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WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS ). • The use of benzodiazepines, including Ativan, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing Ativan and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS ). • The continued use of benzodiazepines, including Ativan, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of Ativan after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue ATIVAN or reduce the dosage (see DOSAGE AND ADMINISTRATION and WARNINGS ).

DESCRIPTION Ativan (lorazepam), an antianxiety agent, has the chemical formula, 7-chloro-5-( o -chlorophenyl)-1,3-dihydro-3-hydroxy-2 H -1,4-benzodiazepin-2-one: C 15 H 10 Cl 2 N 2 O 2 M.W. 321.16 It is a nearly white powder almost insoluble in water. Each Ativan (lorazepam) tablet, to be taken orally, contains 0.5 mg, 1 mg, or 2 mg of lorazepam. The inactive ingredients present are lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium. Ativan chemical structure

CLINICAL PHARMACOLOGY Studies in healthy volunteers show that in single high doses Ativan (lorazepam) has a tranquilizing action on the central nervous system with no appreciable effect on the respiratory or cardiovascular systems. Ativan (lorazepam) is readily absorbed with an absolute bioavailability of 90%. Peak concentrations in plasma occur approximately 2 hours following administration. The peak plasma level of lorazepam from a 2 mg dose is approximately 20 ng/mL. The mean half-life of unconjugated lorazepam in human plasma is about 12 hours and for its major metabolite, lorazepam glucuronide, about 18 hours. At clinically relevant concentrations, lorazepam is approximately 85% bound to plasma proteins. Ativan (lorazepam) is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepam glucuronide has no demonstrable central nervous system (CNS) activity in animals. The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to 6 months. Studies comparing young and elderly subjects have shown that advancing age does not have a significant effect on the pharmacokinetics of lorazepam. However, in one study involving 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.

INDICATIONS AND USAGE Ativan (lorazepam) is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of Ativan (lorazepam) in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

WARNINGS Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including Ativan, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe Ativan concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of Ativan than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Ativan, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when Ativan is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see PRECAUTIONS: Drug Interactions ). Abuse, Misuse, and Addiction The use of benzodiazepines, including Ativan, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse ). Before prescribing Ativan and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of Ativan, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Ativan along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Ativan or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Ativan ). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines, including Ativan, may lead to clinically significant physical dependence.

of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines, including Ativan, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Ativan after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: Dependence ). Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE: Dependence ). 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 PRECAUTIONS: Drug Interactions ). 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. Neonatal Sedation and Withdrawal Syndrome Use of Ativan late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS: Pregnancy ). Monitor neonates exposed to Ativan during pregnancy or labor for signs of sedation and monitor neonates exposed to Ativan during pregnancy for signs of withdrawal; manage these neonates accordingly.

PRECAUTIONS In patients with depression, a possibility for suicide should be borne in mind; benzodiazepines should not be used in such patients without adequate antidepressant therapy. Lorazepam should be used with caution in patients with compromised respiratory function (e.g., COPD, sleep apnea syndrome). Elderly or debilitated patients may be more susceptible to the sedative effects of lorazepam. Therefore, these patients should be monitored frequently and have their dosage adjusted carefully according to patient response; the initial dosage should not exceed 2 mg. Paradoxical reactions have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued. The usual precautions for treating patients with impaired renal or hepatic function should be observed. As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy; therefore, lorazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy. Dosage for patients with severe hepatic insufficiency should be adjusted carefully according to patient response; lower doses may be sufficient in such patients. In patients where gastrointestinal or cardiovascular disorders coexist with anxiety, it should be noted that lorazepam has not been shown to be of significant benefit in treating the gastrointestinal or cardiovascular component. Esophageal dilation occurred in rats treated with lorazepam for more than 1 year at 6 mg/kg/day. The no-effect dose was 1.25 mg/kg/day (approximately 6 times the maximum human therapeutic dose of 10 mg/day). The effect was reversible only when the treatment was withdrawn within 2 months of first observation of the phenomenon. The clinical significance of this is unknown. However, use of lorazepam for prolonged periods and in geriatric patients requires caution, and there should be frequent monitoring for symptoms of upper GI disease. Safety and effectiveness of Ativan (lorazepam) in children of less than 12 years have not been established. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when Ativan is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use of Opioids and PRECAUTIONS: Drug Interactions ). Abuse, Misuse, and Addiction Inform patients that the use of Ativan even at recommended doses, 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: Abuse Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ).

esics), 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: Abuse Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ). Withdrawal Reactions Inform patients that the continued use of Ativan may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Ativan 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. Instruct patients that discontinuation or dosage reduction of Ativan may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ). Pregnancy Advise pregnant females that use of Ativan late in pregnancy 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 Ativan during pregnancy (see PRECAUTIONS: Pregnancy ). Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using Ativan 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 ). Essential Laboratory Tests Some patients on Ativan (lorazepam) have developed leukopenia, and some have had elevations of LDH. As with other benzodiazepines, periodic blood counts and liver function tests are recommended for patients on long-term therapy. Drug Interactions 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 A 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. The benzodiazepines, including Ativan (lorazepam), produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics. Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest. Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate. Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation.

cid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation. Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam. Carcinogenesis and Mutagenesis No evidence of carcinogenic potential emerged in rats during an 18-month study with Ativan (lorazepam). No studies regarding mutagenesis have been performed. Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including Ativan, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications 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 Syndrome and Clinical 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 recognized 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 Ativan during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Ativan during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ). Data 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 and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses. Nursing Mothers Risk Summary 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.

on and increased fetal loss in rabbits which was not seen at lower doses. Nursing Mothers Risk Summary 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 Ativan and any potential adverse effects on the breastfed infant from Ativan or from the underlying maternal condition. Clinical Considerations Infants exposed to Ativan through breast milk should be monitored for sedation, poor feeding and poor weight gain. Geriatric Use Clinical studies of Ativan generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age (see ADVERSE REACTIONS ). Age does not appear to have a 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, and lower doses may be sufficient in these patients (see DOSAGE AND ADMINISTRATION ).

Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when Ativan is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use of Opioids and PRECAUTIONS: Drug Interactions ). Abuse, Misuse, and Addiction Inform patients that the use of Ativan even at recommended doses, 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: Abuse Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ). Withdrawal Reactions Inform patients that the continued use of Ativan may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Ativan 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. Instruct patients that discontinuation or dosage reduction of Ativan may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ). Pregnancy Advise pregnant females that use of Ativan late in pregnancy 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 Ativan during pregnancy (see PRECAUTIONS: Pregnancy ). Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using Ativan 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 ).

Drug Interactions 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 A 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. The benzodiazepines, including Ativan (lorazepam), produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics. Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest. Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate. Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation. Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including Ativan, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications 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 Syndrome and Clinical 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 recognized 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 Ativan during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Ativan during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ). Data 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 and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses.

Nursing Mothers Risk Summary 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 Ativan and any potential adverse effects on the breastfed infant from Ativan or from the underlying maternal condition. Clinical Considerations Infants exposed to Ativan through breast milk should be monitored for sedation, poor feeding and poor weight gain.

