Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1164
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Lorazepam (Injection, Solution)
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Lorazepam must never be used without individualization
of dosage particularly when used with other medications capable of
producing central-nervous-system depression. EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY SHOULD BE IMMEDIATELY
AVAILABLE PRIOR TO INTRAVENOUS ADMINISTRATION OF LORAZEPAM (see���WARNINGS���). Status Epilepticus General Advice Status epilepticus is a potentially life-threatening
condition associated with a high risk of permanent neurological impairment,
if inadequately treated. The treatment of status, however, requires
far more than the administration of an anticonvulsant agent. It involves
observation and management of all parameters critical to maintaining
vital function and the capacity to provide support of those functions
as required. Ventilatory support must be readily available. The use
of benzodiazepines, like Lorazepam Injection, is ordinarily only an
initial step of a complex and sustained intervention which may require
additional interventions, (e.g., concomitant intravenous administration
of phenytoin). Because status epilepticus may result from a correctable
acute cause such as hypoglycemia, hyponatremia, or other metabolic
or toxic derangement, such an abnormality must be immediately sought
and corrected. Furthermore, patients who are susceptible to further
seizure episodes should receive adequate maintenance antiepileptic
therapy. Any health care professional
who intends to treat a patient with status epilepticus should be familiar
with this package insert and the pertinent medical literature concerning
current concepts for the treatment of status epilepticus. A comprehensive
review of the considerations critical to the informed and prudent
management of status epilepticus cannot be provided in drug product
labeling. The archival medical literature contains many informative
references on the management of status epilepticus, among them the
report of the working group on status epilepticus of the Epilepsy
Foundation of America���Treatment of Convulsive Status Epilepticus���(JAMA 1993; 270: 854-859). As noted in the report just cited, it may
be useful to consult with a neurologist if a patient fails to respond
(e.g., fails to regain consciousness). Intravenous Injection For the treatment of status epilepticus, the usual recommended dose
of Lorazepam Injection is 4 mg given slowly (2 mg/min) for patients
18 years and older. If seizures cease, no additional Lorazepam Injection
is required. If seizures continue or recur after a 10- to 15-minute
observation period, an additional 4 mg intravenous dose may be slowly
administered. Experience with further
doses of lorazepam is very limited. The usual precautions
in treating status epilepticus should be employed. An intravenous
infusion should be started, vital signs should be monitored, an unobstructed
airway should be maintained, and artificial ventilation equipment
should be available. Intramuscular Injection IM lorazepam
is not preferred in the treatment of status epilepticus because therapeutic
lorazepam levels may not be reached as quickly as with IV administration.
However, when an intravenous port is not available, the IM route may
prove useful (see���CLINICAL PHARMACOLOGY���-
Pharmacokinetics and Metabolism). Pediatric The safety of lorazepam in pediatric patients has not been established. Preanesthetic Intramuscular Injection For the designated indications as a premedicant,
the usual recommended dose of lorazepam for intramuscular injection
is 0.05 mg/kg up to a maximum of 4 mg. As with all premedicant drugs,
the dose should be individualized (see also���CLINICAL PHARMACOLOGY,������WARNINGS,������PRECAUTIONS,���and���ADVERSE REACTIONS���). Doses
of other central-nervous-system depressant drugs should be ordinarily
reduced (see���PRECAUTIONS���). For optimum effect,measured as lack of recall, intramuscular lorazepam
should be administered at least 2 hours before the anticipated operative procedure.
Narcotic analgesics should be administered at their usual preoperative
time. There are insufficient data to support efficacy to make dosage
recommendations for intramuscular lorazepam in patients less than
18 years of age; therefore, such use is not recommended. Intravenous Injection For the primary purpose of sedation and relief
of anxiety, the usual recommended initial dose of lorazepam for intravenous
injection is 2 mg total, or 0.02 mg/lb (0.044 mg/kg), whichever is
smaller. This dose will suffice for sedating most adult patients and
should not ordinarily be exceeded in patients over 50 years of age.
