ATIVAN- lorazepam injection, solution
Baxter Healthcare Corporation
Lorazepam, a benzodiazepine with antianxiety, sedative, and anticonvulsant effects, is intended for the intramuscular or intravenous routes of administration. It has the chemical formula: 7-chloro-5(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H -1, 4-benzodiazepin-2-one. The molecular weight is 321.16, and the C.A.S. No. is [846-49-1]. The structural formula is:
Lorazepam is a nearly white powder almost insoluble in water. Each mL of sterile injection contains either 2.0 or 4.0 mg of lorazepam, 0.18 mL polyethylene glycol 400 in propylene glycol with 2.0% benzyl alcohol as preservative.
Lorazepam interacts with the γ-aminobutyric acid (GABA)-benzodiazepine receptor complex, which is widespread in the brain of humans as well as other species. This interaction is presumed to be responsible for lorazepam’s mechanism of action. Lorazepam exhibits relatively high and specific affinity for its recognition site but does not displace GABA. Attachment to the specific binding site enhances the affinity of GABA for its receptor site on the same receptor complex. The pharmacodynamic consequences of benzodiazepine agonist actions include antianxiety effects, sedation, and reduction of seizure activity. The intensity of action is directly related to the degree of benzodiazepine receptor occupancy.
Intravenous or intramuscular administration of the recommended dose of 2 mg to 4 mg of ATIVAN Injection to adult patients is followed by dose-related effects of sedation (sleepiness or drowsiness), relief of preoperative anxiety, and lack of recall of events related to the day of surgery in the majority of patients. The clinical sedation (sleepiness or drowsiness) thus noted is such that the majority of patients are able to respond to simple instructions whether they give the appearance of being awake or asleep. The lack of recall is relative rather than absolute, as determined under conditions of careful patient questioning and testing, using props designed to enhance recall. The majority of patients under these reinforced conditions had difficulty recalling perioperative events or recognizing props from before surgery. The lack of recall and recognition was optimum within 2 hours following intramuscular administration and 15 to 20 minutes after intravenous injection.
The intended effects of the recommended adult dose of ATIVAN Injection usually last 6 to 8 hours. In rare instances, and where patients received greater than the recommended dose, excessive sleepiness and prolonged lack of recall were noted. As with other benzodiazepines, unsteadiness, enhanced sensitivity to CNS-depressant effects of ethyl alcohol and other drugs were noted in isolated and rare cases for greater than 24 hours.
Studies in healthy adult volunteers reveal that intravenous lorazepam in doses up to 3.5 mg/70 kg does not alter sensitivity to the respiratory stimulating effect of carbon dioxide and does not enhance the respiratory-depressant effects of doses of meperidine up to 100 mg/70 kg (also determined by carbon dioxide challenge) as long as patients remain sufficiently awake to undergo testing. Upper airway obstruction has been observed in rare instances where the patient received greater than the recommended dose and was excessively sleepy and difficult to arouse (see WARNINGS and ADVERSE REACTIONS).
Clinically employed doses of ATIVAN Injection do not greatly affect the circulatory system in the supine position or employing a 70-degree tilt test. Doses of 8 mg to 10 mg of intravenous lorazepam (2 to 2-1/2 times the maximum recommended dosage) will produce loss of lid reflexes within 15 minutes.
Studies in 6 healthy young adults who received lorazepam injection and no other drugs revealed that visual tracking (the ability to keep a moving line centered) was impaired for a mean of 8 hours following administration of 4 mg of intramuscular lorazepam and 4 hours following administration of 2 mg intramuscularly with considerable subject variation. Similar findings were noted with pentobarbital, 150 and 75 mg. Although this study showed that both lorazepam and pentobarbital interfered with eye-hand coordination, the data are insufficient to predict when it would be safe to operate a motor vehicle or engage in a hazardous occupation or sport.
A 4-mg dose provides an initial concentration of approximately 70 ng/mL.
Following intramuscular administration, lorazepam is completely and rapidly absorbed reaching peak concentrations within 3 hours. A 4-mg dose provides a Cmax of approximately 48 ng/mL. Following administration of 1.5 to 5.0 mg of lorazepam IM, the amount of lorazepam delivered to the circulation is proportional to the dose administered.
At clinically relevant concentrations, lorazepam is 91±2% bound to plasma proteins; its volume of distribution is approximately 1.3 L/kg. Unbound lorazepam penetrates the blood/brain barrier freely by passive diffusion, a fact confirmed by CSF sampling. Following parenteral administration, the terminal half-life and total clearance averaged 14±5 hours and 1.1±0.4 mL/min/kg, respectively.
Lorazepam is extensively conjugated to the 3-O-phenolic glucuronide in the liver and is known to undergo enterohepatic recirculation. Lorazepam glucuronide is an inactive metabolite and is eliminated mainly by the kidneys.
Following a single 2-mg oral dose of 14 C-lorazepam to 8 healthy subjects, 88±4% of the administered dose was recovered in urine and 7±2% was recovered in feces. The percent of administered dose recovered in urine as lorazepam glucuronide was 74±4%. Only 0.3% of the dose was recovered as unchanged lorazepam, and the remainder of the radioactivity represented minor metabolites.
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