Medical Editor: John P. Cunha, DO, FACOEP
What Is Ativan Injection?
Ativan (lorazepam) Injection is a benzodiazepine with antianxiety, sedative, and anticonvulsant effects used for the treatment of status epilepticus, as well as 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.
What Are Side Effects of Ativan Injection?
Common side effects of Ativan Injection include:
- low blood pressure (hypotension),
- abnormal liver function tests,
- abnormal thinking,
- slowed breathing,
- injection site reactions, and
- bladder inflammation
Dosage for Ativan Injection
The recommended adult dose of Ativan Injection is 2 mg to 4 mg.
What Drugs, Substances, or Supplements Interact with Ativan Injection?
Ativan Injection may interact with other CNS depressants (such as ethyl alcohol, phenothiazines, barbiturates, MAO inhibitors, and other antidepressants), scopolamine, loxapine, clozapine, haloperidol, valproate, oral contraceptives, and probenecid. Tell your doctor all medications and supplements you use.
Ativan Injection During Pregnancy and Breastfeeding
Ativan Injection is not recommended for use during pregnancy; it may harm a fetus. Ativan Injection passes into breast milk. Breastfeeding while using Ativan Injection is not recommended. Withdrawal symptoms may occur if you suddenly stop taking Ativan Injection.
Our Ativan (lorazepam) Injection Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Lorazepam can slow or stop your breathing, especially if you have recently used an opioid medication or alcohol. A person caring for you should seek emergency medical attention if you have slow breathing with long pauses, blue colored lips, or if you are hard to wake up.
Call your doctor at once if you have:
- severe drowsiness;
- unusual changes in mood or behavior, being agitated or talkative;
- sudden restless feeling or excitement;
- thoughts of suicide or hurting yourself;
- confusion, aggression, hallucinations;
- sleep problems;
- vision changes; or
- dark urine, or jaundice (yellowing of the skin or eyes).
Drowsiness or dizziness may last longer in older adults. Use caution to avoid falling or accidental injury.
Common side effects may include:
- dizziness, drowsiness;
- weakness; or
- feeling unsteady.
After you stop using lorazepam, get medical help right away if you have symptoms such as: unusual muscle movements, being more active or talkative, sudden and severe changes in mood or behavior, confusion, hallucinations, seizures, suicidal thoughts or actions.
Some withdrawal symptoms may last up to 12 months or longer after stopping this medicine suddenly. Tell your doctor if you have ongoing anxiety, depression, problems with memory or thinking, trouble sleeping, ringing in your ears, a burning or prickly feeling, or a crawling sensation under your skin.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Read the entire detailed patient monograph for Ativan Injection (Lorazepam Injection)
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.
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 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.
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 ATIVAN Injection in a dose-comparison trial of ATIVAN 1 mg, 2 mg, and 4 mg.
TABLE 1. NUMBER (%) OF STUDY EVENTS IN A DOSE COMPARISON CLINICAL TRIAL
|Any Study Event (1 or more)†||16 (12.3%)|
|Body as a whole|
|Infection||1 ( <1%)|
|Liver function tests abnormal||1 ( <1%)|
|Nausea||1 ( <1%)|
|Vomiting||1 ( <1%)|
|Metabolic and Nutritional|
|Acidosis||1 ( <1%)|
|Brain edema||1 ( <1%)|
|Coma||1 ( <1%)|
|Convulsion||1 ( <1%)|
|Thinking abnormal||1 ( <1%)|
|Hyperventilation||1 ( <1%)|
|Hypoventilation||1 ( <1%)|
|Respiratory failure||2 (1.5%)|
|Terms not classifiable|
|Injection site reaction||1 ( <1%)|
|Cystitis||1 ( <1%)|
|* One hundred and thirty (130) patients received ATIVAN Injection.
† 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 ATIVAN Injection or diazepam was given. The table represents the pooling of results from the two controlled trials.
TABLE 2. NUMBER (%) OF STUDY EVENTS IN ACTIVE CONTROLLED CLINICAL TRIAL
|Body System Event||ATIVAN Injection
|Any Study Event (1 or more)†||14 (16.5%)||11 (13.8%)|
|Body as a whole|
|Headache||1 ( 1.2%)||1 (1.3%)|
|Hemic and lymphatic system|
|Hypochromic anemia||0||1 (1.3%)|
|Coma||1 (1.2 %)||1 (1.3%)|
|Somnolence||3 (3.5%)||3 (3.8%)|
|Hypoventilation||1 (1.2%)||2 (2.5%)|
|Apnea||1 (1.2%)||1 (1.3%)|
|Respiratory failure||2 (2.4%)||1 (1.3%)|
|Respiratory disorder||1 (1.2%)||0|
|*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 ATIVAN 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.
†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 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.
Other Events Observed During The Pre-Marketing Evaluation Of Ativan Injection For The Treatment Of Status Epilepticus
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 patientepisodes 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
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.
Central Nervous System
The most frequent adverse drug event reported with injectable lorazepam is central-nervous-system depression. The incidence varied from one study to another, depending on the dosage, route of administration, use of other central-nervous-system depressants, and the investigator’s opinion concerning the degree and duration of desired sedation. Excessive sleepiness and drowsiness were the most common consequences of CNS depression. This interfered with patient cooperation in approximately 6% (25/446) of patients undergoing regional anesthesia, causing difficulty in assessing levels of anesthesia. Patients over 50 years of age had a higher incidence of excessive sleepiness or drowsiness when compared with those under 50 (21/106 versus 24/245) when lorazepam was given intravenously (see DOSAGE AND ADMINISTRATION). On rare occasion (3/1580) the patient was unable to give personal identification in the operating room on arrival, and one patient fell when attempting premature ambulation in the postoperative period.