Geriatric Use Clinical studies of Ativan generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age (see ADVERSE REACTIONS ). Age does not appear to have a 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, and lower doses may be sufficient in these patients (see DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS Most adverse reactions to benzodiazepines, including CNS effects and respiratory depression, are dose dependent, with more severe effects occurring with high doses. In a sample of about 3500 patients treated for anxiety, the most frequent adverse reaction to Ativan (lorazepam) was sedation (15.9%), followed by dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). The incidence of sedation and unsteadiness increased with age. Other adverse reactions to benzodiazepines, including lorazepam are fatigue, drowsiness, amnesia, memory impairment, confusion, disorientation, depression, unmasking of depression, disinhibition, euphoria, suicidal ideation/attempt, ataxia, asthenia, extrapyramidal symptoms, convulsions/seizures, tremor, vertigo, eye function/visual disturbance (including diplopia and blurred vision), dysarthria/slurred speech, change in libido, impotence, decreased orgasm; headache, coma; respiratory depression, apnea, worsening of sleep apnea, worsening of obstructive pulmonary disease; gastrointestinal symptoms including nausea, change in appetite, constipation, jaundice, increase in bilirubin, increase in liver transaminases, increase in alkaline phosphatase; hypersensitivity reactions, anaphylactoid reactions; dermatological symptoms, allergic skin reactions, alopecia; syndrome of inappropriate antidiuretic hormone (SIADH), hyponatremia; thrombocytopenia, agranulocytosis, pancytopenia; hypothermia; and autonomic manifestations. Paradoxical reactions, including anxiety, excitation, agitation, hostility, aggression, rage, sleep disturbances/insomnia, sexual arousal, and hallucinations may occur. Small decreases in blood pressure and hypotension may occur but are usually not clinically significant, probably being related to the relief of anxiety produced by Ativan (lorazepam). To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG ABUSE AND DEPENDENCE Controlled Substance Ativan contains lorazepam, a Schedule IV controlled substance. Abuse Ativan 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 healthcare 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). Dependence Physical Dependence Ativan may produce physical dependence from continued therapy. 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. Abrupt discontinuation or rapid dosage reduction of benzodiazepines 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 ) . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Ativan or reduce the dosage (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Ativan and WARNINGS ) .

frequent doses) and those who have had longer durations of use (see WARNINGS: Dependence and Withdrawal Reactions ) . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Ativan or reduce the dosage (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Ativan and WARNINGS ) . 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 Tolerance to Ativan may develop from continued therapy. 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 Ativan may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Abuse, Misuse, and Addiction ). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

DOSAGE AND ADMINISTRATION Ativan (lorazepam) is administered orally. For optimal results, dose, frequency of administration, and duration of therapy should be individualized according to patient response. To facilitate this, 0.5 mg, 1 mg, and 2 mg tablets are available. The usual range is 2 to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the daily dosage may vary from 1 to 10 mg/day. For anxiety, most patients require an initial dose of 2 to 3 mg/day given two times a day or three times a day. For insomnia due to anxiety or transient situational stress, a single daily dose of 2 to 4 mg may be given, usually at bedtime. For elderly or debilitated patients, an initial dosage of 1 to 2 mg/day in divided doses is recommended, to be adjusted as needed and tolerated. The dosage of Ativan (lorazepam) 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. Discontinuation or Dosage Reduction of Ativan To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Ativan or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence ).

HOW SUPPLIED Ativan ® (lorazepam) Tablets are available in the following dosage strengths: 0.5 mg, white, five-sided (shield shape) tablet with a raised “A” on one side and “BPI” and “63” impressed on reverse side. NDC 0187-0063-01 - Bottles of 100 tablets. 1 mg, white, five-sided (shield shape) tablet with a raised “A” on one side and “BPI” and “64” impressed on scored reverse side. NDC 0187-0064-01 - Bottles of 100 tablets. 2 mg, white, five-sided (regular pentagon) tablet with a raised “A” and impressed “2” on one side and “BPI” and “65” impressed on scored reverse side. NDC 0187-0065-01 - Bottles of 100 tablets. Keep bottles tightly closed. Keep out of reach of children. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight container. Distributed by: Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Bausch Health Companies Inc. Steinbach, MB R5G 1Z7, Canada Ativan is a registered trademark of Bausch Health Companies Inc. or its affiliates. © 2025 Bausch Health Companies Inc. or its affiliates Rev. 07/2025 9644304 20005922

Medication Guide MEDICATION GUIDE ATIVAN (AT-ivan) (lorazepam) Tablets What is the most important information I should know about ATIVAN? • ATIVAN is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens: o shallow or slowed breathing o breathing stops (which may lead to the heart stopping) o excessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking ATIVAN with opioids affects you. • Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines including ATIVAN which can lead to overdose and serious side effects including coma and death. o Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including ATIVAN. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. o You can develop an addiction even if you take ATIVAN exactly as prescribed by your healthcare provider. o Take ATIVAN exactly as your healthcare provider prescribed. o Do not share your ATIVAN with other people. o Keep ATIVAN in a safe place and away from children. • Physical dependence and withdrawal reactions. ATIVAN can cause physical dependence and withdrawal reactions. o Do not suddenly stop taking ATIVAN. Stopping ATIVAN suddenly can cause serious and life-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. o Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. o Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. • Do not take more ATIVAN than prescribed or take ATIVAN for longer than prescribed. What is ATIVAN? • ATIVAN is a prescription medicine used: o to treat anxiety disorders o for the short-term relief of the symptoms of anxiety or anxiety that can happen with symptoms of depression • ATIVAN is a federal controlled substance (CIV) because it contains lorazepam that can be abused or lead to dependence. Keep ATIVAN in a safe place to prevent misuse and abuse. Selling or giving away ATIVAN may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. • It is not known if ATIVAN is safe and effective for use in children less than 12 years of age.

