Ketamine Hydrochloride (Page 4 of 5)
12 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.
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.
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.
Ketamine is a potent bronchodilator suitable for anesthetizing patients at high risk for bronchospasm.
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.
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.
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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been conducted to evaluate the carcinogenic potential of ketamine.
In a published report, ketamine was clastogenic in the in vitro chromosomal aberration assay.
Impairment of Fertility
Adequate 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 IV (0.8 times the average human induction dose of 2 mg/kg IV based on body surface area) on Days 11, 10, and 9 prior to mating. No impact on fertility was noted; however, this study design does not adequately characterize the impact of a 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 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.
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:
- debridement, dressing changes, and skin grafting in burn patients, as well as other superficial surgical procedures.
- neurodiagnostic procedures such as myelograms and lumbar punctures.
- diagnostic and operative procedures of the ear, nose, and mouth, including dental extractions.
- sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.
- extraperitoneal procedures, such as dilatation and curettage.
- orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.
- cardiac catheterization procedures.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied Ketamine hydrochloride injection, USP is a clear colorless to very slight yellow color solution supplied as the hydrochloride salt in concentrations equivalent to ketamine base, as follows:
|Unit of sale||S tre n gth|
|NDC 68083-504-10Unit 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 68083-505-10Unit 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 68083-506-10Unit 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 Ketamine hydrochloride injection, USP 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) [see USP Controlled Room Temperature ]. Protect from light.
17 PATIENT COUNSELING INFORMATION
- Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 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) ].
- Due 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.
Gland Pharma Limited
Hyderabad – 502 307, India
Issued date: November 2022
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