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, 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 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 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 Cmax 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 (Clcr 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 than 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 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 or lorazepam 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.
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