lorazepam 4 MG/ML Injectable Solution [Ativan]

INDICATIONS AND USAGE Status Epilepticus Lorazepam Injection, is indicated for the treatment of the 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 ).

DOSAGE AND ADMINISTRATION NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS, Pediatric Use ). Lorazepam Injection 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 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). 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 Injection 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 Intramuscular Lorazepam Injection is not preferred in the treatment of status epilepticus because therapeutic lorazepam levels may not be reached as quickly as with intravenous administration. However, when an intravenous port is not available, the intramuscular route may prove useful (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ). PEDIATRIC The safety of Lorazepam Injection 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 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 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 CLINICAL PHARMACOLOGY ). DOSE ADJUSTMENT DUE TO DRUG INTERACTIONS The dose of Lorazepam Injection 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 Injection 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. Contents should be mixed thoroughly by gently inverting the container repeatedly until a homogenous solution results. Do not shake vigorously, as this will result in air entrapment. 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. Discard unused portion. Lorazepam Injection is compatible for dilution purposes with the following solutions: Sterile Water for Injection, USP; Sodium Chloride Injection, USP; 5% Dextrose Injection, USP.

WARNINGS 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 ASPIRATIO

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 ).

CLINICAL PHARMACOLOGY Lorazepam interacts with the γ-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 under these 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 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 8 hours following administration of 4 mg of intramuscular lorazepam and 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 C max of approximately 48 ng/mL. Following administration of 1.5 to 5 mg of lorazepam intramuscular, 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 of 14 C-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 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 (Cl cr of 22 ± 9 mL/min), and four patients on chronic maintenance hemodi