Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/497
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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 epilepticuscannot 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. 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. Lorazepam in the Blunt Cannula or InterLink packaging
is not intended for intramuscular (IM) use. 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. 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
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. 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 5.0 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
impairedpatients 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 injectionmay 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. Lorazepam
in the Blunt Cannula or InterLink packaging is not intended
for intramuscular (IM) use. To prevent needle-stick
injuries, needles should not be recapped, purposely bent, or broken by hand. Blunt
cannulas should not be recapped, purposely bent or broken by hand. Protect
from light. Use carton to protect contents from light. Keep
in a refrigerator 2��to 8��C (36��to 46��F). InterLink is
a trademark of Baxter Healthcare Corp. U.S. Pat. Nos. 5,158,554; 5,171,234;
5,188,620; Pat. Pending. HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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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 care must be used in administering
lorazepam to elderly patients, very ill patients, and 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, such as sedation, relief of anxiety, and lack of recall, and
the duration of these effects (about 8 hours), so that they may adequately
perceive the risks as well as the benefits to be derived from its use. 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. 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 depression of the central nervous system when administered with 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 mg, 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 almost3.7-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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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 veryrarely death. Treatment
of overdosage is mainly supportive until the drug is eliminated from the body.
Vital signs and fluid balance should be carefully monitored. 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 anti-depressant 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 categoriesusing 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 Injection
1 mg, 2 mg, and 4 mg. a: One hundred and thirty (130) patients received Lorazepam
Injection. b: Totals are not necessarily the sum of
the individual study events because a patient may report two or more different
study events in the same body system. 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. a: The number indicates the number of���patient-episodes.���Patient-episodes were used rather than���patients���because a
total of 7 patients were reenrolled for the treatment of a second episode
of status: 5 patients received Lorazepam Injection on two occasions that were
far enough apart to establish the diagnosis of status epilepticus for each
episode, and, using the same time criterion, 2 patients received diazepam
on two occasions. b: Totals are not necessarily the
sum of the individual study events because a patient may report two or more
different study events in the same body system. 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 effects seen with injectable lorazepam are an extension
of the central-nervous-system depressant effects of the drug. 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 main side effects. This interfered with
patient cooperation in approximately 6% (25/446) of patients undergoing regional
anesthesia in that they were unable to assess levels of anesthesia in regional
blocks or with caudal 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) whenlorazepam 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 blurred vision.
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 resulted in 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 partial 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 useof 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 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 receiveadequate 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 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. 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 ofthe 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. Ordinarily, an initial
dose of 2 mg may be adequate unless a greater degree of lack of recall is
desired. 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 DETERMINEIF 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. This does not preclude use of the drug 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. 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. 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 rabbits which was not seen at lower doses. Endoscopic Procedures There
are insufficient data to support the use of Lorazepam Injection for outpatient
endoscopic procedures. Inpatient endoscopic procedures require adequate recovery
room observations. 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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