In those patients in whom a greater likelihood of lack of recall for
perioperative events would be beneficial, larger doses as high as
0.05 mg/kg up to a total of 4 mg may be administered (see���CLINICAL PHARMACOLOGY,������WARNINGS,������PRECAUTIONS,���and���ADVERSE REACTIONS���). Doses
of other injectable central-nervous-system depressant drugs should
ordinarily be reduced (see���PRECAUTIONS���). For optimum effect, measured as lack of recall, intravenous
lorazepam should be administered 15 to 20 minutes before the anticipated operative procedure. EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY
SHOULD BE IMMEDIATELY AVAILABLE PRIOR TO INTRAVENOUS ADMINISTRATION
OF LORAZEPAM (see���WARNINGS���). There are insufficient data
to support efficacy or make dosage recommendations for intravenous
lorazepam in patients less than 18 years of age; therefore, such use
is not recommended. Dose Administration in Special Populations Elderly Patients and Patients with
Hepatic Disease No dosage adjustments
are needed in elderly patients and in patients with hepatic disease. Patients with Renal Disease For acute dose administration, adjustment
is not needed for patients with renal disease. However, in patients
with renal disease, caution should be exercised if frequent doses
are given over relatively short periods of time (see also���CLINICAL PHARMACOLOGY���). Dose Adjustment Due to
Drug Interactions The dose of lorazepam
should be reduced by 50% when coadministered with probenecid or valproate
(see���PRECAUTIONS���- Drug Interactions). It may be necessary to increase
the dose of lorazepam in female patients who are concomitantly taking
oral contraceptives. Administration When given intramuscularly,
Lorazepam Injection, undiluted, should be injected deep in the muscle
mass. Injectable lorazepam can
be used with atropine sulfate, narcotic analgesics, other parenterally
used analgesics, commonly used anesthetics, and muscle relaxants. Immediately prior to intravenous use,
Lorazepam Injection must be diluted with an equal volume of compatible
solution. Contents should be mixed thoroughly by gently inverting
the container repeatedly until a homogenous solution results. Do not
shake vigorously, as this will result in air entrapment. When properly
diluted the drug may be injected directly into a vein or into the
tubing of an existing intravenous infusion. The rate of injection
should not exceed 2 mg per minute. Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever solution
and container permit. Do not use if solution is discolored or contains
a precipitate. Lorazepam Injection
is compatible for dilution purposes with the following solutions:
Sterile Water for Injection, USP; Sodium Chloride Injection, USP;
5% Dextrose Injection, USP.
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Lorazepam, a benzodiazepine with antianxiety and
sedative and anticonvulsant effects, is intended for intramuscular
or intravenous route 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 molecular
formula is CHClN. The structural formula is: Lorazepam is a nearly white powder almost insoluble in water.
Each mL of sterile injection contains either 2 or 4 mg of lorazepam,
0.18 mL polyethylene glycol 400 in propylene glycol with 2% benzyl
alcohol as preservative.
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Lorazepam interacts with the��-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 Cof 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 ofC-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 (CIof 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.
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Lorazepam Injection is contraindicated in patients
with a known sensitivity to benzodiazepines or its vehicle (polyethylene
glycol, propylene glycol, and benzyl alcohol), in patients with acute
narrow-angle glaucoma, or in patients with sleep apnea syndrome. It
is also contraindicated in patients with severe respiratory insufficiency,
except in those patients requiring relief of anxiety and/or diminished
recall of events while being mechanically ventilated. The use of Lorazepam
Injection intra-arterially is contraindicated because, as with other
injectable benzodiazepines, inadvertent intra-arterial injection may
produce arteriospasm resulting in gangrene which may require amputation
(see���WARNINGS���).
