WARNINGS
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 impairment of consciousness seen in the post-ictal state.
Preanesthetic Use
AIRWAY OBSTRUCTION MAY OCCUR IN HEAVILY SEDATED PATIENTS. INTRAVENOUS LORAZEPAM AT ANY DOSE, WHEN GIVEN EITHER ALONE OR IN COMBINATION WITH OTHER DRUGS ADMINISTERED DURING ANESTHESIA, MAY PRODUCE HEAVY SEDATION; THEREFORE, EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY AND TO SUPPORT RESPIRATION/VENTILATION SHOULD BE AVAILABLE.
As is true of similar CNS-acting drugs, the decision as to when patients who have received injectable lorazepam, particularly on an outpatient basis, may again operate machinery, drive a motor vehicle, or engage in hazardous or other activities requiring attention and coordination, must be individualized. It is recommended that no patient engage in such activities for a period of 24 to 48 hours or until the effects of the drug, such as drowsiness, have subsided, whichever is longer. Impairment of performance may persist for greater intervals because of extremes of age, concomitant use of other drugs, stress of surgery, or the general condition of the patient.
Clinical trials have shown that patients over the age of 50 years may have a more profound and prolonged sedation with intravenous lorazepam. (See also
DOSAGE AND ADMINISTRATION:
Preanesthetic
.)
As with all central-nervous-system depressant drugs, care should be exercised in patients given injectable lorazepam as premature ambulation may result in injury from falling.
There is no added beneficial effect 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)
P
RIOR 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 rabbits which 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.
PRECAUTIONS
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.
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.
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.
Drug Interactions
Lorazepam injection, like other injectable benzodiazepines, produces additive depression of the central nervous system when administered with other CNS depressants such as ethyl alcohol, phenothiazines, barbiturates, MAO inhibitors, and other antidepressants. When scopolamine is used concomitantly with injectable lorazepam, an increased incidence of sedation, hallucinations, and irrational behavior has been observed.
There have been rare reports of significant respiratory depression, stupor and/or hypotension with the concomitant use of loxapine and lorazepam.
Marked sedation, excessive salivation, ataxia, and, rarely, death have been reported with the concomitant use of clozapine and lorazepam.
Apnea, coma, bradycardia, arrhythmia, heart arrest, and death have been reported with the concomitant use of haloperidol and lorazepam.
The risk of using lorazepam in combination with scopolamine, loxapine, clozapine, haloperidol, or other CNS-depressant drugs has not been systematically evaluated. Therefore, caution is advised if the concomitant administration of lorazepam and these drugs is required.
Concurrent administration of any of the following drugs with lorazepam had no effect on the pharmacokinetics of lorazepam: metoprolol, cimetidine, ranitidine, disulfiram, propranolol, metronidazole, and propoxyphene. No change in lorazepam dosage is necessary when concomitantly given with any of these drugs.
Lorazepam-Valproate Interaction
Concurrent administration of lorazepam (2 mg intravenously) with valproate (250 mg twice daily orally for 3 days) to 6 healthy male subjects resulted in decreased total clearance of lorazepam by 40% and decreased formation rate of lorazepam-glucuronide by 55%, as compared with lorazepam administered alone. Accordingly, lorazepam plasma concentrations were about two-fold higher for at least 12 hours post-dose administration during valproate treatment. Lorazepam dosage should be reduced to 50% of the normal adult dose when this drug combination is prescribed in patients (see also
DOSAGE AND ADMINISTRATION
).
Lorazepam-Oral Contraceptive Steroids Interaction
Coadministration of lorazepam (2 mg intravenously) with oral contraceptive steroids (norethindrone acetate, 1 mg, and ethinyl estradiol, 50 mcg, for at least 6 months) to healthy females (n=7) was associated with a 55% decrease in half-life, a 50% increase in the volume of distribution, thereby resulting in an almost 3.7-fold increase in total clearance of lorazepam as compared with control healthy females (n=8). It may be necessary to increase the dose of Lorazepam in female patients who are concomitantly taking oral contraceptives (see also
DOSAGE AND ADMINISTRATION
).
Lorazepam-Probenecid Interaction
Concurrent administration of lorazepam (2 mg intravenously) with probenecid (500 mg orally every 6 hours) to 9 healthy volunteers resulted in a prolongation of lorazepam half-life by 130% and a decrease in its total clearance by 45%. No change in volume of distribution was noted during probenecid co-treatment. Lorazepam dosage needs to be reduced by 50% when coadministered with probenecid (see also
DOSAGE AND ADMINISTRATION
).
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.
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.
Pregnancy
Teratogenic Effects - Pregnancy Category D (See
WARNINGS
.)
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.
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.
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, 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 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.
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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