lace to prevent misuse and abuse. Selling or giving away ATIVAN may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. • It is not known if ATIVAN is safe and effective for use in children less than 12 years of age. • It is not known if ATIVAN is safe and effective for use for longer than 4 months. Do not take ATIVAN if you: • are allergic to lorazepam, other benzodiazepines, or any of the ingredients in ATIVAN. See the end of this Medication Guide for a complete list of ingredients in ATIVAN. Before you take ATIVAN, tell your healthcare provider about all of your medical conditions, including if you: • have or have had depression, mood problems, or suicidal thoughts or behavior • have a history of drug or alcohol abuse or addiction • have lung disease or breathing problems (such as COPD, sleep apnea syndrome) • have liver or kidney problems • have or have had seizures • are pregnant or plan to become pregnant • Taking ATIVAN late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems). • Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with ATIVAN. • There is a pregnancy registry for women who take ATIVAN during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with ATIVAN, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/. • are breastfeeding or plan to breastfeed. ATIVAN passes into your breast milk • Breastfeeding during treatment with ATIVAN may cause your baby to have sleepiness, feeding problems, and decreased weight gain. • Talk to your healthcare provider about the best way to feed your baby if you take ATIVAN. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking ATIVAN with certain other medicines can cause side effects or affect how well ATIVAN or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. How should I take ATIVAN? • Take ATIVAN exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much ATIVAN to take and when to take it. • If you take too much ATIVAN, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of ATIVAN? ATIVAN may cause serious side effects, including: • See “What is the most important information I should know about ATIVAN?” • ATIVAN can make you sleepy or dizzy and can slow your thinking and motor skills. o Do not drive, operate heavy machinery, or do other dangerous activities until you know how ATIVAN affects you. o Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking ATIVAN without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, ATIVAN may make your sleepiness or dizziness much worse. • Depression . Pre-existing depression may emerge or worsen during use of benzodiazepines including ATIVAN. The most common side effects of ATIVAN include: • sedation • dizziness • weakness • unsteadiness These are not all the possible side effects of ATIVAN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

or worsen during use of benzodiazepines including ATIVAN. The most common side effects of ATIVAN include: • sedation • dizziness • weakness • unsteadiness These are not all the possible side effects of ATIVAN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ATIVAN? • Store ATIVAN in a tightly closed container at room temperature between 68°F to 77°F (20°C to 25°C). • Keep ATIVAN and all medicines out of the reach of children. General information about the safe and effective use of ATIVAN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ATIVAN for a condition for which it was not prescribed. Do not give ATIVAN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ATIVAN that is written for health professionals. What are the ingredients in ATIVAN? Active ingredient: lorazepam Inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium. Distributed by: Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Bausch Health Companies Inc. Steinbach, MB R5G 1Z7, Canada ATIVAN is a registered trademark of Bausch Health Companies Inc. or its affiliates. For more information, call 1-800-321-4576. © 2025 Bausch Health Companies Inc. or its affiliates This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 07/2025 9644304 20005922 c4symbol

<table width="100%"><col width="86%"/><col width="11%"/><tbody><tr><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">MEDICATION GUIDE</content></paragraph><paragraph><content styleCode="bold">ATIVAN (AT-ivan)</content></paragraph><paragraph><content styleCode="bold">(lorazepam) Tablets</content></paragraph><renderMultiMedia ID="id-44305193" referencedObject="CAD21725-7113-4122-8C31-0EB2C96EDD3B"/></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about ATIVAN?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">ATIVAN is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.</content> Get emergency help right away if any of the following happens:<list listType="unordered"><item><caption>o</caption>shallow or slowed breathing</item><item><caption>o</caption>breathing stops (which may lead to the heart stopping)</item><item><caption>o</caption>excessive sleepiness (sedation)</item></list></item></list><paragraph> Do not drive or operate heavy machinery until you know how taking ATIVAN with opioids</paragraph><paragraph> affects you.</paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Risk of abuse, misuse, and addiction.</content> There is a risk of abuse, misuse, and addiction with benzodiazepines including ATIVAN which can lead to overdose and serious side effects including coma and death.<list listType="unordered"><item><caption>o</caption><content styleCode="bold">Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including ATIVAN.</content> These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.</content></item><item><caption>o</caption><content styleCode="bold">You can develop an addiction even if you take ATIVAN exactly as prescribed by your healthcare provider.</content></item><item><caption>o</caption><content styleCode="bold">Take ATIVAN exactly as your healthcare provider prescribed.</content></item><item><caption>o</caption>Do not share your ATIVAN with other people.</item><item><caption>o</caption>Keep ATIVAN in a safe place and away from children.</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">Physical dependence and withdrawal reactions.</content> ATIVAN can cause physical dependence and withdrawal reactions.<list listType="unordered"><item><caption>o</caption><content styleCode="bold">Do not suddenly stop taking ATIVAN.</content> Stopping ATIVAN suddenly can cause serious and life-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions.

fe-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms.</content></item><item><caption>o</caption><content styleCode="bold">Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months,</content> including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.</item><item><caption>o</caption>Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.</item></list></item><item><caption>&#x2022;</caption> Do not take more ATIVAN than prescribed or take ATIVAN for longer than prescribed.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is ATIVAN?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>ATIVAN is a prescription medicine used:<list listType="unordered"><item><caption>o</caption>to treat anxiety disorders</item><item><caption>o</caption>for the short-term relief of the symptoms of anxiety or anxiety that can happen with symptoms of depression</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">ATIVAN is a federal controlled substance (CIV) because it contains lorazepam that can be abused or lead to dependence.</content> Keep ATIVAN in a safe place to prevent misuse and abuse. Selling or giving away ATIVAN may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.</item><item><caption>&#x2022;</caption>It is not known if ATIVAN is safe and effective for use in children less than 12 years of age.</item><item><caption>&#x2022;</caption>It is not known if ATIVAN is safe and effective for use for longer than 4 months.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Do not take ATIVAN if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>are allergic to lorazepam, other benzodiazepines, or any of the ingredients in ATIVAN.

/item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Do not take ATIVAN if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>are allergic to lorazepam, other benzodiazepines, or any of the ingredients in ATIVAN. See the end of this Medication Guide for a complete list of ingredients in ATIVAN.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Before you take ATIVAN, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have or have had depression, mood problems, or suicidal thoughts or behavior</item><item><caption>&#x2022;</caption>have a history of drug or alcohol abuse or addiction</item><item><caption>&#x2022;</caption>have lung disease or breathing problems (such as COPD, sleep apnea syndrome)</item><item><caption>&#x2022;</caption>have liver or kidney problems</item><item><caption>&#x2022;</caption>have or have had seizures</item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant</item><item><caption>&#x2022;</caption>Taking ATIVAN late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).</item><item><caption>&#x2022;</caption>Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with ATIVAN.</item><item><caption>&#x2022;</caption>There is a pregnancy registry for women who take ATIVAN during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with ATIVAN, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/.</item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. ATIVAN passes into your breast milk</item><item><caption>&#x2022;</caption>Breastfeeding during treatment with ATIVAN may cause your baby to have sleepiness, feeding problems, and decreased weight gain.</item><item><caption>&#x2022;</caption>Talk to your healthcare provider about the best way to feed your baby if you take ATIVAN.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph><paragraph>Taking ATIVAN with certain other medicines can cause side effects or affect how well ATIVAN or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take ATIVAN?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Take ATIVAN exactly as your healthcare provider tells you to take it.