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Lorazepam Injection, USP is available as: Directions for Dilution for IV use. For IM use. For IV route,
see directions. Protect from light. Use carton
to protect contents from light. Keep in a refrigerator
2��to 8��C (36��to 46��F). August, 2006
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General: The additive central-nervous-system effects of other
drugs, such as phenothiazines, narcotic analgesics, barbiturates,
antidepressants, scopolamine, and monoamine-oxidase inhibitors, should
be borne in mind when these other drugs are used concomitantly with
or during the period of recovery from Lorazepam Injection (see���CLINICAL PHARMACOLOGY���and���WARNINGS���). Extreme caution must be used in administering lorazepam
to elderly patients, very ill patients, or to patients with limited
pulmonary reserve because of the possibility that underventilation
and/or hypoxic cardiac arrest may occur. Resuscitative equipment for
ventilatory support should be readily available (see���WARNINGS���and���DOSAGE AND ADMINISTRATION���). When Lorazepam Injection is
used IV as the premedicant prior to regional or local anesthesia,
the possibility of excessive sleepiness or drowsiness may interfere
with patient cooperation to determine levels of anesthesia. This is
most likely to occur when greater than 0.05 mg/kg is given and when
narcotic analgesics are used concomitantly with the recommended dose
(see���ADVERSE REACTIONS���). As with all benzodiazepines, paradoxical reactions
may occur in rare instances and in an unpredictable fashion (see���ADVERSE REACTIONS���). In
these instances, further use of the drug in these patients should
be considered with caution. There
have been reports of possible propylene glycol toxicity (e.g., lactic
acidosis, hyperosmolality, hypotension) and possible polyethylene
glycol toxicity (e.g., acute tubular necrosis) during administration
of Lorazepam Injection at higher than recommended doses. Symptoms
may be more likely to develop in patients with renal impairment.<br/>Information for Patients: Patients should be informed of the pharmacological
effects of the drug, including sedation, relief of anxiety, and lack
of recall, the duration of these effects (about 8 hours), and be apprised
of the risks as well as the benefits of therapy. Patients who receive lorazepam as a premedicant should
be cautioned that driving a motor vehicle or operating hazardous machinery,
or engaging in hazardous or other activities requiring attention and
coordination, should be delayed for 24 to 48 hours following the injection
or until the effects of the drug, such as drowsiness, have subsided,
whichever is longer. Sedatives, tranquilizers, and narcotic analgesics
may produce a more prolonged and profound effect when administered
along with injectable lorazepam. This effect may take the form of
excessive sleepiness or drowsiness and, on rare occasions, interfere
with recall and recognition of events of the day of surgery and the
day after. Patients should be advised
that getting out of bed unassisted may result in falling and injury
if undertaken within 8 hours of receiving Lorazepam Injection. Since
tolerance for CNS depressants will be diminished in the presence of
Lorazepam Injection, these substances should either be avoided or
taken in reduced dosage. Alcoholic beverages should not be consumed
for at least 24 to 48 hours after receiving lorazepam injectable due
to the additive effects on central-nervous-system depression seen
with benzodiazepines in general. Elderly patients should be told that
lorazepam may make them very sleepy for a period longer than six (6)
to eight (8) hours following surgery.<br/>Laboratory Tests: In clinical trials no laboratory test abnormalities
were identified with either single or multiple doses of Lorazepam
Injection. These tests included: CBC, urinalysis, SGOT, SGPT, bilirubin,
alkaline phosphatase, LDH, cholesterol, uric acid, BUN, glucose, calcium,
phosphorus, and total proteins.<br/>Drug Interactions: Lorazepam Injection, like other injectable benzodiazepines,
produces additive depression of the central nervous system when administered
with other CNS depressants such as ethyl alcohol, phenothiazines,
barbiturates, MAO inhibitors, and other antidepressants. When scopolamine
is used concomitantly with injectable lorazepam, an increased incidence
of sedation, hallucinations, and irrational behavior has been observed. There have been rare reports of significant
respiratory depression, stupor and/or hypotension with the concomitant
use of loxapine and lorazepam. Marked sedation, excessive salivation, ataxia, and, rarely, death
have been reported with the concomitant use of clozapine and lorazepam. Apnea, coma, bradycardia, arrhythmia, heart
arrest, and death have been reported with the concomitant use of haloperidol
and lorazepam. The risk of using
lorazepam in combination with scopolamine, loxapine, clozapine, haloperidol,
or other CNS-depressant drugs has not been systematically evaluated.
Therefore, caution is advised if the concomitant administration of
lorazepam and these drugs is required. Concurrent
administration of any of the following drugs with lorazepam had no
effect on the pharmacokinetics of lorazepam: metoprolol, cimetidine,
ranitidine, disulfiram, propranolol, metronidazole, and propoxyphene.
No change in lorazepam dosage is necessary when concomitantly given
with any of these drugs. Lorazepam-Valproate Interaction Concurrent administration of lorazepam (2 mg intravenously)
with valproate (250 mg twice daily orally for 3 days) to 6 healthy
male subjects resulted in decreased total clearance of lorazepam by
40% and decreased formation rate of lorazepam-glucuronide by 55%,
as compared with lorazepam administered alone. Accordingly, lorazepam
plasma concentrations were about two-fold higher for at least 12 hours
post-dose administration during valproate treatment. Lorazepam dosage
should be reduced to 50% of the normal adult dose when this drug combination
is prescribed in patients (see also���DOSAGE
AND ADMINISTRATION���). Lorazepam-Oral Contraceptive Steroids Interaction Coadministration of lorazepam (2 mg intravenously)
with oral contraceptive steroids (norethindrone acetate, 1 mg, and
ethinyl estradiol, 50 mcg, for at least 6 months) to healthy females
(n=7) was associated with a 55% decrease in half-life, a 50% increase
in the volume of distribution, thereby resulting in an almost 3.7-fold
increase in total clearance of lorazepam as compared with control
healthy females (n=8).It may be necessary to increase the dose of
lorazepam in female patients who are concomitantly taking oral contraceptives
(see also���DOSAGE AND ADMINISTRATION���). Lorazepam-Probenecid
Interaction Concurrent administration
of lorazepam (2 mg intravenously) with probenecid (500 mg orally every
6 hours) to 9 healthy volunteers resulted in a prolongation of lorazepam
half-life by 130% and a decrease in its total clearance by 45%. No
change in volume of distribution was noted during probenecid co-treatment.
