Ativan

Ativan (lorazepam) is a drug used for treating anxiety. Lorazepam belongs to the benzodiazepine family of drugs, the same family that includes

• diazepam (Valium),
• alprazolam (Xanax),
• clonazepam (Klonopin),
• flurazepam (Dalmane), and
• others.

Lorazepam injection is used before certain medical procedures, such as surgery, to relieve anxiety. When lorazepam is used before surgery, the patient will not remember some of the details about the procedure. This medicine is also used to treat certain convulsive (seizure) disorders, such as epilepsy.

Lorazepam is a benzodiazepine. Benzodiazepines belong to the group of medicines called central nervous system (CNS) depressants, which are medicines that slow down the nervous system.

This medicine is available only with your doctor's prescription.

This product is available in the following dosage forms:

• Solution

Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam. Ativan (lorazepam) is not recommended for use in patients with a primary depressive disorder or psychosis.

Use of benzodiazepines, including lorazepam, both used alone and in combination with other CNS depressants, may lead to potentially fatal respiratory depression. (See DRUG INTERACTIONS).

Use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence. As with all patients on CNS-depressant drugs, patients receiving lorazepam should be warned not to operate dangerous machinery or motor vehicles and that their tolerance for alcohol and other CNS depressants will be diminished.

Physical And Psychological Dependence

The use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence. The risk of dependence increases with higher doses and longer term use and is further increased in patients with a history of alcoholism or drug abuse or in patients with significant personality disorders. The dependence potential is reduced when lorazepam is used at the appropriate dose for short-term treatment. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving lorazepam or other psychotropic agents.

In general, benzodiazepines should be prescribed for short periods only (e.g., 2 to 4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended. Withdrawal symptoms (e.g., rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy. Abrupt discontinuation of product should be avoided and a gradual dosage-tapering schedule followed after extended therapy.

Abrupt termination of treatment may be accompanied by withdrawal symptoms. Symptoms reported following discontinuation of benzodiazepines include headache, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, rebound phenomena, dysphoria, dizziness, derealization, depersonalization, hyperacusis, numbness/tingling of extremities, hypersensitivity to light, noise, and physical contact/perceptual changes, involuntary movements, nausea, vomiting, diarrhea, loss of appetite, hallucinations/delirium, convulsions/seizures, tremor, abdominal cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, vertigo, hyperreflexia, short-term memory loss, and hyperthermia. Convulsions/seizures may be more common in patients with pre-existing seizure disorders or who are taking other drugs that lower the convulsive threshold such as antidepressants.

There is evidence that tolerance develops to the sedative effects of benzodiazepines.

Lorazepam may have abuse potential, especially in patients with a history of drug and/or alcohol abuse.

Ativan is a prescription medicine used to treat the symptoms of anxiety, anxiety disorders, and anxiety associated with depression.

Ativan injection given through the vein is used to treat a seizure emergency called status epilepticus

Ativan injection to be given into the muscle is used to help you relax before having surgery.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Before taking Ativan, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• have had an allergic reaction to any benzodiazepines, to Ativan, or to any of the ingredients within the Ativan doses
• have seizures or a history of seizures
• have glaucoma
• have lung, heart, or liver disease
• have a history of depression or psychosis
• have a history of alcohol or drug abuse
• have liver or kidney problems
• are pregnant or plan to become pregnant
• suffer from breathing problems
• are breastfeeding
• if you are having surgery, including dental surgery
• if you use tobacco products. Cigarette smoking may decrease the effectiveness of this medication

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your doctor if you are breastfeeding or plan to breastfeed.

You should not take Ativan if you are breastfeeding. It may be excreted in your breast milk and may harm your nursing child.

Take Ativan exactly as prescribed.

This medication comes in tablet or liquid form and can be taken 1 to 3 times per day, with or without food.

Ativan concentrate (liquid) comes with a specially marked dropper for measuring the dose. Ask your pharmacist to show you how to use the dropper. Dilute the concentrate in 1 ounce (30 milliliters) or more of water, juice, or carbonated beverages just before taking it. It also may be mixed with applesauce or pudding just before taking the dose.