ealthcare provider.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take ATIVAN?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Take ATIVAN exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much ATIVAN to take and when to take it.</item><item><caption>&#x2022;</caption>If you take too much ATIVAN, call your healthcare provider or go to the nearest hospital emergency room right away.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of ATIVAN?</content></paragraph><paragraph><content styleCode="bold">ATIVAN may cause serious side effects, including:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">See &#x201C;What is the most important information I should know about ATIVAN?&#x201D;</content></item><item><caption>&#x2022;</caption><content styleCode="bold">ATIVAN can make you sleepy or dizzy and can slow your thinking and motor skills.</content><list listType="unordered"><item><caption>o</caption>Do not drive, operate heavy machinery, or do other dangerous activities until you know how ATIVAN affects you.</item><item><caption>o</caption><content styleCode="bold">Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking ATIVAN without first talking to your healthcare provider.</content> When taken with alcohol or drugs that cause sleepiness or dizziness, ATIVAN may make your sleepiness or dizziness much worse.</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">Depression</content>. Pre-existing depression may emerge or worsen during use of benzodiazepines including ATIVAN.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">The most common side effects of ATIVAN include:</content></paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> &#x2022; sedation &#x2022; dizziness</paragraph><paragraph> &#x2022; weakness &#x2022; unsteadiness</paragraph><paragraph>These are not all the possible side effects of ATIVAN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store ATIVAN?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Store ATIVAN in a tightly closed container at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item><item><caption>&#x2022;</caption><content styleCode="bold">Keep ATIVAN and all medicines out of the reach of children.</content></item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of ATIVAN</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ATIVAN for a condition for which it was not prescribed. Do not give ATIVAN to other people, even if they have the same symptoms that you have. It may harm them.

fective use of ATIVAN</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ATIVAN for a condition for which it was not prescribed. Do not give ATIVAN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ATIVAN that is written for health professionals.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in ATIVAN?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content> lorazepam</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content> lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium.</paragraph><paragraph><content styleCode="bold">Distributed by:</content> Bausch Health US, LLC Bridgewater, NJ 08807 USA <content styleCode="bold">Manufactured by:</content> Bausch Health Companies Inc. Steinbach, MB R5G 1Z7, Canada</paragraph><paragraph>ATIVAN is a registered trademark of Bausch Health Companies Inc. or its affiliates. For more information, call 1-800-321-4576.</paragraph><paragraph>&#xA9; 2025 Bausch Health Companies Inc. or its affiliates</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule " valign="top"><paragraph>This Medication Guide has been approved by the U.S. Food and Drug Administration.</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Revised: 07/2025</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>9644304 20005922</paragraph></td></tr></tbody></table>

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS ). • The use of benzodiazepines, including Lorazepam Injection, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing Lorazepam Injection and throughout treatment, assess each patient's risk for abuse, misuse, and addiction (see WARNINGS ) . • The continued use of benzodiazepines for several days to weeks may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although Lorazepam Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of Lorazepam Injection may precipitate acute withdrawal reactions, which can be life-threatening. For patients using Lorazepam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Lorazepam Injection (see WARNINGS ).

DESCRIPTION Lorazepam, a benzodiazepine with antianxiety, sedative, and anticonvulsant effects, is intended for the intramuscular or intravenous routes of administration. It has the chemical formula: 7-chloro-5(2- chlorophenyl)-1,3-dihydro-3-hydroxy-2 H -1, 4-benzodiazepin-2-one. The molecular weight is 321.16, and the C.A.S. No. is [846-49-1]. The structural formula is: Lorazepam is a nearly white powder almost insoluble in water. Each mL of sterile injection contains 2 mg of lorazepam, 0.18 mL polyethylene glycol 400 in propylene glycol with 2% benzyl alcohol as preservative. loraz-struc-01.jpg

CLINICAL PHARMACOLOGY Lorazepam interacts with the γ-aminobutyric acid (GABA)-benzodiazepine receptor complex, which is widespread in the brain of humans as well as other species. This interaction is presumed to be responsible for lorazepam's mechanism of action. Lorazepam exhibits relatively high and specific affinity for its recognition site but does not displace GABA. Attachment to the specific binding site enhances the affinity of GABA for its receptor site on the same receptor complex. The pharmacodynamic consequences of benzodiazepine agonist actions include antianxiety effects, sedation, and reduction of seizure activity. The intensity of action is directly related to the degree of benzodiazepine receptor occupancy. Effects in Pre-Operative Patients Intravenous or intramuscular administration of the recommended dose of 2 mg to 4 mg of Lorazepam Injection to adult patients is followed by dose-related effects of sedation (sleepiness or drowsiness), relief of preoperative anxiety, and lack of recall of events related to the day of surgery in the majority of patients. The clinical sedation (sleepiness or drowsiness) thus noted is such that the majority of patients are able to respond to simple instructions whether they give the appearance of being awake or asleep. The lack of recall is relative rather than absolute, as determined under conditions of careful patient questioning and testing, using props designed to enhance recall. The majority of patients under these reinforced conditions had difficulty recalling perioperative events or recognizing props from before surgery. The lack of recall and recognition was optimum within 2 hours following intramuscular administration and 15 to 20 minutes after intravenous injection. The intended effects of the recommended adult dose of Lorazepam Injection usually last 6 to 8 hours. In rare instances, and where patients received greater than the recommended dose, excessive sleepiness and prolonged lack of recall were noted. As with other benzodiazepines, unsteadiness, enhanced sensitivity to CNS-depressant effects of ethyl alcohol and other drugs were noted in isolated and rare cases for greater than 24 hours. Physiologic Effects in Healthy Adults Studies in healthy adult volunteers reveal that intravenous lorazepam in doses up to 3.5 mg/70 kg does not alter sensitivity to the respiratory stimulating effect of carbon dioxide and does not enhance the respiratory-depressant effects of doses of meperidine up to 100 mg/70 kg (also determined by carbon dioxide challenge) as long as patients remain sufficiently awake to undergo testing. Upper airway obstruction has been observed in rare instances where the patient received greater than the recommended dose and was excessively sleepy and difficult to arouse (see WARNINGS and ADVERSE REACTIONS ). Clinically employed doses of Lorazepam Injection do not greatly affect the circulatory system in the supine position or employing a 70-degree tilt test. Doses of 8 mg to 10 mg of intravenous lorazepam (2 to 2-1/2 times the maximum recommended dosage) will produce loss of lid reflexes within 15 minutes. Studies in 6 healthy young adults who received lorazepam injection and no other drugs revealed that visual tracking (the ability to keep a moving line centered) was impaired for a mean of 8 hours following administration of 4 mg of intramuscular lorazepam and 4 hours following administration of 2 mg intramuscularly with considerable subject variation.