Lorazepam dosage needs to be reduced by 50% when coadministered with
probenecid (see also���DOSAGE AND
ADMINISTRATION���).<br/>Drug/Laboratory Test Interactions: No laboratory test abnormalities were identified
when lorazepam was given alone or concomitantly with another drug,
such as narcotic analgesics, inhalation anesthetics, scopolamine,
atropine, and a variety of tranquilizing agents.<br/>Carcinogenesis, Mutagenesis,Impairment of Fertility: No evidence of carcinogenic potential emerged in
rats and mice during an 18-month study with oral lorazepam. No studies
regarding mutagenesis have been performed. The results of a preimplantation
study in rats, in which the oral lorazepam dose was 20 mg/kg, showed
no impairment of fertility.<br/>Pregnancy: Teratogenic Effects - Pregnancy Category D (see���WARNINGS���).<br/>Labor and Delivery: There are insufficient data to support the use of
Lorazepam Injection during labor and delivery, including cesarean
section; therefore, its use in this situation is not recommended.<br/>Nursing Mothers: Lorazepam has been detected in human breast milk.
Therefore, lorazepam should not be administered to nursing mothers
because, like other benzodiazepines, the possibility exists that lorazepam
may sedate or otherwise adversely affect the infant.<br/>Pediatric Use: Status Epilepticus The safety of lorazepam in pediatric patients
with status epilepticus has not been systematically evaluated. Open-label
studies described in the medical literature included 273 pediatric/adolescent
patients; the age range was from a few hours old to 18 years of age.
Paradoxical excitation was observed in 10% to 30% of the pediatric
patients under 8 years of age and was characterized by tremors, agitation,
euphoria, logorrhea, and brief episodes of visual hallucinations.
Paradoxical excitation in pediatric patients also has been reported
with other benzodiazepines when used for status epilepticus, as an
anesthesia, or for pre-chemotherapy treatment. Pediatric patients (as well as adults) with atypical
petit mal status epilepticus have developed brief tonic-clonic seizures
shortly after lorazepam was given. This���paradoxical���effect was also reported for diazepam and clonazepam. Nevertheless,
the development of seizures after treatment with benzodiazepines is
probably rare, based on the incidence in the uncontrolled treatment
series reported (i.e., seizures were not observed for 112 pediatric
patients and 18 adults or during approximately 400 doses). Preanesthetic There are insufficient data to support the
efficacy of injectable lorazepam as a preanesthetic agent in patients
less than 18 years of age. General Seizure
activity and myoclonus have been reported to occur following administration
of Lorazepam Injection, especially in very low birth weight neonates. Pediatric patients may exhibit a sensitivity
to benzyl alcohol, polyethelene glycol and propylene glycol, components
of Lorazepam Injection (see also���CONTRAINDICATIONS���). The���gasping syndrome,���characterized by central
nervous system depression, metabolic acidosis, gasping respirations,
and high levels of benzyl alcohol and its metabolites found in the
blood and urine, has been associated with benzyl alcohol dosages>99
mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms
may include gradual neurological deterioration, seizures, intracranial
hemorrhage, hematologic abnormalities, skin breakdown, hepatic and
renal failure, hypotension, bradycardia, and cardiovascular collapse.