This medication is also available in an injectable form to be given directly into a vein (IV) or muscle (IM) by a healthcare professional.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Ativan at the same time.

Benzodiazepine; anticonvulsant, anxiolytic, and sedative.a b c d

Storage

Oral

Tight containers at 20–25°C.c

2–8°C; protect from light.a

Parenteral

2–8°C; protect from light.d

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

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 Ativan 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 Ativan 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 Ativan 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

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 Cmax of approximately 48 ng/mL. Following administration of 1.5 to 5.0 mg of lorazepam IM, the amount of lorazepam delivered to the circulation is proportional to the dose administered.

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 14C-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

Pediatrics

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. 

There is no information on the pharmacokinetic profile of lorazepam in infants in the age range of 1 month to 2 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.

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 Ativan 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.

Gender has no effect on the pharmacokinetics of lorazepam.

Young Americans (n=15) and Japanese subjects (n=7) had very comparable mean total clearance value of 1.0 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.

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 (Clcr of 22±9 mL/min), and four patients on chronic maintenance hemodialysis were given single 1.5 to 3.0 mg intravenous doses of lorazepam. Mean volume of distribution and terminal half-life values of lorazepam were 40% and 25% higher, respectively, in renally impaired patients than in normal subjects. Both parameters were 75% higher in patients undergoing hemodialysis than in normal subjects. Overall, though, in this group of subjects the mean total clearance of lorazepam did not change. About 8% of the administered intravenous dose was removed as intact lorazepam during the 6-hour dialysis session.

The kinetics of lorazepam glucuronide were markedly affected by renal dysfunction. The mean terminal half-life was prolonged by 55% and 125% in renally impaired patients and patients under hemodialysis, respectively, as compared to normal subjects. The mean metabolic clearance decreased by 75% and 90% in renally impaired patients and patients under hemodialysis, respectively, as compared with normal subjects. About 40% of the administered lorazepam intravenous dose was removed as glucuronide conjugate during the 6-hour dialysis session.

Because cytochrome oxidation is not involved with the metabolism of lorazepam, liver disease would not be expected to have an effect on metabolic clearance. This prediction is supported by the observation that following a single 2 mg intravenous dose of lorazepam, cirrhotic male patients (n=13) and normal male subjects (n=11) exhibited no substantive difference in their ability to clear lorazepam.

Administration of a single 2 mg intravenous dose of lorazepam showed that there was no difference in any of the pharmacokinetic parameters of lorazepam between cigarette smokers (n=10, mean=31 cigarettes per day) and nonsmoking subjects (n=10) who were matched for age, weight and gender.

Clinical Studies

The effectiveness of Ativan Injection in status epilepticus was established in two multi-center controlled trials in 177 patients. With rare exceptions, patients were between 18 and 65 years of age. More than half the patients in each study had tonic-clonic status epilepticus; patients with simple partial and complex partial status epilepticus comprised the rest of the population studied, along with a smaller number of patients who had absence status.

One study (n=58) was a double-blind active-control trial comparing Ativan Injection and diazepam. Patients were randomized to receive Ativan 2 mg IV (with an additional 2 mg IV if needed) or diazepam 5 mg IV (with an additional 5 mg IV if needed). The primary outcome measure was a comparison of the proportion of responders in each treatment group, where a responder was defined as a patient whose seizures stopped within 10 minutes after treatment and who continued seizure-free for at least an additional 30 minutes. Twenty-four of the 30 (80%) patients were deemed responders to Ativan and 16/28 (57%) patients were deemed responders to diazepam (p=0.04). Of the 24 Ativan responders, 23 received both 2 mg infusions.

Non-responders to Ativan 4 mg were given an additional 2 to 4 mg Ativan; non-responders to diazepam 10 mg were given an additional 5 to 10 mg diazepam. After this additional dose administration, 28/30 (93%) of patients randomized to Ativan and 24/28 (86%) of patients randomized to diazepam were deemed responders, a difference that was not statistically significant.