who received lorazepam injection and no other drugs revealed that visual tracking (the ability to keep a moving line centered) was impaired for a mean of 8 hours following administration of 4 mg of intramuscular lorazepam and 4 hours following administration of 2 mg intramuscularly with considerable subject variation. Similar findings were noted with pentobarbital, 150 and 75 mg. Although this study showed that both lorazepam and pentobarbital interfered with eye-hand coordination, the data are insufficient to predict when it would be safe to operate a motor vehicle or engage in a hazardous occupation or sport. Pharmacokinetics and Metabolism ABSORPTION Intravenous A 4-mg dose provides an initial concentration of approximately 70 ng/mL. Intramuscular Following intramuscular administration, lorazepam is completely and rapidly absorbed reaching peak concentrations within 3 hours. A 4-mg dose provides a C max of approximately 48 ng/mL. Following administration of 1.5 to 5 mg of lorazepam intramuscular, the amount of lorazepam delivered to the circulation is proportional to the dose administered. DISTRIBUTION/METABOLISM/ELIMINATION At clinically relevant concentrations, lorazepam is 91±2% bound to plasma proteins; its volume of distribution is approximately 1.3 L/kg. Unbound lorazepam penetrates the blood/brain barrier freely by passive diffusion, a fact confirmed by CSF sampling. Following parenteral administration, the terminal half- life and total clearance averaged 14±5 hours and 1.1±0.4 mL/min/kg, respectively. Lorazepam is extensively conjugated to the 3-O-phenolic glucuronide in the liver and is known to undergo enterohepatic recirculation. Lorazepam glucuronide is an inactive metabolite and is eliminated mainly by the kidneys. Following a single 2-mg oral dose of 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 EFFECT OF AGE Pediatrics NEONATES (BIRTH TO 1 MONTH) Following a single 0.05 mg/kg (n=4) or 0.1 mg/kg (n=6) intravenous dose of lorazepam, mean total clearance normalized to body weight was reduced by 80% compared to normal adults, terminal half-life was prolonged 3-fold, and volume of distribution was decreased by 40% in neonates with asphyxia neonatorum compared to normal adults. All neonates were of ≥37 weeks of gestational age. INFANTS (1 MONTH UP TO 2 YEARS) There is no information on the pharmacokinetic profile of lorazepam in infants in the age range of 1 month to 2 years. CHILDREN (2 YEARS TO 12 YEARS) Total (bound and unbound) lorazepam had a 50% higher mean volume of distribution (normalized to body-weight) and a 30% longer mean half-life in children with acute lymphocytic leukemia in complete remission (2 to 12 years, n=37) compared to normal adults (n=10). Unbound lorazepam clearance normalized to body-weight was comparable in children and adults. ADOLESCENTS (12 YEARS TO 18 YEARS) Total (bound and unbound) lorazepam had a 50% higher mean volume of distribution (normalized to body-weight) and a mean half-life that was two fold greater in adolescents with acute lymphocytic leukemia in complete remission (12 to 18 years, n=13) compared to normal adults (n=10). Unbound lorazepam clearance normalized to body-weight was comparable in adolescents and adults. Elderly Following single intravenous doses of 1.5 to 3 mg of Lorazepam Injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age.

normalized to body-weight was comparable in adolescents and adults. Elderly Following single intravenous doses of 1.5 to 3 mg of Lorazepam Injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age. Consequently, no dosage adjustment appears to be necessary in elderly subjects based solely on their age. EFFECT OF GENDER Gender has no effect on the pharmacokinetics of lorazepam. EFFECT OF RACE Young Americans (n=15) and Japanese subjects (n=7) had very comparable mean total clearance value of 1 mL/min/kg. However, elderly Japanese subjects had a 20% lower mean total clearance than elderly Americans, 0.59 mL/min/kg vs 0.77 mL/min/kg, respectively. PATIENTS WITH RENAL INSUFFICIENCY Because the kidney is the primary route of elimination of lorazepam glucuronide, renal impairment would be expected to compromise its clearance. This should have no direct effect on the glucuronidation (and inactivation) of lorazepam. There is a possibility that the enterohepatic circulation of lorazepam glucuronide leads to a reduced efficiency of the net clearance of lorazepam in this population. Six normal subjects, six patients with renal impairment (Cl cr of 22±9 mL/min), and four patients on chronic maintenance hemodialysis were given single 1.5 to 3 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. HEPATIC DISEASE 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. EFFECT OF SMOKING 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 Lorazepam 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 Lorazepam Injection and diazepam.

tudy 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 Lorazepam Injection and diazepam. Patients were randomized to receive Lorazepam Injection 2 mg intravenous (with an additional 2 mg intravenous if needed) or diazepam 5 mg intravenous (with an additional 5 mg intravenous 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 Lorazepam Injection and 16/28 (57%) patients were deemed responders to diazepam (p=0.04). Of the 24 Lorazepam Injection responders, 23 received both 2 mg infusions. Non-responders to Lorazepam Injection 4 mg were given an additional 2 to 4 mg Lorazepam Injection; 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 Lorazepam Injection 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 Lorazepam Injection as the treatment for status epilepticus, it cannot speak reliably or meaningfully to the comparative performance of either diazepam (Valium) or Lorazepam Injection under the conditions of actual use. A second study (n=119) was a double-blind dose-comparison trial with 3 doses of Lorazepam Injection: 1 mg, 2 mg, and 4 mg. Patients were randomized to receive one of the three doses of Lorazepam Injection. The primary outcome and definition of responder were as in the first study. Twenty-five of 41 patients (61%) responded to 1 mg Lorazepam Injection; 21/37 patients (57%) responded to 2 mg Lorazepam Injection; and 31/41 (76%) responded to 4 mg Lorazepam Injection. The p-value for a statistical test of the difference between the Lorazepam Injection 4 mg dose group and the Lorazepam Injection 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 Lorazepam Injection in status epilepticus, the numbers of patients evaluated were too few to allow a definitive conclusion about the role these factors may play.

Pharmacokinetics and Metabolism ABSORPTION Intravenous A 4-mg dose provides an initial concentration of approximately 70 ng/mL. Intramuscular Following intramuscular administration, lorazepam is completely and rapidly absorbed reaching peak concentrations within 3 hours. A 4-mg dose provides a C max of approximately 48 ng/mL. Following administration of 1.5 to 5 mg of lorazepam intramuscular, the amount of lorazepam delivered to the circulation is proportional to the dose administered. DISTRIBUTION/METABOLISM/ELIMINATION At clinically relevant concentrations, lorazepam is 91±2% bound to plasma proteins; its volume of distribution is approximately 1.3 L/kg. Unbound lorazepam penetrates the blood/brain barrier freely by passive diffusion, a fact confirmed by CSF sampling. Following parenteral administration, the terminal half- life and total clearance averaged 14±5 hours and 1.1±0.4 mL/min/kg, respectively. Lorazepam is extensively conjugated to the 3-O-phenolic glucuronide in the liver and is known to undergo enterohepatic recirculation. Lorazepam glucuronide is an inactive metabolite and is eliminated mainly by the kidneys. Following a single 2-mg oral dose of 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.