Central nervous system toxicity, including seizures and intraventricular
hemorrhage, as well as unresponsiveness, tachypnea, tachycardia, and
diaphoresis have been associated with propylene glycol toxicity. Although
normal therapeutic doses of Lorazepam Injection contain very small
amounts of these compounds, premature and low-birth-weight infants
as well as pediatric patients receiving high dosages may be more susceptible
to their effects.<br/>Geriatric Use: Clinical studies of lorazepam generally were not
adequate to determine whether subjects aged 65 and over respond differently
than younger subjects, however, age over 65 years may be associated
with a greater incidence of central nervous system depression and
more respiratory depression (see���WARNINGS���-
Preanesthetic Use,���PRECAUTIONS���-
General, and���ADVERSE
REACTIONS���- Preanesthetic). Age does not appear to have significant effect on lorazepam
kinetics (see���CLINICAL PHARMACOLOGY���). Clinical circumstances, some
of which may be more common in the elderly, such as hepatic or renal
impairment, should be considered. Greater sensitivity (e.g., sedation)
of some older individuals cannot be ruled out. In general, dose selection
for an elderly patient should be cautious, usually starting at the
low end of the dosing range (see���DOSAGE
AND ADMINISTRATION���).
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Symptoms Overdosage of benzodiazepines is usually manifested by
varying degrees of central-nervous-system depression, ranging from
drowsiness to coma. In mild cases symptoms include drowsiness, mental
confusion, and lethargy. In more serious examples, symptoms may include
ataxia, hypotonia, hypotension, hypnosis, stages one (1) to three
(3) coma, and very rarely death. Treatment Treatment
of overdosage is mainly supportive until the drug is eliminated from
the body. Vital signs and fluid balance should be carefully monitored
in conjunction with close observation of the patient. An adequate
airway should be maintained and assisted respiration used as needed.
With normally functioning kidneys, forced diuresis with intravenous
fluids and electrolytes may accelerate elimination of benzodiazepines
from the body. In addition, osmotic diuretics, such as mannitol, may
be effective as adjunctive measures. In more critical situations,
renal dialysis and exchange blood transfusions may be indicated. Lorazepam
does not appear to be removed in significant quantities by dialysis,
although lorazepam glucuronide may be highly dialyzable. The value
of dialysis has not been adequately determined for lorazepam. The benzodiazepine antagonist flumazenil may
be used in hospitalized patients as an adjunct to, not as a substitute
for, proper management of benzodiazepine overdose. The prescriber should be aware of a risk of seizure
in association with flumazenil treatment, particularly in long-term benzodiazepine users and cyclic antidepressant
overdose. The complete flumazenil package insert including���CONTRAINDICATIONS���,���WARNINGS���, and���PRECAUTIONS���should be consulted prior to use.
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Lorazepam
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Lorazepam (Injection, Solution)
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Status Epilepticus The most important adverse clinical event
caused by the use of Lorazepam Injection is respiratory depression
(see���WARNINGS���). The adverse clinical events most commonly
observed with the use of Lorazepam Injection in clinical trials evaluating
its use in status epilepticus were hypotension, somnolence, and respiratory
failure. Incidence
in Controlled Clinical Trials All
adverse events were recorded during the trials by the clinical investigators
using terminology of their own choosing. Similar types of events were
grouped into standardized categories using modified COSTART dictionary
terminology. These categories are used in the table and listings below
with the frequencies representing the proportion of individuals exposed
to Lorazepam Injection or to comparative therapy. The prescriber should be aware that these figures
cannot be used to predict the frequency of adverse events in the course
of usual medical practice where patient characteristics and other
factors may differ from those prevailing during clinical studies.
Similarly, the cited frequencies cannot be directly compared with
figures obtained from other clinical investigators involving different
treatment, uses, or investigators. An inspection of these frequencies,
however, does provide the prescribing physician with one basis to
estimate the relative contribution of drug and nondrug factors to
the adverse event incidences in the population studied. Commonly Observed Adverse
Events in a Controlled Dose-Comparison Clinical Trial Table 1 lists the treatment-emergent adverse events that
occurred in the patients treated with Lorazepam Injection in a dose-comparison
trial of lorazepam 1 mg, 2 mg, and 4 mg. Commonly Observed
Adverse Events in Active-Controlled Clinical Trials In two studies, patients who completed the course of treatment
for status epilepticus were permitted to be reenrolled and to receive
treatment for a second status episode, given that there was a sufficient
interval between the two episodes. Safety was determined from all
treatment episodes for all intent-to-treat patients,i.e., from all���patient-episodes.���Table 2 lists the treatment emergent
adverse events that occurred in at least 1% of the patient-episodes
in which Lorazepam Injection or diazepam was given. The table represents
the pooling of results from the two controlled trials. These trials were not designed or intended to demonstrate
the comparative safety of the two treatments. The overall adverse experience profile for lorazepam
was similar between women and men. There are insufficient data to
support a statement regarding the distribution of adverse events by
race. Generally, age greater than 65 years may be associated with
a greater incidence of central-nervous-system depression and more
respiratory depression. Other Events Observed During the Pre-marketing
Evaluation of Lorazepam Injection for the Treatment of Status Epilepticus Lorazepam Injection, active comparators, and
Lorazepam Injection in combination with a comparator were administered
to 488 individuals during controlled and open-label clinical trials.