Although this study provides support for the efficacy of Ativan as the treatment for status epilepticus, it cannot speak reliably or meaningfully to the comparative performance of either diazepam (Valium) or lorazepam (Ativan Injection) under the conditions of actual use.

A second study (n=119) was a double-blind dose-comparison trial with 3 doses of Ativan Injection: 1 mg, 2 mg, and 4 mg. Patients were randomized to receive one of the three doses of Ativan. The primary outcome and definition of responder were as in the first study. Twenty-five of 41 patients (61%) responded to 1 mg Ativan; 21/37 patients (57%) responded to 2 mg Ativan; and 31/41 (76%) responded to 4 mg Ativan. The p-value for a statistical test of the difference between the Ativan 4 mg dose group and the Ativan 1-mg dose group was 0.08 (two-sided). Data from all randomized patients were used in this test.

Although analyses failed to detect an effect of age, sex, or race on the effectiveness of Ativan in status epilepticus, the numbers of patients evaluated were too few to allow a definitive conclusion about the role these factors may play.

Status Epilepticus

The most important adverse clinical event caused by the use of Ativan Injection is respiratory depression (see WARNINGS).

The adverse clinical events most commonly observed with the use of Ativan Injection in clinical trials evaluating its use in status epilepticus were hypotension, somnolence, and respiratory failure.

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 Ativan 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.

Table 1 lists the treatment-emergent adverse events that occurred in the patients treated with Ativan Injection in a dose-comparison trial of Ativan 1 mg, 2 mg, and 4 mg.

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 Ativan Injection or diazepam was given. The table represents the pooling of results from the two controlled trials.

These trials were not designed or intended to demonstrate the comparative safety of the two treatments.

The overall adverse experience profile for Ativan 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.

Ativan Injection, active comparators, and Ativan 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. Ativan 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 Ativan 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

Preanesthetic

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.

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).

Hypertension (0.1%) and hypotension (0.1%) have occasionally been observed after patients have received injectable lorazepam.

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, WARNINGSand PRECAUTIONS).

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 Ativan (lorazepam) Injection that have been received since market introduction and that may have no causal relationship with the use of Ativan 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).

Controlled Substance Class

Lorazepam is a controlled substance in Schedule IV.

Abuse and Physical and Psychological Dependence

As with other benzodiazepines, Ativan Injection has a potential for abuse and may lead to dependence. Physicians should be aware that repeated doses over a prolonged period of time may result in physical and psychological dependence and withdrawal symptoms, following abrupt discontinuance, similar in character to those noted with barbiturates and alcohol.

NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS - Pediatric Use).

Ativan 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

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 Ativan 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 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 Ativan Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures cease, no additional Ativan 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 Ativan 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.

IM Ativan is not preferred in the treatment of status epilepticus because therapeutic lorazepam levels may not be reached as quickly as with IV administration. However, when an intravenous port is not available, the IM route may prove useful (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).

The safety of Ativan in pediatric patients has not been established.

Preanesthetic

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 also 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.

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

No dosage adjustments are needed in elderly patients and in patients with hepatic 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 also CLINICAL PHARMACOLOGY).

The dose of Ativan should be reduced by 50% when coadministered with probenecid or valproate (see PRECAUTIONS, Drug Interactions).

It may be necessary to increase the dose of Ativan in female patients who are concomitantly taking oral contraceptives.

Administration

When given intramuscularly, Ativan Injection, undiluted, should be injected deep in the muscle mass.

Injectable Ativan can be used with atropine sulfate, narcotic analgesics, other parenterally used analgesics, commonly used anesthetics, and muscle relaxants.

Immediately prior to intravenous use, Ativan 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 2.0 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.

Ativan Injection is compatible for dilution purposes with the following solutions: Sterile Water for Injection, USP; Sodium Chloride Injection, USP; 5% Dextrose Injection, USP.