Clinical Studies The effectiveness of Lorazepam 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 Lorazepam Injection and diazepam. Patients were randomized to receive Lorazepam Injection 2 mg intravenous (with an additional 2 mg intravenous if needed) or diazepam 5 mg intravenous (with an additional 5 mg intravenous 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 Lorazepam Injection and 16/28 (57%) patients were deemed responders to diazepam (p=0.04). Of the 24 Lorazepam Injection responders, 23 received both 2 mg infusions. Non-responders to Lorazepam Injection 4 mg were given an additional 2 to 4 mg Lorazepam Injection; 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 Lorazepam Injection 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 Lorazepam Injection as the treatment for status epilepticus, it cannot speak reliably or meaningfully to the comparative performance of either diazepam (Valium) or Lorazepam Injection under the conditions of actual use. A second study (n=119) was a double-blind dose-comparison trial with 3 doses of Lorazepam Injection: 1 mg, 2 mg, and 4 mg. Patients were randomized to receive one of the three doses of Lorazepam Injection. The primary outcome and definition of responder were as in the first study. Twenty-five of 41 patients (61%) responded to 1 mg Lorazepam Injection; 21/37 patients (57%) responded to 2 mg Lorazepam Injection; and 31/41 (76%) responded to 4 mg Lorazepam Injection. The p-value for a statistical test of the difference between the Lorazepam Injection 4 mg dose group and the Lorazepam Injection 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 Lorazepam Injection in status epilepticus, the numbers of patients evaluated were too few to allow a definitive conclusion about the role these factors may play.

INDICATIONS AND USAGE Status Epilepticus Lorazepam Injection is indicated for the treatment of status epilepticus. Preanesthetic Lorazepam Injection is indicated in adult patients for preanesthetic medication, producing sedation (sleepiness or drowsiness), relief of anxiety, and a decreased ability to recall events related to the day of surgery. It is most useful in those patients who are anxious about their surgical procedure and who would prefer to have diminished recall of the events of the day of surgery (see PRECAUTIONS, Information for Patients ).

CONTRAINDICATIONS Lorazepam Injection is contraindicated in patients with a known sensitivity to benzodiazepines or its vehicle (polyethylene glycol, propylene glycol, and benzyl alcohol), in patients with acute narrow-angle glaucoma, or in patients with sleep apnea syndrome. It is also contraindicated in patients with severe respiratory insufficiency, except in those patients requiring relief of anxiety and/or diminished recall of events while being mechanically ventilated. The use of Lorazepam Injection intra-arterially is contraindicated because, as with other injectable benzodiazepines, inadvertent intra-arterial injection may produce arteriospasm resulting in gangrene which may require amputation (see WARNINGS ). Lorazepam Injection is contraindicated for use in premature infants because the formulation contains benzyl alcohol (see WARNINGS and PRECAUTIONS, Pediatric Use ).

WARNINGS Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including Lorazepam Injection, and opioids may result in profound sedation, respiratory depression, coma, and death. If a decision is made to use Lorazepam Injection concomitantly with opioids, monitor patients closely for respiratory depression and sedation (see PRECAUTIONS, Drug Interactions ). Abuse, Misuse, and Addiction The use of benzodiazepines, including Lorazepam Injection, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE, Abuse ). Before prescribing Lorazepam Injection and throughout treatment, assess each patient's risk for abuse, misuse, and addiction. Use of Lorazepam Injection, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Lorazepam Injection along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions After Use of Lorazepam Injection More Frequently Than Recommended For patients using Lorazepam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Lorazepam Injection (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. ACUTE WITHDRAWAL REACTIONS The continued use of benzodiazepines may lead to clinically significant physical dependence. Although Lorazepam Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of Lorazepam Injection, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE, Dependence ). PROTRACTED WITHDRAWAL SYNDROME In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE, Dependence ). Use in Status Epilepticus MANAGEMENT OF STATUS EPILEPTICUS Status epilepticus is a potentially life-threatening condition associated with a high risk of permanent neurological impairment, if inadequately treated. The treatment of status, however, requires far more than the administration of an anticonvulsant agent.

). Use in Status Epilepticus MANAGEMENT OF STATUS EPILEPTICUS Status epilepticus is a potentially life-threatening condition associated with a high risk of permanent neurological impairment, if inadequately treated. The treatment of status, however, requires far more than the administration of an anticonvulsant agent. It involves observation and management of all parameters critical to maintaining vital function and the capacity to provide support of those functions as required. Ventilatory support must be readily available. The use of benzodiazepines, like Lorazepam Injection, is ordinarily only one step of a complex and sustained intervention which may require additional interventions (e.g., concomitant intravenous administration of phenytoin). Because status epilepticus may result from a correctable acute cause such as hypoglycemia, hyponatremia, or other metabolic or toxic derangement, such an abnormality must be immediately sought and corrected. Furthermore, patients who are susceptible to further seizure episodes should receive adequate maintenance antiepileptic therapy. Any healthcare professional who intends to treat a patient with status epilepticus should be familiar with this package insert and the pertinent medical literature concerning current concepts for the treatment of status epilepticus. A comprehensive review of the considerations critical to the informed and prudent management of status epilepticus cannot be provided in drug product labeling. The archival medical literature contains many informative references on the management of status epilepticus, among them the report of the working group on status epilepticus of the Epilepsy Foundation of America “Treatment of Convulsive Status Epilepticus” (JAMA 1993; 270:854-859). As noted in the report just cited, it may be useful to consult with a neurologist if a patient fails to respond (e.g., fails to regain consciousness). For the treatment of status epilepticus, the usual recommended dose of Lorazepam Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures cease, no additional Lorazepam Injection is required. If seizures continue or recur after a 10- to 15-minute observation period, an additional 4 mg intravenous dose may be slowly administered. Experience with further doses of Lorazepam Injection is very limited. The usual precautions in treating status epilepticus should be employed. An intravenous infusion should be started, vital signs should be monitored, an unobstructed airway should be maintained, and artificial ventilation equipment should be available. RESPIRATORY DEPRESSION The most important risk associated with the use of Lorazepam Injection in status epilepticus is respiratory depression. Accordingly, airway patency must be assured and respiration monitored closely. Ventilatory support should be given as required. EXCESSIVE SEDATION Because of its prolonged duration of action, the prescriber should be alert to the possibility, especially when multiple doses have been given, that the sedative effects of lorazepam may add to the impairment of consciousness seen in the post-ictal state. Preanesthetic Use AIRWAY OBSTRUCTION MAY OCCUR IN HEAVILY SEDATED PATIENTS. INTRAVENOUS LORAZEPAM AT ANY DOSE, WHEN GIVEN EITHER ALONE OR IN COMBINATION WITH OTHER DRUGS ADMINISTERED DURING ANESTHESIA, MAY PRODUCE HEAVY SEDATION; THEREFORE, EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY AND TO SUPPORT RESPIRATION/VENTILATION SHOULD BE AVAILABLE. As is true of similar CNS-acting drugs, the decision as to when patients who have received injectable lorazepam, particularly on an outpatient basis, may again operate machinery, drive a motor vehicle, or engage in hazardous or other activities requiring attention and coordination must be individualized.