Because of reenrollments, these 488 patients participated in a total
of 521 patient-episodes. Lorazepam Injection alone was given in 69%
of these patient-episodes (n=360). The safety information below is
based on data available from 326 of these patient-episodes in which
Lorazepam Injection was given alone. All
adverse events that were seen once are listed, except those already
included in previous listings (Table 1 and Table 2). Study events were classified by body system in descending
frequency by using the following definitions: frequent adverse events
were those that occurred in at least 1/100 individuals; infrequent
study events were those that occurred in 1/100 to 1/1000 individuals. Frequent and Infrequent Study Events Preanesthetic Central Nervous
System The most frequent adverse drug
event reported with injectable lorazepam in central-nervous-system
depression. The incidence varied from one study to another, depending
on the dosage, route of administration, use of other central-nervous-system
depressants, and the investigator's opinion concerning the
degree and duration of desired sedation. Excessive sleepiness and
drowsiness were the most common consequences of CNS depression. This
interfered with patient cooperation in approximately 6% (25/446) of
patients undergoing regional anesthesia, causing difficulty in assessing
levels of anesthesia. Patients over 50 years of age had a higher incidence
of excessive sleepiness or drowsiness when compared with those under
50 (21/106 vs 24/245) when lorazepam was given intravenously (see���DOSAGE AND ADMINISTRATION���). On rare occasion (3/1580) the patient was unable to give personal
identification in the operating room on arrival, and one patient fell
when attempting premature ambulation in the postoperative period. Symptoms such as restlessness, confusion,
depression, crying, sobbing, and delirium occurred in about 1.3% (20/1580).
One patient injured himself by picking at his incision during the
immediate postoperative period. Hallucinations were present in about 1% (14/1580) of patients and
were visual and self-limiting. An
occasional patient complained of dizziness, diplopia and/or blurredvision. Depressed hearing was infrequently reported during the peak-effect
period. An occasional patient had
a prolonged recovery room stay, either because of excessive sleepiness
or because of some form of inappropriate behavior. The latter was
seen most commonly when scopolamine was given concomitantly as a premedicant. Limited information derived from patients
who were discharged the day after receiving injectable lorazepam showed
one patient complained of some unsteadiness of gait and a reduced
ability to perform complex mental functions. Enhanced sensitivity
to alcoholic beverages has been reported more than 24 hours after
receiving injectable lorazepam, similar to experience with other benzodiazepines. Local Effects Intramuscular injection of lorazepam has resultedin pain at the injection site, a sensation of burning, or observed
redness in the same area in a very variable incidence from one study
to another. The overall incidence of pain and burning in patients
was about 17% (146/859) in the immediate postinjection period and
about 1.4% (12/859) at the 24-hour observation time. Reactions at
the injection site (redness) occurred in approximately 2% (17/859)
in the immediate postinjection period and were present 24 hours later
in about 0.8% (7/859). Intravenous
administration of lorazepam resulted in painful responses in 13/771
patients or approximately 1.6% in the immediate postinjection period,
and 24 hours later 4/771 patients or about 0.5% still complained of
pain. Redness did not occur immediately following intravenous injection
but was noted in 19/771 patients at the 24-hour observation period.
