FDA label d2cde812-4f5e-41ce-9ee2-e144b36a4e5f

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 to the addition of scopolamine to injectable lorazepam, and their combined effect may result in an increased incidence of sedation, hallucination, and irrational behavior. General (All Uses) PRIOR TO INTRAVENOUS USE, LORAZEPAM INJECTION MUST BE DILUTED WITH AN EQUAL AMOUNT OF COMPATIBLE DILUENT (SEE “DOSAGE AND ADMINISTRATION”). INTRAVENOUS INJECTION SHOULD BE MADE SLOWLY AND WITH REPEATED ASPIRATION. CARE SHOULD BE TAKEN TO DETERMINE THAT ANY INJECTION WILL NOT BE INTRA-ARTERIAL AND THAT PERIVASCULAR EXTRAVASATION WILL NOT TAKE PLACE. IN THE EVENT THAT A PATIENT COMPLAINS OF PAIN DURING INTENDED INTRAVENOUS INJECTION OF LORAZEPAM INJECTION, THE INJECTION SHOULD BE STOPPED IMMEDIATELY TO DETERMINE IF INTRA-ARTERIAL OR PERIVASCULAR EXTRAVASATION HAS TAKEN PLACE. Since the liver is the most likely site of conjugation of lorazepam and since excretion of conjugated lorazepam (glucuronide) is a renal function, this drug is not recommended for use in patients with hepatic and/or renal failure . 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.

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) a Any Study Event (1 or more) b 16 (12.3%) Body as a whole Infection 1 (less than 1%) Cardiovascular system Hypotension 2 (1.5%) Digestive system Liver function tests abnormal Nausea Vomiting 1 (less than 1%) 1 (less than 1%) 1 (less than 1%) Metabolic and Nutritional Acidosis 1 (less than 1%) Nervous system Brain edema Coma Convulsion Somnolence Thinking abnormal 1 (less than 1%) 1 (less than 1%) 1 (less than 1%) 2 (1.5%) 1 (less than 1%) Respiratory system Hyperventilation Hypoventilation Respiratory failure 1 (less than 1%) 1 (less than 1%) 2 (1.5%) Terms not classifiable injection site reaction 1 (less than 1%) Urogenital system Cystitis 1 (less than 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 Boby System Event Lorazepam Injection (n=85) a Diazepam (n=80) a Any Study Event (1 or more) b 14 916.5%) 11 (13.8%) Body as a whole Headache 1 91.2%) 1 (1.3%) Cardiovascular system Hypotension 2 (2.4%) 0 Hemic and lymphatic system Hypochromic anemia Leukocytosis Thrombocythemia 0 0 0 1 (1.3%) 1 (1.3%) 1 (1.3%) Nervous system Coma Somnolence Stupor 1 (1.2%) 3 (3.5%) 1 (1.2%) 1 (1.3%) 3 (3.8%) 0 Respiratory system Hypoventilation Apnea Respiratory failure Respiratory disorder 1 (1.2%) 1 (1.2%) 2 (2.4%) 1 (1.2%) 2 (2.5%) 1 (1.3%) 1 (1.3%) 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 in 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 vs 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 blurredvision. 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 resultedin 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).

<table ID="i43bd395b-062f-4fc0-8b2d-e9850281cc1c" width="60%"> <caption>TABLE 1. NUMBER (%) OF STUDY EVENTS IN A DOSE COMPARISON CLINICAL TRIAL </caption> <tbody> <tr> <td> <content styleCode="bold">Body System </content>Event </td> <td> <content styleCode="bold">Lorazepam Injection </content>(n=130)^a </td> </tr> <tr> <td> <content styleCode="bold">Any Study Event</content> (1 or more)^b </td> <td>16 (12.3%) </td> </tr> <tr> <td> <content styleCode="bold">Body as a whole </content> Infection </td> <td> 1 (less than 1%) </td> </tr> <tr> <td> <content styleCode="bold">Cardiovascular system </content>Hypotension</td> <td> 2 (1.5%) </td> </tr> <tr> <td> <content styleCode="bold">Digestive system</content> Liver function tests abnormal Nausea Vomiting </td> <td> 1 (less than 1%) 1 (less than 1%) 1 (less than 1%) </td> </tr> <tr> <td> <content styleCode="bold">Metabolic and Nutritional</content> Acidosis </td> <td> 1 (less than 1%) </td> </tr> <tr> <td> <content styleCode="bold">Nervous system</content> Brain edema Coma Convulsion Somnolence Thinking abnormal </td> <td> 1 (less than 1%) 1 (less than 1%) 1 (less than 1%) 2 (1.5%) 1 (less than 1%) </td> </tr> <tr> <td> <content styleCode="bold">Respiratory system</content> Hyperventilation Hypoventilation Respiratory failure </td> <td> 1 (less than 1%) 1 (less than 1%) 2 (1.5%) </td> </tr> <tr> <td> <content styleCode="bold">Terms not classifiable</content> injection site reaction </td> <td> 1 (less than 1%) </td> </tr> <tr> <td> <content styleCode="bold">Urogenital system</content> Cystitis </td> <td> 1 (less than 1%) </td> </tr> </tbody> </table>

