(LORAZEPAM (NDC 0409-1985-30))
The additive central-nervous-system effects of other drugs, such as phenothiazines, narcotic analgesics, barbiturates, antidepressants, scopolamine, and monoamine-oxidase inhibitors, should be borne in mind when these other drugs are used concomitantly with or during the period of recovery from lorazepam injection (see CLINICAL PHARMACOLOGY and WARNINGS).
Extreme caution must be used when administering lorazepam injection to elderly patients, very ill patients, or to patients with limited pulmonary reserve because of the possibility that hypoventilation and/or hypoxic cardiac arrest may occur. Resuscitative equipment for ventilatory support should be readily available (see WARNINGS and DOSAGE AND ADMINISTRATION).
When lorazepam injection is used intravenous as the premedicant prior to regional or local anesthesia, the possibility of excessive sleepiness or drowsiness may interfere with patient cooperation in determining levels of anesthesia. This is most likely to occur when greater than 0.05 mg/kg is given and when narcotic analgesics are used concomitantly with the recommended dose (see ADVERSE REACTIONS).
As with all benzodiazepines, paradoxical reactions may occur in rare instances and in an unpredictable fashion (see ADVERSE REACTIONS). In these instances, further use of the drug in these patients should be considered with caution.
There have been reports of possible propylene glycol toxicity (e.g., lactic acidosis, hyperosmolality, hypotension) and possible polyethylene glycol toxicity (e.g., acute tubular necrosis) during administration of Lorazepam injection at higher than recommended doses. Symptoms may be more likely to develop in patients with renal impairment.
Concomitant use of benzodiazepines, including Lorazepam injection, and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS and PRECAUTIONS, Drug Interactions).
Inform patients that the use of Lorazepam injection more frequently than recommended, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug (see WARNINGS and DRUG ABUSE AND DEPENDENCE).
Inform patients that use of Lorazepam injection more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Lorazepam injection may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see WARNINGS and DRUG ABUSE AND DEPENDENCE).
Patients should be informed of the pharmacological effects of the drug, including sedation, relief of anxiety, and lack of recall, the duration of these effects (about 8 hours), and be apprised of the risks as well as the benefits of therapy.
Patients who receive lorazepam injection as a premedicant should be cautioned that driving a motor vehicle, operating machinery, or engaging in hazardous or other activities requiring attention and coordination, should be delayed for 24 to 48 hours following the injection or until the effects of the drug, such as drowsiness, have subsided, whichever is longer. Sedatives, tranquilizers and narcotic analgesics may produce a more prolonged and profound effect when administered along with injectable lorazepam. This effect may take the form of excessive sleepiness or drowsiness and on rare occasions, interfere with recall and recognition of events of the day of surgery and the day after.
Patients should be advised that getting out of bed unassisted may result in falling and injury if undertaken within 8 hours of receiving lorazepam injection. Since tolerance for CNS depressants will be diminished in the presence of lorazepam injection, these substances should either be avoided or taken in reduced dosage. Alcoholic beverages should not be consumed for at least 24 to 48 hours after receiving lorazepam injectable due to the additive effects on central-nervous-system depression seen with benzodiazepines in general. Elderly patients should be told that lorazepam injection may make them very sleepy for a period longer than 6 to 8 hours following surgery.
Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs (see WARNINGS, Pediatric Neurotoxicity).
Advise pregnant females who are administered Lorazepam injection late in pregnancy that Lorazepam injection can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS, Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS, Pregnancy). Instruct patients to inform their healthcare provider if they are pregnant.
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Lorazepam injection during pregnancy (see PRECAUTIONS, Pregnancy).
Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who are administered Lorazepam injection to monitor infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs (see PRECAUTIONS, Nursing Mothers).
In clinical trials, no laboratory test abnormalities were identified with either single or multiple doses of lorazepam injection. These tests included: CBC, urinalysis, SGOT, SGPT, bilirubin, alkaline phosphatase, LDH, cholesterol, uric acid, BUN, glucose, calcium, phosphorus, and total proteins.
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 GABAA 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.
Lorazepam 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 CNS-depressant 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 lorazepam 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).
Coadministration of lorazepam (2 mg intravenously) with oral contraceptive steroids (norethindrone acetate, 1 mg, and ethinyl estradiol, 50 mcg, 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 lorazepam 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. Lorazepam dosage needs to be reduced by 50% when coadministered with probenecid (see DOSAGE AND ADMINISTRATION)
No laboratory test abnormalities were identified when lorazepam was given alone or concomitantly with another drug, such as narcotic analgesics, inhalation anesthetics, scopolamine, atropine, and a variety of tranquilizing agents.
