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 ).
Contraindications
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 ). Lorazepam Injection is contraindicated for use in premature infants because the formulation contains benzyl alcohol (see WARNINGS and PRECAUTIONS, Pediatric Use ).
Warnings and precautions
Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including Lorazepam Injection, and opioids may result in profound sedation, respiratory depression, coma, and death. If a decision is made to use Lorazepam Injection concomitantly with opioids, monitor patients closely for respiratory depression and sedation (see PRECAUTIONS, Drug Interactions ). Abuse, Misuse, and Addiction The use of benzodiazepines, including Lorazepam Injection, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death.
Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE, Abuse ). Before prescribing Lorazepam Injection and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction.
Use of Lorazepam Injection, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Lorazepam Injection along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug.
If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions After Use of Lorazepam Injection More Frequently Than Recommended For patients using Lorazepam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Lorazepam Injection (a patient-specific plan should be used to taper the dose).
Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. ACUTE WITHDRAWAL REACTIONS The continued use of benzodiazepines may lead to clinically significant physical dependence. Although Lorazepam Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of Lorazepam Injection, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE, Dependence ).
PROTRACTED WITHDRAWAL SYNDROME In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE, Dependence ). 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 healthcare 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 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
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Interactions
Drug Interactions INTERACTION WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.
Monitor patients closely for respiratory depression and sedation. 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 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 μg, 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 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 DOSAGE AND ADMINISTRATION ).
Pregnancy and breastfeeding
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.
Pregnancy Teratogenic Effects (see WARNINGS ). Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.
In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human.
The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits (see WARNINGS , Pediatric Neurotoxicity , Pediatric Use , and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ).
Adverse reactions
Status Epilepticus The most important adverse clinical event caused by the use of Lorazepam Injection is respiratory depression (see WARNINGS ). The adverse clinical events most commonly observed with the use of Lorazepam Injection in clinical trials evaluating its use in status epilepticus were hypotension, somnolence, and respiratory failure. INCIDENCE IN CONTROLLED CLINICAL TRIALS All adverse events were recorded during the trials by the clinical investigators using terminology of their own choosing.
Similar types of events were grouped into standardized categories using modified COSTART dictionary terminology. These categories are used in the table and listings below with the frequencies representing the proportion of individuals exposed to Lorazepam Injection or to comparative therapy. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies.
Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigators involving different treatment, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. COMMONLY OBSERVED ADVERSE EVENTS IN A CONTROLLED DOSE-COMPARISON CLINICAL TRIAL Table 1 lists the treatment-emergent adverse events that occurred in the patients treated with Lorazepam Injection in a dose-comparison trial of lorazepam 1 mg, 2 mg, and 4 mg.
TABLE 1. NUMBER (%) OF STUDY EVENTS IN A DOSE COMPARISON CLINICAL TRIAL Body System Event Lorazepam Injection (n=130) One hundred and thirty (130) patients received Lorazepam Injection. Any Study Event (1 or more) 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. 16 (12.3%) Body as a whole Infection 1 (<1%) Cardiovascular system Hypotension 2 (1.5%) Digestive system Liver function tests abnormal 1 (<1%) Nausea 1 (<1%) Vomiting 1 (<1%) Metabolic and Nutritional Acidosis 1 (<1%) Nervous system Brain edema 1 (<1%) Coma 1 (<1%) Convulsion 1 (<1%) Somnolence 2 (1.5%) Thinking abnormal 1 (<1%) Respiratory system Hyperventilation 1 (<1%) Hypoventilation 1 (<1%) Respiratory failure 2 (1.5%) Terms not classifiable Injection site reaction 1 (<1%) Urogenital system Cystitis 1 (<1%) 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. TABLE 2. NUMBER (%) OF STUDY EVENTS IN ACTIVE CONTROLLED CLINICAL TRIAL Body System Event Lorazepam Injection (n=85) 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.
Diazepam (n=80) Any Study Event (1 or more) 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. 14 (16.5%) 11 (13.8%) Body as a whole Headache 1 (1.2%) 1 (1.3%) Cardiovascular system Hypotension 2 (2.4%) 0 Hemic and lymphatic system Hypochromic anemia 0 1 (1.3%) Leukocytosis 0 1 (1.3%) Thrombocythemia 0 1 (1.3%) Nervous system Coma 1 (1.2 %) 1 (1.3%) Somnolence 3 (3.5%) 3 (3.8%) Stupor 1 (1.2%) 0 Respiratory system Hypoventilation 1 (1.2%) 2 (2.5%) Apnea 1 (1.2%) 1 (1.3%) Respiratory failure 2 (2.4%) 1 (1.3%) Respiratory disorder 1 (1.2%) 0 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 BODY AS A WHOLE - Infrequent: asthenia, chills, headache, infection. DIGESTIVE SYSTEM - Infrequent: abnormal liver function test, increased salivation, nausea, vomiting.
METABOLIC AND NUTRITIONAL - Infrequent: acidosis, alkaline phosphatase increased. NERVOUS SYSTEM - Infrequent: agitation, ataxia, brain edema, coma, confusion, convulsion, hallucinations, myoclonus, stupor, thinking abnormal, tremor. RESPIRATORY SYSTEM - Frequent: apnea; Infrequent: hyperventilation, hypoventilation, respiratory disorder. TERMS NOT CLASSIFIABLE - Infrequent: injection site reaction. UROGENITAL SYSTEM- Infrequent: cystitis.
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
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Composition
Active ingredients
LORAZEPAM 4MG/ML
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
