mester of gestation through the first several months of life, but may extend out to approximately three years of age in humans (see precautions: pregnancy ). 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.

n may result in respiratory depression or apnea and enhanced pressor response. in surgical procedures involving visceral pain pathways, ketamine hydrochloride injection should be supplemented with an agent which obtunds visceral pain. use with caution in the chronic alcoholic and the acutely alcohol-intoxicated patient. an increase in cerebrospinal fluid pressure has been reported following administration of ketamine hydrochloride. use with extreme caution in patients with preanesthetic elevated cerebrospinal fluid pressure.

s recommended for use in the patient whose stomach is not empty when, in the judgment of the practitioner, the benefits of the drug outweigh the possible risks. 2. atropine, scopolamine, or another drying agent should be given at an appropriate interval prior to induction. onset and duration because of rapid induction following the initial intravenous injection, the patient should be in a supported position during administration. the onset of action of ketamine hydrochloride injection is rapid; an intravenous dose of 2 mg/kg of body weight usually produces surgical anesthesia within 30 seconds after injection, with the anesthetic effect usually lasting five to ten minutes. if a longer effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia without producing significant cumulative effects. intramuscular doses, in a range of 9 mg/kg to 13 mg/kg usually produce surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes.

ction). 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. psychological (see special note .) neurological in some patients, enhanced skeletal muscle tone may be manifested by tonic and clonic movements sometimes resembling seizures (see dosage and administration section). gastrointestinal anorexia, nausea and vomiting have been observed; however, this is not usually severe and allows the great majority of patients to take liquids by mouth shortly after regaining consciousness (see dosage and administration section). general anaphylaxis. local pain and exanthema at the injection site have infrequently been reported. transient erythema and/or morbilliform rash have also been reported. for medical advice about adverse reactions contact your medical professional. to report suspected adverse reactions, contact mylan at 1-877-446-3679 (1-877-4-info-rx) or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

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 to 4% and 15 to 20%, respectively. clinical considerations since the safe use in pregnancy, including obstetrics (either vaginal or abdominal delivery), has not been established, such use is not recommended (see animal pharmacology and toxicology ). data animal data 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 6 to 10 or gestation days 11 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 6 to 10 or gestation days 11 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 18 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 (see warnings: pediatric neurotoxicity , precautions: pediatric use , and animal toxicology and pharmacology ).

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 pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data (see warnings: pediatric neurotoxicity and precautions: pregnancy ).

(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. the anesthetic action is terminated by a combination of redistribution from the cns to slower equilibrating peripheral tissues and by hepatic biotransformation to metabolite i. this metabolite is about 1/3 as active as ketamine in reducing halothane requirements (mac) of the rat. the later half-life of ketamine (beta phase) is 2.5 hours. the anesthetic state produced by ketamine hydrochloride injection has been termed "dissociative anesthesia" in that it appears to selectively interrupt association pathways of the brain before producing somatesthetic sensory blockade. it may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems). elevation of blood pressure begins shortly after injection, reaches a maximum within a few minutes and usually returns to preanesthetic values within 15 minutes after injection. 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 (see contraindications section). ketamine has a wide margin of safety; several instances of unintentional administration of overdoses of ketamine hydrochloride injection (up to ten times that usually required) have been followed by prolonged but complete recovery. ketamine hydrochloride injection has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients from 105 separate studies. during the course of these studies ketamine hydrochloride injection was administered as the sole agent, as induction for other general agents, or to supplement low-potency agents. specific areas of application have included the following: 1. debridement, painful dressings, and skin grafting in burn patients, as well as other superficial surgical procedures. 2. neurodiagnostic procedures such as pneumonencephalograms, ventriculograms, myelograms, and lumbar punctures. see also precaution concerning increased intracranial pressure. 3. diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental extractions. 4. diagnostic and operative procedures of the pharynx, larynx, or bronchial tree. note: muscle relaxants, with proper attention to respiration, may be required (see precautions section). 5. sigmoidoscopy and minor surgery of the anus and rectum, and circumcision. 6. extraperitoneal procedures used in gynecology such as dilatation and curettage. 7. orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies. 8. as an anesthetic in poor-risk patients with depression of vital functions. 9. in procedures where the intramuscular route of administration is preferred. 10. in cardiac catheterization procedures. in these studies, the anesthesia was rated either "excellent" or "good" by the anesthesiologist and the surgeon at 90% and 93%, respectively; rated "fair" at 6% and 4%, respectively; and rated "poor" at 4% and 3%, respectively. in a second method of evaluation, the anesthesia was rated "adequate" in at least 90%, and "inadequate" in 10% or less of the procedures.

y ).