Your pharmacist can provide more information about lorazepam.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Usual Adult Dose of Ativan for Anxiety:

Tablets:
Initial dose: 2 to 3 mg orally per day administered 2 to 3 times per day
Maintenance dose: 1 to 2 mg orally 2 to 3 times a day
Parenteral:
IV: 2 mg total, or 0.044 mg/kg, whichever is smaller

Comments:
-The daily dosage may vary from 1 to 10 mg per day.
-The dosage should be increased gradually when needed to help avoid adverse effects.
-When higher dosage is indicated, the evening dose should be increased before the daytime doses.

Use: Management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms

Usual Adult Dose for Light Anesthesia:

IM: 0.05 mg/kg up to a maximum of 4 mg
IV: 2 mg total, or 0.044 mg/kg, whichever is smaller

Comments:
-Doses of other injectable central-nervous-system depressant drugs should be reduced.
-For optimum effect, intramuscular drug should be administered at least 2 hours before the anticipated operative procedure.
-Narcotic analgesics should be administered at their usual preoperative time.
-IV: This dose should not ordinarily be exceeded in patients over 50 years of age.
-IV: Larger doses as high as 0.05 mg/kg up to a total of 4 mg may be administered.
-For optimum effect, intravenous drug should be administered 15 to 20 minutes before the anticipated operative procedure.

Use:
-Preanesthetic medication for adult patients, producing sedation (sleepiness or drowsiness), relief of anxiety, and a decreased ability to recall events related to the day of surgery

Usual Adult Dose for Status Epilepticus:

0.1 mg/kg IV up to 4 mg per dose; may repeat in 5 to 10 minutes
Maximum dose: 8 mg

Comments:
-Vital signs should be monitored, an unobstructed airway should be maintained, and artificial ventilation equipment should be available.
-When an intravenous port is not available, the IM route may prove useful.

Use: Treatment of status epilepticus

Usual Adult Dose for Insomnia:

2 to 4 mg orally administered at bedtime

Comments:
-The dosage should be increased gradually when needed to help avoid adverse effects.

Use: Management of insomnia

Usual Geriatric Dose for Anxiety:

Elderly or debilitated patients:
1 to 2 mg orally per day in divided doses

Comments:
-The dosage should be increased gradually when needed to help avoid adverse effects.

Use: Management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms

Usual Pediatric Dose for Anxiety:

12 years or older:
Initial dose: 2 to 3 mg orally per day administered 2 to 3 times per day
Maintenance dose: 1 to 2 mg orally 2 to 3 times a day

Comments:
-The daily dosage may vary from 1 to 10 mg per day.
-The dosage should be increased gradually when needed to help avoid adverse effects.
-When higher dosage is indicated, the evening dose should be increased before the daytime doses.

Use: Management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms

Usual Pediatric Dose for Insomnia:

12 years or older:
2 to 4 mg orally administered at bedtime

Comments:
-For elderly or debilitated patients, an initial dosage of 1 to 2 mg/day in divided doses is recommended.
-The dosage should be increased gradually when needed to help avoid adverse effects.

Use: Management of insomnia

Taking Ativan with other drugs that make you sleepy or slow your breathing can cause dangerous side effects or death. Ask your doctor before taking Ativan with a sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxer, or medicine for anxiety, depression or seizures.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• any other medicines to treat anxiety;

• probenecid;

• aminophylline or theophylline;

• an antidepressant, or medicine to treat mental illness;

• a barbiturate such as phenobarbital;

• narcotic pain medicine;

• seizure medicine; or

• medicine that contains an antihistamine (such as sleep medicine, cold or allergy medicine).

This list is not complete. Other drugs may interact with lorazepam, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Applies to lorazepam: oral solution, oral tablet

Other dosage forms:

• injection solution

Along with its needed effects, lorazepam (the active ingredient contained in Ativan) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking lorazepam:

• Drowsiness
• relaxed and calm
• sleepiness

• Abdominal or stomach pain
• aggressive, angry
• agitation
• attack, assault, or force
• black, tarry stools
• bleeding gums
• blood in the urine or stools
• bluish lips or skin
• blurred vision
• change in consciousness
• chills
• coma
• confusion
• confusion about identity, place, and time
• convulsions
• cough or hoarseness
• dark urine
• decreased urine output
• difficulty with breathing or swallowing
• difficulty with speaking
• discouragement
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• drooling
• dry mouth
• excitation
• false or unusual sense of well-being
• fast or irregular heartbeat
• feeling sad or empty
• fever with or without chills
• general feeling of tiredness or weakness
• headache
• hives, itching, or rash
• hyperventilation
• increased thirst
• irregular, fast or slow, or shallow breathing
• irritability
• loss of appetite
• loss of balance control
• loss of consciousness
• loss of interest or pleasure
• loss of memory
• lower back or side pain
• muscle pain or cramps
• muscle trembling, jerking, or stiffness
• nausea or vomiting
• not breathing
• painful or difficult urination
• pale or blue lips, fingernails, or skin
• pinpoint red spots on the skin
• problems with memory
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• reddening of the skin, especially around ears
• restlessness
• seeing, hearing, or feeling things that are not there
• seizures
• shaking
• shuffling walk
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stiffness of the limbs
• sweating
• swelling of the eyes or inside of the nose
• swelling of the face, ankles, or hands
• swollen glands
• thoughts or attempts at killing oneself
• tightness in the chest
• trouble concentrating
• trouble sleeping
• twisting movements of body
• uncontrolled movements, especially of the face, neck, and back
• unexplained bleeding or bruising
• unpleasant breath odor
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood
• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur while taking lorazepam:

• Changes in patterns and rhythms of speech
• increased sweating
• loss of strength or energy
• nightmares
• shakiness and unsteady walk
• slurred speech
• trouble speaking
• unsteadiness, trembling, or other problems with muscle control or coordination
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• unusual excitement, nervousness, restlessness, or irritability
• unusual paleness
• unusual weak feeling

Some side effects of lorazepam may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Being forgetful
• clumsiness
• constipation
• decreased interest in sexual intercourse
• disturbed color perception
• dizziness or lightheadedness
• double vision
• drowsiness
• feeling of constant movement of self or surroundings
• hair loss or thinning of the hair
• halos around lights
• inability to have or keep an erection
• increased in sexual ability, desire, drive, or performance
• increased interest in sexual intercourse
• lack or loss of self-control
• lethargy
• loss in sexual ability, desire, drive, or performance
• muscle aches, twitching, or weakness
• night blindness
• overbright appearance of lights
• rapid weight gain
• sensation of spinning
• shakiness in the legs, arms, hands, or feet
• shivering
• stupor
• trembling or shaking of the hands or feet
• tunnel vision
• weak or feeble pulse

Animal studies have shown occasional anomalies (reduction of tarsals, tibia, metatarsals, malrotated limbs, gastroschisis, malformed skull, and microphthalmia). There are no adequate studies in pregnant women. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Use should be avoided. AU TGA pregnancy category: C US FDA pregnancy category: D Comments: -The child born to a mother taking benzodiazepines may be at risk for withdrawal symptoms. -The patient should be warned of the potential risks to the fetus and instructed to discontinue the drug prior to becoming pregnant. -There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been taking benzodiazepines late in pregnancy. -Glucuronidation of this drug may competitively inhibit the conjugation of bilirubin, leading to hyperbilirubinemia in neonates.

LactMed Record Number

364

Last Revision Date

20130907

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.

Avoid drinking alcohol. Dangerous side effects could occur.

Lorazepam may impair your thinking or reactions. Avoid driving or operating machinery until you know how this medicine will affect you. Dizziness or severe drowsiness can cause falls or other accidents.

Taking lorazepam with other drugs that make you sleepy or slow your breathing can cause dangerous side effects or death. Ask your doctor before taking a sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxer, or medicine for anxiety, depression, or seizures.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• any other medicines to treat anxiety;

• probenecid;

• aminophylline or theophylline;

• an antidepressant, or medicine to treat mental illness;

• a barbiturate such as phenobarbital;

• narcotic pain medicine;

• seizure medicine; or

• medicine that contains an antihistamine (such as sleep medicine, cold or allergy medicine).

This list is not complete. Other drugs may interact with lorazepam, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.