<table ID="i53a2d21b-5c2c-4bea-8830-8e248e1c2862" width="60%"> <caption>TABLE 2. NUMBER (%) OF STUDY EVENTS IN ACTIVE CONTROLLED CLINICAL TRIAL</caption> <tbody> <tr> <td> <content styleCode="bold">Boby System </content>Event </td> <td> <content styleCode="bold">Lorazepam Injection </content>(n=85)^a </td> <td> <content styleCode="bold">Diazepam </content>(n=80)^a </td> </tr> <tr> <td> <content styleCode="bold">Any Study Event</content>(1 or more)^b </td> <td>14 916.5%) </td> <td>11 (13.8%) </td> </tr> <tr> <td> <content styleCode="bold">Body as a whole</content> Headache </td> <td> 1 91.2%) </td> <td> 1 (1.3%) </td> </tr> <tr> <td> <content styleCode="bold">Cardiovascular system</content> Hypotension </td> <td> 2 (2.4%) </td> <td> 0 </td> </tr> <tr> <td> <content styleCode="bold">Hemic and lymphatic system</content> Hypochromic anemia Leukocytosis Thrombocythemia </td> <td> 0 0 0 </td> <td> 1 (1.3%) 1 (1.3%) 1 (1.3%) </td> </tr> <tr> <td> <content styleCode="bold">Nervous system</content> Coma Somnolence Stupor </td> <td> 1 (1.2%) 3 (3.5%) 1 (1.2%) </td> <td> 1 (1.3%) 3 (3.8%) 0 </td> </tr> <tr> <td> <content styleCode="bold">Respiratory system</content> Hypoventilation Apnea Respiratory failure Respiratory disorder </td> <td> 1 (1.2%) 1 (1.2%) 2 (2.4%) 1 (1.2%) </td> <td> 2 (2.5%) 1 (1.3%) 1 (1.3%) 0 </td> </tr> </tbody> </table>

<table width="100%" ID="i05f80ed4-c7b5-4c8e-8faa-ab7aece2a656"> <tbody> <tr> <td> <content styleCode="italics">BODY AS A WHOLE -</content> </td> <td> <paragraph>Infrequent: asthenia, chills, headache, infection. </paragraph> </td> </tr> <tr> <td> <content styleCode="italics">DIGESTIVE SYSTEM -</content> </td> <td> <paragraph>Infrequent: abnormal liver function test, increased salivation, nausea, vomiting.</paragraph> </td> </tr> <tr> <td> <content styleCode="italics">METABOLIC AND NUTRITIONAL - </content> </td> <td>Infrequent: acidosis, alkaline phosphatase increased.</td> </tr> <tr> <td> <content styleCode="italics">NERVOUS SYSTEM -</content> </td> <td> <paragraph>Infrequent: agitation, ataxia, brain edema, coma, confusion, convulsion, hallucinations, myoclonus, stupor, thinking abnormal, tremor.</paragraph> </td> </tr> <tr> <td> <content styleCode="italics">RESPIRATORY SYSTEM -</content> </td> <td>Frequent: apnea; Infrequent: hyperventilation, hypoventilation, respiratory disorder.</td> </tr> <tr> <td> <content styleCode="italics">TERMS NOT CLASSIFIABLE -</content> </td> <td>Infrequent: injection site reaction.</td> </tr> <tr> <td> <content styleCode="italics">UROGENITAL SYSTEM -</content> </td> <td> <paragraph>Infrequent: cystitis.</paragraph> </td> </tr> </tbody> </table>