BE AVAILABLE. As is true of similar CNS-acting drugs, the decision as to when patients who have received injectable lorazepam, particularly on an outpatient basis, may again operate machinery, drive a motor vehicle, or engage in hazardous or other activities requiring attention and coordination must be individualized. It is recommended that no patient engage in such activities for a period of 24 to 48 hours or until the effects of the drug, such as drowsiness, have subsided, whichever is longer. Impairment of performance may persist for greater intervals because of extremes of age, concomitant use of other drugs, stress of surgery, or the general condition of the patient. Clinical trials have shown that patients over the age of 50 years may have a more profound and prolonged sedation with intravenous lorazepam (see DOSAGE AND ADMINISTRATION, Preanesthetic ). As with all central-nervous-system-depressant drugs, care should be exercised in patients given injectable lorazepam as premature ambulation may result in injury from falling. There is no added beneficial effect from the addition of scopolamine to injectable lorazepam, and their combined effect may result in an increased incidence of sedation, hallucination and irrational behavior. General (All Uses) PRIOR TO INTRAVENOUS USE, LORAZEPAM INJECTION MUST BE DILUTED WITH AN EQUAL AMOUNT OF COMPATIBLE DILUENT (see DOSAGE AND ADMINISTRATION ). INTRAVENOUS INJECTION SHOULD BE MADE SLOWLY AND WITH REPEATED ASPIRATION. CARE SHOULD BE TAKEN TO DETERMINE THAT ANY INJECTION WILL NOT BE INTRA-ARTERIAL AND THAT PERIVASCULAR EXTRAVASATION WILL NOT TAKE PLACE. IN THE EVENT THAT A PATIENT COMPLAINS OF PAIN DURING INTENDED INTRAVENOUS INJECTION OF LORAZEPAM INJECTION, THE INJECTION SHOULD BE STOPPED IMMEDIATELY TO DETERMINE IF INTRA-ARTERIAL INJECTION OR PERIVASCULAR EXTRAVASATION HAS TAKEN PLACE. Since the liver is the most likely site of conjugation of lorazepam and since excretion of conjugated lorazepam (glucuronide) is a renal function, this drug is not recommended for use in patients with hepatic and/or renal failure . Lorazepam Injection should be used with caution in patients with mild-to-moderate hepatic or renal disease (see DOSAGE AND ADMINISTRATION ). Neonatal Sedation and Withdrawal Syndrome Use of Lorazepam Injection late in pregnancy can result in sedation (respiratory depression. lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS, Pregnancy ). Monitor neonates exposed to Lorazepam Injection during pregnancy or labor for signs of sedation and monitor neonates exposed to Lorazepam Injection during pregnancy for signs of withdrawal; manage these neonates accordingly. Usage in Preterm Infants and Neonates Lorazepam Injection contains benzyl alcohol. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including Lorazepam Injection) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of Lorazepam Injection for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known.

eservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of Lorazepam Injection for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see WARNINGS and PRECAUTIONS, Pediatric Use ). Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, 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 three years of age in humans (see PRECAUTIONS, Pregnancy , Pediatric Use ; ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks. Endoscopic Procedures There are insufficient data to support the use of Lorazepam Injection for outpatient endoscopic procedures. Inpatient endoscopic procedures require adequate recovery room observation time. When Lorazepam Injection is used for peroral endoscopic procedures, adequate topical or regional anesthesia is recommended to minimize reflex activity associated with such procedures.

PRECAUTIONS General 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. Information for Patients RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines, including Lorazepam Injection, and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS and PRECAUTIONS, Drug Interactions ). ABUSE, MISUSE, AND ADDICTION 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 ). WITHDRAWAL REACTIONS 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 ). EXCESSIVE SEDATION 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.

n 12 months (see WARNINGS and DRUG ABUSE AND DEPENDENCE ). EXCESSIVE SEDATION 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 Injection. 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. EFFECT OF ANESTHETIC AND SEDATION DRUGS ON EARLY BRAIN DEVELOPMENT 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 ). PREGNANCY 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. NURSING 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 ). Laboratory Tests 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. Drug Interactions 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 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.

cause 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 Injection dosage is necessary when concomitantly given with any of these drugs. LORAZEPAM-VALPROATE INTERACTION 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 ). LORAZEPAM-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 Lorazepam Injection in female patients who are concomitantly taking oral contraceptives (see DOSAGE AND ADMINISTRATION ). LORAZEPAM-PROBENECID INTERACTION 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 Injection dosage needs to be reduced by 50% when coadministered with probenecid (see DOSAGE AND ADMINISTRATION ).

thy 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 Injection dosage needs to be reduced by 50% when coadministered with probenecid (see DOSAGE AND ADMINISTRATION ). Drug/Laboratory Test Interactions 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. Carcinogenesis, Mutagenesis, Impairment of Fertility 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 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 Syndrome and Clinical 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 ). Labor or Delivery There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in cesarean section. Such use, therefore, is not recommended. Data 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 al lower doses. Nursing Mothers RISK SUMMARY 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.

venously and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen al lower doses. Nursing Mothers RISK SUMMARY 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. Clinical Considerations 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 , and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). Pediatric Use STATUS EPILEPTICUS The safety and effectiveness of Lorazepam Injection for status epilepticus have not been established in pediatric patients. A randomized, double-blind, superiority-design clinical trial of Lorazepam Injection versus intravenous diazepam in 273 pediatric patients ages 3 months to 17 years failed to establish the efficacy of Lorazepam Injection for the treatment of status epilepticus. In that trial, assisted ventilation was required in 18% of patients treated with Lorazepam Injection versus 16% of patients treated with diazepam. Patients treated with Lorazepam Injection were also more likely to be reported as sedated (67% for Lorazepam Injection vs. 50% for diazepam), and the time for return to baseline mental status was, on average, 2 hours longer for Lorazepam Injection 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 Injection was given. This “paradoxical” effect was also reported for diazepam and clonazepam.

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 Injection 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. PREANESTHETIC There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age. GENERAL 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 Injection 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.

tic and sedation drugs, such as Lorazepam Injection 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 ). Geriatric Use Clinical studies of Lorazepam Injection 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 ).

General 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.

Information for Patients RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines, including Lorazepam Injection, and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS and PRECAUTIONS, Drug Interactions ). ABUSE, MISUSE, AND ADDICTION 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 ). WITHDRAWAL REACTIONS 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 ). EXCESSIVE SEDATION 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 Injection. 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. EFFECT OF ANESTHETIC AND SEDATION DRUGS ON EARLY BRAIN DEVELOPMENT 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.

longer than 6 to 8 hours following surgery. EFFECT OF ANESTHETIC AND SEDATION DRUGS ON EARLY BRAIN DEVELOPMENT 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 ). PREGNANCY 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. NURSING 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 ).

Laboratory Tests 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.

Drug Interactions 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 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 Injection dosage is necessary when concomitantly given with any of these drugs. LORAZEPAM-VALPROATE INTERACTION 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 ). LORAZEPAM-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 Lorazepam Injection in female patients who are concomitantly taking oral contraceptives (see DOSAGE AND ADMINISTRATION ).

e 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 Injection in female patients who are concomitantly taking oral contraceptives (see DOSAGE AND ADMINISTRATION ). LORAZEPAM-PROBENECID INTERACTION 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 Injection dosage needs to be reduced by 50% when coadministered with probenecid (see DOSAGE AND ADMINISTRATION ).