No evidence of carcinogenic potential emerged in rats and mice during an 18-month study with oral lorazepam. No studies regarding mutagenesis have been performed. The results of a preimplantation study in rats, in which the oral lorazepam dose was 20 mg/kg, showed no impairment of fertility.
Pregnancy Exposure Registry
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications including Lorazepam Injection during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medication’s at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.
Risk Summary
Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS, Neonatal Sedation and Withdrawal SyndromeandClinical Considerations). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data).
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognizable pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates. Monitor neonates exposed to Lorazepam injection during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Lorazepam injection during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS, Neonatal Sedation and Withdrawal Syndrome).
There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in cesarean section. Such use, therefore, is not recommended.
Human Data
Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.
Animal Data
Reproductive studies in animals were performed in mice, rats, and two strains of rabbits. Occasional anomalies (reduction of tarsals, tibia, metatarsals, malrotated limbs, gastroschisis, malformed skull, and microphthalmia) were seen in drug-treated rabbits without relationship to dosage. Although all of these anomalies were not present in the concurrent control group, they have been reported to occur randomly in historical controls. At doses of 40 mg/kg orally or 4 mg/kg intravenously and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses.
Lorazepam is present in breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of lorazepam on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Lorazepam injection and any potential adverse effects on the breastfed infant from Lorazepam injection or from the underlying maternal condition.
Infants exposed to Lorazepam injection through breast milk should be monitored for sedation, poor feeding and poor weight gain.
Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.
In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits (see WARNINGS,Pediatric Neurotoxicity,Pediatric Use,andANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).
The safety and effectiveness of lorazepam for status epilepticus have not been established in pediatric patients. A randomized, double-blind, superiority-design clinical trial of lorazepam versus intravenous diazepam in 273 pediatric patients ages 3 months to 17 years failed to establish the efficacy of lorazepam for the treatment of status epilepticus. In that trial, assisted ventilation was required in 18% of patients treated with lorazepam versus 16% of patients treated with diazepam. Patients treated with lorazepam were also more likely to be reported as sedated (67% for lorazepam vs. 50% for diazepam), and the time for return to baseline mental status was, on average, 2 hours longer for lorazepam than for diazepam.
Open-label studies described in the medical literature included 273 pediatric patients; the age range was from a few hours old to 18 years of age. Paradoxical excitation was observed in 10% to 30% of the pediatric patients under 8 years of age and was characterized by tremors, agitation, euphoria, logorrhea, and brief episodes of visual hallucinations. Paradoxical excitation in pediatric patients also has been reported with other benzodiazepines when used for status epilepticus, as an anesthesia, or for pre-chemotherapy treatment.
Pediatric patients (as well as adults) with atypical petit mal status epilepticus have developed brief tonic-clonic seizures shortly after lorazepam was given. This "paradoxical" effect was also reported for diazepam and clonazepam. Nevertheless, the development of seizures after treatment with benzodiazepines is probably rare, based on the incidence in the uncontrolled treatment series reported (i.e., seizures were not observed for 112 pediatric patients and 18 adults or during approximately 400 doses).
Lorazepam injection contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome", (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages greater than 99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
Seizure activity and myoclonus have been reported to occur following administration of Lorazepam injection, especially in very low birth weight neonates.
Pediatric patients may exhibit a sensitivity to benzyl alcohol, polyethylene glycol and propylene glycol, components of Lorazepam injection (see CONTRAINDICATIONS). The "gasping syndrome", characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine, has been associated with the administration of intravenous solutions containing the preservative benzyl alcohol in neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Central nervous system toxicity, including seizures and intraventricular hemorrhage, as well as unresponsiveness, tachypnea, tachycardia, and diaphoresis have been associated with propylene glycol toxicity. Although normal therapeutic doses of Lorazepam injection contain very small amounts of these compounds, premature and low-birth-weight infants as well as pediatric patients receiving high doses may be more susceptible to their effects.
Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as lorazepam that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.
In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates and young children who require procedures with the potential risks suggested by the nonclinical data (see WARNINGS, Pediatric Neurotoxicity; PRECAUTIONS, Pregnancy; ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).
Clinical studies of lorazepam generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, age over 65 may be associated with a greater incidence of central nervous system depression and more respiratory depression (see WARNINGS, Preanesthetic Use, PRECAUTIONS, General and ADVERSE REACTIONS, Preanesthetic). Age does not appear to have a clinically significant effect on lorazepam kinetics (see CLINICAL PHARMACOLOGY).
Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered. Greater sensitivity (e.g., sedation) of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range (see DOSAGE AND ADMINISTRATION).
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