kg/min. -

• Intramuscular route: Initially, 6.5 to 13 mg/kg. Maintenance of anesthesia: Increments of one-half to the full induction dose may be repeated as needed.

Adjust the dose according to the patient's anesthetic needs and whether an additional anesthetic agent is employed.

Supplement to other anesthetic agents

The regimen of a reduced dose of KETALAR supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents. 2.1 Important Dosage and Administration Information 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.

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. 2.2 Recommended Dosage and Administration 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.

The initial dose of KETALAR administered intravenously may range from 1 mg/kg to 4.5 mg/kg. The average amount required to produce to 10 minutes of surgical anesthesia within 30 seconds following injection is 2 mg/kg. Administer KETALAR 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 KETALAR administered intramuscularly may range from 6.5 to 13 mg/kg. A dose of to 13 mg/kg usually produces surgical anesthesia within to 4 minutes following injection, with the anesthetic effect usually lasting to 25 minutes.

Administer a benzodiazepine, if clinically indicated, for the prevention of neuropsychological manifestations during emergence from 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.

KETALAR 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 KETALAR.

KETALAR with an intravenous benzodiazepine for the prevention of neuropsychological manifestations during emergence.

KETALAR 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

KETALAR can be used to produce balanced anesthesia when used in combination with other anesthetic agents. 2.3 Preparation of Dilution 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.

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.

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.

KETALAR injection is a clear, colorless solution supplied as the hydrochloride salt in concentrations equivalent to ketamine base, as follows: Unit of sale Strength NDC 42023-113-10 Unit of 10 200 mg in 20 mL multiple-dose vial (10 mg/mL) 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride) NDC 42023-114-10 Unit of 10 500 mg in 10 mL multiple-dose vial (50 mg/mL) 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) NDC 42023-115-10 Unit of 10 500 mg in 5 mL multiple-dose vial (100 mg/mL) 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride) Storage and Handling KETALAR injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) .

Protect from light.

Available data on the use of ketamine in pregnant women mostly describe its use at the time of cesarean section and have not identified a drug-associated risk of adverse maternal or fetal outcomes.

The data are limited by retrospective collection, small sample sizes, and a lack of long-term follow-up.

There are no available data on ketamine use during other stages of pregnancy to allow for an evaluation of drug-associated risk of major birth defects or miscarriage.

In animal reproduction studies in rats developmental delays (hypoplasia of skeletal tissues) were noted at 0.3 times the human intramuscular dose of 10 mg/kg. In rabbits, developmental delays and increased fetal resorptions were noted at 0.6 times the human dose.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.

The clinical significance of these nonclinical findings is not known, and the benefits of appropriate anesthesia in pregnant women who require procedures should be balanced with the potential risks suggested by the nonclinical data.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days to 10 or Gestation Days to 15.

Ketamine treatment produced an increased incidence of hypoplastic skull, phalanges, and sternebrae in the pups.

Pregnant rabbits were treated intramuscularly with 20 mg/kg ketamine (0.6 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days to 10 or Gestation Days to 15.

An increase in resorptions and skeletal hypoplasia of the fetuses were noted.

Additional pregnant rabbits were treated intramuscularly with a single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg IM based on body surface area) on Gestation Day 6 only.

Skeletal hypoplasia was reported in the fetuses.

In a study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) from Gestation Day to 21.

There was a slight increase in incidence of delayed parturition by one day in treated dams of this group.

No adverse effects on the litters or pups were noted; however, learning and memory assessments were not completed.

Three pregnant beagle dogs were treated intramuscularly with 25 mg/kg ketamine (1.3 times the human dose of 10 mg/kg IM based on body surface area) twice weekly for the three weeks of the first, second, and third trimesters of pregnancy, respectively, without the development of adverse effects in the pups.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal 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.

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.

Clinical studies of ketamine hydrochloride did not include sufficient numbers of subjects aged 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.