Symptoms such as restlessness, confusion, depression, crying, sobbing, and delirium occurred in about 1.3% (20/1580). One patient injured himself by picking at his incision during the immediate postoperative period.
Hallucinations were present in about 1% (14/1580) of patients and were visual and self-limiting.
An occasional patient complained of dizziness, diplopia and/or blurred vision. Depressed hearing was infrequently reported during the peak-effect period.
An occasional patient had a prolonged recovery room stay, either because of excessive sleepiness or because of some form of inappropriate behavior. The latter was seen most commonly when scopolamine was given concomitantly as a premedicant. Limited information derived from patients who were discharged the day after receiving injectable lorazepam showed one patient complained of some unsteadiness of gait and a reduced ability to perform complex mental functions. Enhanced sensitivity to alcoholic beverages has been reported more than 24 hours after receiving injectable lorazepam, similar to experience with other benzodiazepines.
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 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.
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).
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).
Interaction With Benzodiazepines And Other CNS Depressants
The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Monitor patients closely for respiratory depression and sedation.
ATIVAN Injection, like other injectable benzodiazepines, produces additive depression of the central nervous system when administered with other CNS depressants such as ethyl alcohol, phenothiazines, barbiturates, MAO inhibitors, and other antidepressants.
When scopolamine is used concomitantly with injectable lorazepam, an increased incidence of sedation, hallucinations and irrational behavior has been observed.
There have been rare reports of significant respiratory depression, stupor and/or hypotension with the concomitant use of loxapine and lorazepam.
Marked sedation, excessive salivation, ataxia, and, rarely, death have been reported with the concomitant use of clozapine and lorazepam.
Apnea, coma, bradycardia, arrhythmia, heart arrest, and death have been reported with the concomitant use of haloperidol and lorazepam.
The risk of using lorazepam in combination with scopolamine, loxapine, clozapine, haloperidol, or other CNSdepressant drugs has not been systematically evaluated. Therefore, caution is advised if the concomitant administration of lorazepam and these drugs is required.
Concurrent administration of any of the following drugs with lorazepam had no effect on the pharmacokinetics of lorazepam: metoprolol, cimetidine, ranitidine, disulfiram, propranolol, metronidazole, and propoxyphene. No change in ATIVAN dosage is necessary when concomitantly given with any of these drugs.
Concurrent administration of lorazepam (2 mg intravenously) with valproate (250 mg twice daily orally for 3 days) to 6 healthy male subjects resulted in decreased total clearance of lorazepam by 40% and decreased formation rate of lorazepam glucuronide by 55%, as compared with lorazepam administered alone.
Accordingly, lorazepam plasma concentrations were about two-fold higher for at least 12 hours post-dose administration during valproate treatment. Lorazepam dosage should be reduced to 50% of the normal adult dose when this drug combination is prescribed in patients (see DOSAGE AND ADMINISTRATION).
Oral Contraceptive Steroids Interaction
Coadministration of lorazepam (2 mg intravenously) with oral contraceptive steroids (norethindrone acetate, 1 mg, and ethinyl estradiol, 50 μg, for at least 6 months) to healthy females (n=7) was associated with a 55% decrease in half-life, a 50% increase in the volume of distribution, thereby resulting in an almost 3.7-fold increase in total clearance of lorazepam as compared with control healthy females (n=8). It may be necessary to increase the dose of ATIVAN in female patients who are concomitantly taking oral contraceptives (see DOSAGE AND ADMINISTRATION).
Concurrent administration of lorazepam (2 mg intravenously) with probenecid (500 mg orally every 6 hours) to 9 healthy volunteers resulted in a prolongation of lorazepam half-life by 130% and a decrease in its total clearance by 45%. No change in volume of distribution was noted during probenecid co-treatment. ATIVAN dosage needs to be reduced by 50% when coadministered with probenecid (see DOSAGE AND ADMINISTRATION).
Drug Abuse And Dependence
ATIVAN Injection contains lorazepam, a Schedule IV controlled substance.
ATIVAN Injection is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.
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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS, Abuse, Misuse, And Addiction).
The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.
The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).
PHYSICAL DEPENDENCE AFTER USE OF ATIVAN INJECTION MORE FREQUENTLY THAN RECOMMENDED
ATIVAN Injection may produce physical dependence if used more frequently than recommended. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Although ATIVAN Injection is indicated only for intermittent use (see INDICATIONS and DOSAGE AND ADMINISTRATION), if used inappropriately more frequently than recommended, abrupt discontinuation or rapid dosage reduction or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening.
Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see WARNINGS, Dependence And Withdrawal Reactions).
For patients using ATIVAN Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue ATIVAN Injection (see WARNINGS, Dependence And Withdrawal Reactions).
Acute Withdrawal Signs and Symptoms
Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.
Protracted Withdrawal Syndrome
Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.
Tolerance to ATIVAN Injection may develop after use more frequently than recommended. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of benzodiazepines may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.
Read the entire FDA prescribing information for Ativan Injection (Lorazepam Injection)
© Ativan Injection Patient Information is supplied by Cerner Multum, Inc. and Ativan Injection Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.
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