Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2804
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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 requireadditional 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 ordinarily should be 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 or 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 ordinarily
should not 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 also CLINICAL PHARMACOLOGY ,WARNINGS , PRECAUTIONS ,and ADVERSE REACTIONS). Doses of other injectable central-nervous-system
depressant drugs ordinarily should 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. 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, sedative,
and anticonvulsant effects, is intended for the intramuscular or intravenous
routes of administration. It has the chemical formula 7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one. The molecular
weight is 321.16, and the C.A.S. No. is [846-49-1]. The molecular
formula is CHClNO. The structural formula is: Lorazepam is a nearly white powder almost insoluble in water. Each
mL of sterile injection contains 2 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, 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 underthese reinforced conditions
had difficulty recalling perioperative events or recognizing props
from before surgery. The lack of recall and recognition was optimum
within 2 hours following intramuscular administration and 15
to 20 minutes after intravenous injection. The
intended effects of the recommended adult dose of lorazepam injection
usually last 6 to 8 hours. In rare instances and where patients
received greater than the recommended dose, excessive sleepiness and
prolonged lack of recall were noted. As with other benzodiazepines,
unsteadiness, enhanced sensitivity to CNS-depressant effects of ethyl
alcohol and other drugs were noted in isolated and rare cases for
greater than 24 hours. Physiologic Effects in Healthy Adults Studies in healthy adult volunteers reveal that intravenous lorazepam
in doses up to 3.5 mg/70 kg does not alter sensitivity to the respiratory
stimulating effect of carbon dioxide and does not enhance the respiratory
depressant effects of doses of meperidine up to 100 mg/70 kg (also
determined by carbon dioxide challenge) as long as patients remain
sufficiently awake to undergo testing. Upper airway obstruction has
been observed in rare instances where the patient received greater
than the recommended dose and was excessively sleepy and difficult
to arouse. (See WARNINGS and ADVERSE REACTIONS.) Clinically employed doses of lorazepam injection
do not greatly affect the circulatory system in the supine position
or employing a 70-degree tilt test. Doses of 8 mg to 10 mg of intravenous
lorazepam (2 to 2-1/2 times the maximum recommended dosage) will produce
loss of lid reflexes within 15 minutes. Studies
in six (6) healthy young adults who received lorazepam injection and
no other drugs revealed that visual tracking (the ability to keep
a moving line centered) was impaired for a mean of eight (8) hours
following administration of 4 mg of intramuscular lorazepam and four
(4) hours following administration of 2 mg intramuscularly with considerable
subject variation. Similar findings were noted with pentobarbital,
150 and 75 mg. Although this study showed that both lorazepam and
pentobarbital interfered with eye-hand coordination, the data are
insufficient to predict when it would be safe to operate a motor vehicle
or engage in a hazardous occupation or sport. Pharmacokinetics and Metabolism Absorption Intravenous A 4-mg dose provides an initial concentration
of approximately 70 ng/mL. Intramuscular Following intramuscular administration, lorazepam is completely and
rapidly absorbed reaching peak concentrations within 3 hours. A 4-mg
dose provides a 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 (Clof 22��9 mL/min), and four patients on chronic maintenance
hemodialysis were given single 1.5 to 3.0 mg intravenous doses of
lorazepam. Mean volume of distribution and terminal half-life values
of lorazepam were 40% and 25% higher, respectively, in renally impaired
patients than in normal subjects. Both parameters were 75% higher
in patients undergoing hemodialysis than innormal 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.<br/>Clinical Studies: The effectiveness of Lorazepam Injection in status
epilepticus was established in two multi-center controlled trials
in 177 patients. With rare exceptions, patients were between 18 and
65 years of age. More than half the patients in each study had tonic-clonic
status epilepticus; patients with simple partial and complex partial
status epilepticus comprised the rest of the population studied, along
with a smaller number of patients who had absence status. One study (n=58) was a double-blind active-control trial
comparing lorazepam and diazepam. Patients were randomized to receive
lorazepam 2 mg IV (with an additional 2 mg IV if needed) or diazepam
5 mg IV (with an additional 5 mg IV if needed). The primary outcome
measure was a comparison of the proportion of responders in each treatment
group, where a responder was defined as a patient whose seizures stopped
within 10 minutes after treatment and who continued seizure-free for
at least an additional 30 minutes. Twenty-four of the 30 (80%) patients
were deemed responders to lorazepam and 16/28 (57%) patients were
deemed responders to diazepam (p=0.04). Of the 24 lorazepam responders,
23 received both 2 mginfusions. Non-responders
to lorazepam 4 mg were given an additional 2 to 4 mg lorazepam; non-responders
to diazepam 10 mg were given an additional 5 to 10 mg diazepam. After
this additional dose administration, 28/30 (93%) of patients randomized
to lorazepam and 24/28 (86%) of patients randomized to diazepam were
deemed responders, a difference that was not statistically significant. Although this study provides support for the efficacy
of lorazepam as the treatment for status epilepticus, it cannot speak
reliably or meaningfully to the comparative performance of either
diazepam or lorazepam under the conditions of actual use. A second study (n=119) was a double-blind dose-comparison
trial with 3 doses of Lorazepam Injection: 1 mg, 2 mg, and 4 mg. Patients
were randomized to receive one of the three doses of lorazepam. The
primary outcome and definition of responder were as in the first study.
Twenty-five of 41 patients (61%) responded to 1 mg lorazepam; 21/37
patients (57%) responded to 2 mg lorazepam; and 31/41 (76%) responded
to 4 mg lorazepam. The p-value for a statistical test of the difference
between the lorazepam 4 mg dose group and the lorazepam 1 mg dose
group was 0.08 (two-sided). Data from all randomized patients
were used in this test. Although analyses failed
to detect an effect of age, sex, or race on the effectiveness of lorazepam
in status epilepticus, the numbers of patients evaluated were too
few to allow a definitive conclusion about the role these factors
may play.
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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: For IM use. For IV route,
see directions. Protect from light. Do not remove
cartridge from individual package until time of use. Keep in a refrigerator 2��to 8��C (36��to 46��F). Directions for iSecure Syringe Note: To prevent needlestick injuries, needles
and blunt cannulas should not be recapped, purposely bent, or broken
by hand. Revised: August, 2007
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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 when administering lorazepam to elderly
patients, very ill patients, or to patients with limited pulmonary
reserve because of the possibility that hypoventilation 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 in
determining 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, 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, operating 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.
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 necessaryto 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 clinical circumstance 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 excitationin 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 reportedto occur following administration of Lorazepam Injection, especially
in very low birth weight neonates. Pediatric
patients may exhibit a sensitivity to benzyl alcohol, polyethylene
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 the administration of intravenous
solutions containing the preservative benzyl alcohol in 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 withpropylene 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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| dailymed-instance:overdosag... |
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 tobe 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
andin cyclic antidepressant overdose. The complete flumazenil
package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use.
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| dailymed-instance:genericMe... |
Lorazepam
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Lorazepam (Injection, Solution)
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| dailymed-instance:adverseRe... |
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 involvingdifferent 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 is 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 versus 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 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 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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| dailymed-instance:warning |
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 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). 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 impairmentof 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 from 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
INJECTION 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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| dailymed-instance:name |
Lorazepam
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