This incidence is similar to that observed with an intravenous infusion
before lorazepam is given. Intra-arterial injection may produce arteriospasm
resulting in gangrene which may require amputation (see���CONTRAINDICATIONS���). Cardiovascular System Hypertension (0.1%) and hypotension (0.1%)
have occasionally been observed after patients have received injectable
lorazepam. Respiratory
System Five patients (5/446) who underwent
regional anesthesia were observed to have airway obstruction. This
was believed due to excessive sleepiness at the time of the procedure
and resulted in temporary hypoventilation. In this instance, appropriate
airway management may become necessary (see also���CLINICAL PHARMACOLOGY,������WARNINGS,���and���PRECAUTIONS���). Other Adverse Experiences Skin rash, nausea, and vomiting have occasionally
been noted in patients who have received injectable lorazepam combined
with other drugs during anesthesia and surgery. Paradoxical Reactions As with all benzodiazepines, paradoxical reactions such
as stimulation, mania, irritability, restlessness, agitation, aggression,
psychosis, hostility, rage, or hallucinations may occur in rare instances
and in an unpredictable fashion. In these instances, further use of
the drug in these patients should be considered with caution (see���PRECAUTIONS���- General). Postmarketing Reports Voluntary reports of other adverse events
temporally associated with the use of Lorazepam Injection that have
been received since market introduction and that may have no causal
relationship with the use of Lorazepam Injection include the following:
acute brain syndrome, aggravation of pheochromocytoma, amnesia, apnea/respiratory
arrest, arrhythmia, bradycardia, brain edema, coagulation disorder,
coma, convulsion, gastrointestinal hemorrhage, heart arrest/failure,
heart block, liver damage, lung edema, lung hemorrhage, nervousness,
neuroleptic malignant syndrome, paralysis, pericardial effusion, pneumothorax,
pulmonary hypertension, tachycardia, thrombocytopenia, urinary incontinence,
ventricular arrhythmia. Fatalities
also have been reported, usually in patients on concomitant medications
(e.g., respiratory depressants) and/or with other medical conditions
(e.g., obstructive sleep apnea).
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Use in Status Epilepticus Management
of Status Epilepticus Status epilepticus
is a potentially life-threatening condition associated with a high
risk of permanent neurological impairment, if inadequately treated.
The treatment of status, however, requires far more than the administration
of an anticonvulsant agent. It involves observation and management
of all parameters critical to maintaining vital function and the capacity
to provide support of those functions as required. Ventilatory support
must be readily available. The use of benzodiazepines, like Lorazepam
Injection, is ordinarily only one step of a complex and sustained
intervention which may require additional interventions (e.g., concomitant
intravenous administration of phenytoin). Because status epilepticusmay result from a correctable acute cause such as hypoglycemia, hyponatremia,
or other metabolic or toxic derangement, such an abnormality must
be immediately sought and corrected. Furthermore, patients who are
susceptible to further seizure episodes should receive adequate maintenance
antiepileptic therapy. Any health
care professional who intends to treat a patient with status epilepticus
should be familiar with this package insert and the pertinent medical
literature concerning current concepts for the treatment of status
epilepticus. A comprehensive review of the considerations critical
to the informed and prudent management of status epilepticus cannot
be provided in drug product labeling. The archival medical literature
contains many informative references on the management of status epilepticus,
among them the report of the working group on status epilepticus of
the Epilepsy Foundation of America���Treatment of Convulsive
Status Epilepticus���(JAMA 1993; 270:854-859). As noted in the
report just cited, it may be useful to consult with a neurologist
if a patient fails to respond (e.g., fails to regain consciousness). For the treatment of status epilepticus,
the usual recommended dose of Lorazepam Injection is 4 mg given slowly
(2 mg/min) for patients 18 years and older. If seizures cease, no
additional Lorazepam Injection is required. If seizures continue or
recur after a 10- to 15- minute observation period, an additional
4 mg intravenous dose may be slowly administered. Experience with furtherdoses of lorazepam is very limited.
The usual precautions in treating status epilepticus should be employed.
An intravenous infusion should be started, vital signs should be monitored,
an unobstructed airway should be maintained, and artificial ventilation
equipment should be available. Respiratory Depression The most important risk associated with the use of Lorazepam
Injection in status epilepticus is respiratory depression. Accordingly,
airway patency must be assured and respiration monitored closely.
Ventilatory support should be given as required. Excessive Sedation Because of its prolonged duration of action, the prescriber
should be alert to the possibility, especially when multiple doses
have been given, that the sedative effects of lorazepam may add to
the impairment of consciousness seen in the post-ictal state. Preanesthetic Use AIRWAY OBSTRUCTION MAY OCCUR IN HEAVILY SEDATED PATIENTS.
