Lorazepam (Lorazepam) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

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 and sedation, and reduction of seizure activity. The intensity of action is directly related to the degree of benzodiazepine receptor occupancy.

Effects in Pre-Operative Patients

Intravenous or intramuscular administration of the recommended dose of 2 mg to 4 mg of Lorazepam 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 Lorazepam 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.

Physiologic Effects in Healthy Adults

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 Lorazepam Injection do not greatly affect the circulatory system in the supine position or employing a 70-degree tilt test. Doses of 8 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 six (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 eight (8) hours following administration of 4 mg of intramuscular lorazepam and four (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.

Pharmacokinetics and Metabolism

Absorption

Intravenous

A 4-mg dose provides an initial concentration of approximately 70 ng/mL.

Intramuscular

Following intramuscular administration, lorazepam is completely and rapidly absorbed reaching peak concentrations within 3 hours. A 4-mg dose provides a C_max of approximately 48 ng/mL. Following administration of 1.5 to 5 mg of lorazepam IM, the amount of lorazepam delivered to the circulation is proportional to the dose administered.

Distribution/Metabolism/Elimination

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 ¹⁴C-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.

Special Populations

Effect of Age

Pediatrics

  Neonates (Birth to 1 month)

Following a single 0.05 mg/kg (n=4) or 0.1 mg/kg (n=6) intravenous dose of lorazepam, mean total clearance normalized to body weight was reduced by 80% compared to normal adults, terminal half-life was prolonged 3-fold, and volume of distribution was decreased by 40% in neonates with asphyxia neonatorum compared to normal adults. All neonates were of ≥ 37 weeks of gestational age.

   Infants (1 month up to 2 years)

There is no information on the pharmacokinetic profile of lorazepam in infants in the age range of 1 month to 2 years.

  Children (2 years to 12 years)

Total (bound and unbound) lorazepam had a 50% higher mean volume of distribution (normalized to body weight) and a 30% longer mean half-life in children with acute lymphocytic leukemia in complete remission (2 to 12 years, n=37) compared to normal adults (n=10). Unbound lorazepam clearance normalized to body weight was comparable in children and adults.

   Adolescents (12 years to 18 years)

Total (bound and unbound) lorazepam had a 50% higher mean volume of distribution (normalized to body weight) and a mean half-life that was two fold greater in adolescents with acute lymphocytic leukemia in complete remission (12 to 18 years, n=13) compared to normal adults (n=10). Unbound lorazepam clearance normalized to body weight was comparable in adolescents and adults.

Elderly

Following single intravenous doses of 1.5 to 3 mg of Lorazepam Injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age. Consequently, no dosage adjustment appears to be necessary in elderly subjects based solely on their age.

Effect of Gender

Gender has no effect on the pharmacokinetics of lorazepam.

Effect of Race

Young Americans (n=15) and Japanese subjects (n=7) had very comparable mean total clearance value of 1.0 mL/min/kg. However, elderly Japanese subjects had a 20% lower mean total clearance than elderly Americans; 0.59 mL/min/kg vs 0.77 mL/min/kg, respectively.

Patients with Renal Insufficiency

Because the kidney is the primary route of elimination of lorazepam-glucuronide, renal impairment would be expected to compromise its clearance. This should have no direct effect on the glucuronidation (and inactivation) of lorazepam. There is a possibility that the enterohepatic circulation of lorazepam-glucuronide leads to a reduced efficiency of the net clearance of lorazepam in this population.

   Six normal subjects, six patients with renal impairment (CI_cr of 22 ± 9 mL/min), and four patients on chronic maintenance hemodialysis were given single 1.5 to 3.0 mg intravenous doses of lorazepam. Mean volume of distribution and terminal half-life values of lorazepam were 40% and 25% higher, respectively, in renally impaired patients then in normal subjects. Both parameters were 75% higher in patients undergoing hemodialysis than in normal subjects. Overall, though, in this group of subjects the mean total clearance of lorazepam did not change. About 8% of the administered intravenous dose was removed as intact lorazepam during the 6-hour dialysis session.

   The kinetics of lorazepam-glucuronide were markedly affected by renal dysfunction. The mean terminal half-life was prolonged by 55% and 125% in renally impaired patients and patients under hemodialysis, respectively, as compared to normal subjects. The mean metabolic clearance decreased by 75% and 90% in renally impaired patients and patients under hemodialysis, respectively, as compared to normal subjects. About 40% of the administered lorazepam intravenous dose was removed as glucuronide conjugate during the 6-hour dialysis session.

Hepatic Disease

Because cytochrome oxidation is not involved with the metabolism of lorazepam, liver disease would not be expected to have an effect on metabolic clearance. This prediction is supported by the observation that following a single 2 mg intravenous dose of lorazepam, cirrhotic male patients (n=13) and normal male subjects (n=11) exhibited no substantive difference in their ability to clear lorazepam.

Effect of Smoking

Administration of a single 2 mg intravenous dose of lorazepam showed that there was no difference in any of the pharmacokinetic parameters of lorazepam between cigarette smokers (n=10, mean=31 cigarettes per day) and nonsmoking subjects (n=10) who were matched for age, weight, and gender.

Clinical Studies

The effectiveness of Lorazepam Injection in status epilepticus was established in two multi-center controlled trials in 177 patients. With rare exceptions, patients were between 18 and 65 years of age. More than half the patients in each study had tonic-clonic status epilepticus; patients with simple partial and complex partial status epilepticus comprised the rest of the population studied, along with a smaller number of patients who had absence status.

  One study (n=58) was a double-blind active-control trial comparing Lorazepam Injection and diazepam. Patients were randomized to receive lorazepam 2 mg IV (with an additional 2 mg IV if needed) or diazepam 5 mg IV (with an additional 5 mg IV if needed). The primary outcome measure was a comparison of the proportion of responders in each treatment group, where a responder was defined as a patient whose seizures stopped within 10 minutes after treatment and who continued seizure-free for at least an additional 30 minutes. Twenty-four of the 30 (80%) patients were deemed responders to lorazepam and 16/28 (57%) patients were deemed responders to diazepam (p=0.04). Of the 24 lorazepam responders, 23 received both 2 mg infusions.

   Non-responders to lorazepam 4 mg were given an additional 2 to 4 mg lorazepam; non-responders to diazepam 10 mg were given an additional 5 to 10 mg diazepam. After this additional dose administration, 28/30 (93%) of patients randomized to lorazepam and 24/28 (86%) of patients randomized to diazepam were deemed responders, a difference that was not statistically significant.

   Although this study provides support for the efficacy of lorazepam as the treatment for status epilepticus, it cannot speak reliably or meaningfully to the comparative performance of either diazepam (valium) or lorazepam (Lorazepam Injection) under the conditions of actual use.

  A second study (n=119) was a double-blind dose-comparison trial with 3 doses of Lorazepam Injection: 1 mg, 2 mg, and 4 mg. Patients were randomized to receive one of the three doses of lorazepam. The primary outcome and definition of responder were as in the first study. Twenty-five of 41 patients (61%) responded to 1 mg lorazepam; 21/37 patients (57%) responded to 2 mg lorazepam; and 31/41 (76%) responded to 4 mg lorazepam. The p-value for a statistical test of the difference between the lorazepam 4 mg dose group and the lorazepam 1 mg dose group was 0.08 (two-sided). Data from all randomized patients were used in this test.

  Although analyses failed to detect an effect of age, sex, or race on the effectiveness of lorazepam in status epilepticus, the numbers of patients evaluated were too few to allow a definitive conclusion about the role these factors may play.