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 | Lorazepam Injection |
| Event | (n=130)a |
| Any Study Event (1 or more)b | |
|
Body as a whole
| 16 (12.3%) |
| 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%) |
a: One hundred and thirty (130) patients received lorazepam injection.
b: Totals are not necessarily the sum of the individual study events because a patient may report two or more different study events in the same body system.
Commonly Observed Adverse Events in Active-Controlled Clinical Trials
In two studies, patients who completed the course of treatment for status epilepticus were permitted to be reenrolled and to receive treatment for a second status episode, given that there was a sufficient interval between the two episodes. Safety was determined from all treatment episodes for all intent-to-treat patients, i.e., from all "patient-episodes." Table 2 lists the treatment emergent adverse events that occurred in at least 1% of the patient-episodes in which lorazepam injection or diazepam was given. The table represents the pooling of results from the two controlled trials.
TABLE 2. NUMBER (%) OF STUDY EVENTS IN ACTIVE CONTROLLED CLINICAL TRIAL | Body System | Lorazepam Injection | Diazepam |
| Event | (n=85)a | (n=80)a |
| Any Study Event (1 or more)b | 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 |
a: The number indicates the number of "patient-episodes." Patient-episodes were used rather than
"patients" because a total of 7 patients were reenrolled for the treatment of a second episode of status: 5 patients received lorazepam injection on two occasions that were far enough apart to establish the diagnosis of status epilepticus for each episode, and, using the same time criterion, 2 patients received diazepam on two occasions.
b: Totals are not necessarily the sum of the individual study events because a patient may report two or more different study events in the same body system.
These trials were not designed or intended to demonstrate the comparative safety of the two treatments.
The overall adverse experience profile for lorazepam was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse events by race. Generally, age greater than 65 years may be associated with a greater incidence of central-nervous-system depression and more respiratory depression.
Other Events Observed During the Pre-Marketing Evaluation of Lorazepam Injection for the Treatment of Status Epilepticus
Lorazepam injection, active comparators, and lorazepam injection in combination with a comparator were administered to 488 individuals during controlled and open-label clinical trials. Because of reenrollments, these 488 patients participated in a total of 521 patient-episodes. Lorazepam injection alone was given in 69% of these patient-episodes (n=360). The safety information below is based on data available from 326 of these patient-episodes in which lorazepam injection was given alone.
All adverse events that were seen once are listed, except those already included in previous listings (Table 1 and Table 2).
Study events were classified by body system in descending frequency by using the following definitions: frequent adverse events were those that occurred in at least 1/100 individuals; infrequent study events were those that occurred in 1/100 to 1/1000 individuals.
Frequent and Infrequent Study Events
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, 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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