INTRAVENOUS LORAZEPAM AT ANY DOSE, WHEN GIVEN EITHER ALONE OR IN COMBINATION
WITH OTHER DRUGS ADMINISTERED DURING ANESTHESIA, MAY PRODUCE HEAVY
SEDATION; THEREFORE, EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY
AND TO SUPPORT RESPIRATION/VENTILATION SHOULD BE AVAILABLE. As is true of similar CNS-acting drugs,
the decision as to when patients who have received injectable lorazepam,particularly
on an outpatient basis, may again operate machinery, drive a motor
vehicle, or engage in hazardous or other activities requiring attention
and coordination must be individualized. It is recommended that no
patient engage in such activities for a period of 24 to 48 hours or
until the effects of the drug, such as drowsiness, have subsided,
whichever is longer. Impairment of performance may persist for greater
intervals because of extremes of age, concomitant use of other drugs,
stress of surgery, or the general condition of the patient. Clinical trials have shown that patients
over the age of 50 years may have a more profound and prolonged sedation
with intravenous lorazepam (see also���DOSAGE
AND ADMINISTRATION���-Preanesthetic). As with all central-nervous-system
depressant drugs, care should be exercised in patients given injectable
lorazepam as premature ambulation may result in injury from falling. There is no added beneficial effect to the
addition of scopolamine to injectable lorazepam, and their combined
effect may result in an increased incidence of sedation, hallucination,
and irrational behavior. General (All Uses) PRIOR TO INTRAVENOUS USE, LORAZEPAM INJECTION MUST
BE DILUTED WITH AN EQUAL AMOUNT OF COMPATIBLE DILUENT (SEE���DOSAGE
AND ADMINISTRATION���). INTRAVENOUS INJECTION SHOULD BE MADE
SLOWLY AND WITH REPEATED ASPIRATION.
CARE SHOULD BE TAKEN TO DETERMINE THAT ANY INJECTION WILL NOT BE INTRA-ARTERIAL
AND THAT PERIVASCULAR EXTRAVASATION WILL NOT TAKE PLACE. IN THE EVENT
THAT A PATIENT COMPLAINS OF PAIN DURING INTENDED INTRAVENOUS INJECTION
OF LORAZEPAM INJECTION, THE INJECTION SHOULD BE STOPPED IMMEDIATELY
TO DETERMINE IF INTRA-ARTERIAL OR PERIVASCULAR EXTRAVASATION HAS TAKEN
PLACE. Since the liver
is the most likely site of conjugation of lorazepam and since excretion
of conjugated lorazepam (glucuronide) is a renal function, this drug
is not recommended for use in patients with hepatic and/or renal failure. Lorazepam should be used with
caution in patients with mild-to-moderate hepatic or renal disease
(see���DOSAGE AND ADMINISTRATION���). Pregnancy LORAZEPAM MAY CAUSE FETAL DAMAGE WHEN ADMINISTERED
TO PREGNANT WOMEN. Ordinarily, Lorazepam Injection should not be used
during pregnancy except in serious or life-threatening conditions
where safer drugs cannot be used or are ineffective. Status epilepticus
may represent such a serious and life-threatening condition. An increased risk of congenital malformations
associated with the use of minor tranquilizers (chlordiazepoxide,
diazepam, and meprobamate) during the first trimester of pregnancy
has been suggested in several studies. In humans, blood levels obtained
from umbilical cord blood indicate placental transfer of lorazepam
and lorazepam glucuronide. Reproductive
studies in animals were performed in mice, rats, and two strains of
rabbits. Occasional anomalies (reduction of tarsals, tibia, metatarsals,
malrotated limbs, gastroschisis, malformed skull, and microphthalmia)
were seen in drug-treated rabbits without relationship to dosage.
Although all of these anomalies were not present in the concurrent
control group, they have been reported to occur randomly in historical
controls. At doses of 40 mg/kg orally or 4 mg/kg intravenously and
higher, there was evidence of fetal resorption and increased fetal
loss in rabbitswhich was not seen at lower doses. The possibility that a woman of childbearing potential
may be pregnant at the time of therapy should be considered. There are insufficient data regarding obstetrical
safety of parenteral lorazepam, including use in cesarean section.
Such use, therefore, is not recommended. Endoscopic Procedures There are insufficient data to support the use of Lorazepam Injection
for outpatient endoscopic procedures. Inpatient endoscopic procedures
require adequate recovery room observation time. When Lorazepam Injection is used for peroral endoscopic
procedures; adequate topical or regional anesthesia is recommended
to minimize reflex activity associated with such procedures.
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Status Epilepticus Lorazepam Injection is indicated for the treatment
of status epilepticus. Preanesthetic Lorazepam Injection
is indicated in adult patients for preanesthetic medication, producing
sedation (sleepiness or drowsiness), relief of anxiety, and a decreased
ability to recall events related to the day of surgery. It is most
useful in those patients who are anxious about their surgical procedure
and who would prefer to have diminished recall of the events of the
day of surgery (see���PRECAUTIONS���-
Information for Patients).
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Lorazepam
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