Drug/Laboratory Test Interactions 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility 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 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 Syndrome and Clinical 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 ). Labor or Delivery There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in cesarean section. Such use, therefore, is not recommended. Data 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 al lower doses.

Nursing Mothers RISK SUMMARY 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. Clinical Considerations 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 , and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ).

Pediatric Use STATUS EPILEPTICUS The safety and effectiveness of Lorazepam Injection for status epilepticus have not been established in pediatric patients. A randomized, double-blind, superiority-design clinical trial of Lorazepam Injection versus intravenous diazepam in 273 pediatric patients ages 3 months to 17 years failed to establish the efficacy of Lorazepam Injection for the treatment of status epilepticus. In that trial, assisted ventilation was required in 18% of patients treated with Lorazepam Injection versus 16% of patients treated with diazepam. Patients treated with Lorazepam Injection were also more likely to be reported as sedated (67% for Lorazepam Injection vs. 50% for diazepam), and the time for return to baseline mental status was, on average, 2 hours longer for Lorazepam Injection 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 Injection 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. PREANESTHETIC There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age.

Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. PREANESTHETIC There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age. GENERAL 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 Injection 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 ).

Geriatric Use Clinical studies of Lorazepam Injection 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 ).

ADVERSE REACTIONS Status Epilepticus The most important adverse clinical event caused by the use of Lorazepam Injection is respiratory depression (see WARNINGS ). The adverse clinical events most commonly observed with the use of Lorazepam Injection in clinical trials evaluating its use in status epilepticus were hypotension, somnolence, and respiratory failure. INCIDENCE IN CONTROLLED CLINICAL TRIALS All adverse events were recorded during the trials by the clinical investigators using terminology of their own choosing. Similar types of events were grouped into standardized categories using modified COSTART dictionary terminology. These categories are used in the table and listings below with the frequencies representing the proportion of individuals exposed to Lorazepam Injection or to comparative therapy. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigators involving different treatment, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. COMMONLY OBSERVED ADVERSE EVENTS IN A CONTROLLED DOSE-COMPARISON CLINICAL TRIAL Table 1 lists the treatment-emergent adverse events that occurred in the patients treated with Lorazepam Injection in a dose-comparison trial of Lorazepam Injection 1 mg, 2 mg, and 4 mg. TABLE 1. NUMBER (%) OF STUDY EVENTS IN A DOSE COMPARISON CLINICAL TRIAL a: One hundred and thirty (130) patients received Lorazepam Injection. b: Totals are not necessarily the sum of the individual study events because a patient may report two or more different study events in the same body system. Body System Event Lorazepam Injection (n=130) a Any Study Event (1 or more) b 16 (12.3%) Body as a whole Infection 1 (<1%) Cardiovascular system Hypotension 2 (1.5%) Digestive system Liver function tests abnormal 1 (<1%) Nausea 1 (<1%) Vomiting 1 (<1%) Metabolic and Nutritional Acidosis 1 (<1%) Nervous system Brain edema 1 (<1%) Coma 1 (<1%) Convulsion 1 (<1%) Somnolence 2 (1.5%) Thinking abnormal 1 (<1%) Respiratory system Hyperventilation 1 (<1%) Hypoventilation 1 (<1%) Respiratory failure 2 (1.5%) Terms not classifiable Injection site reaction 1 (<1%) Urogenital system Cystitis 1 (<1%) COMMONLY OBSERVED ADVERSE EVENTS IN ACTIVE-CONTROLLED CLINICAL TRIALS In two studies, patients who completed the course of treatment for status epilepticus were permitted to be reenrolled and to receive treatment for a second status episode, given that there was a sufficient interval between the two episodes. Safety was determined from all treatment episodes for all intent-to-treat patients, i.e., from all “patient-episodes.” Table 2 lists the treatment-emergent adverse events that occurred in at least 1% of the patient-episodes in which Lorazepam Injection or diazepam was given. The table represents the pooling of results from the two controlled trials. TABLE 2.

episodes for all intent-to-treat patients, i.e., from all “patient-episodes.” Table 2 lists the treatment-emergent adverse events that occurred in at least 1% of the patient-episodes in which Lorazepam Injection or diazepam was given. The table represents the pooling of results from the two controlled trials. TABLE 2. NUMBER (%) OF STUDY EVENTS IN ACTIVE CONTROLLED CLINICAL TRIAL a: The number indicates the number of “patient-episodes.” Patient-episodes were used rather than “patients” because a total of 7 patients were reenrolled for the treatment of a second episode of status: 5 patients received Lorazepam Injection on two occasions that were far enough apart to establish the diagnosis of status epilepticus for each episode, and, using the same time criterion, 2 patients received diazepam on two occasions. b: Totals are not necessarily the sum of the individual study events because a patient may report two or more different study events in the same body system. Body System Lorazepam Injection Diazepam Event (n=85) a (n=80) a Any Study Event (1 or more) b 14 (16.5%) 11 (13.8%) Body as a whole Headache 1 ( 1.2%) 1 (1.3%) Cardiovascular system Hypotension 2 (2.4%) 0 Hemic and lymphatic system Hypochromic anemia 0 1 (1.3%) Leukocytosis 0 1 (1.3%) Thrombocythemia 0 1 (1.3%) Nervous system Coma 1 (1.2 %) 1 (1.3%) Somnolence 3 (3.5%) 3 (3.8%) Stupor 1 (1.2%) 0 Respiratory system 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 These trials were not designed or intended to demonstrate the comparative safety of the two treatments. The overall adverse experience profile for Lorazepam Injection was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse events by race. Generally, age greater than 65 years may be associated with a greater incidence of central-nervous-system depression and more respiratory depression. OTHER EVENTS OBSERVED DURING THE PRE-MARKETING EVALUATION OF LORAZEPAM INJECTION FOR THE TREATMENT OF STATUS EPILEPTICUS Lorazepam Injection, active comparators, and Lorazepam Injection in combination with a comparator were administered to 488 individuals during controlled and open-label clinical trials. Because of reenrollments, these 488 patients participated in a total of 521 patient-episodes. Lorazepam Injection alone was given in 69% of these patient-episodes (n=360). The safety information below is based on data available from 326 of these patient-episodes in which Lorazepam Injection was given alone. All adverse events that were seen once are listed, except those already included in previous listings ( Table 1 and Table 2 ). Study events were classified by body system in descending frequency by using the following definitions: frequent adverse events were those that occurred in at least 1/100 individuals; infrequent study events were those that occurred in 1/100 to 1/1000 individuals. Frequent and Infrequent Study Events BODY AS A WHOLE - Infrequent: asthenia, chills, headache, infection. DIGESTIVE SYSTEM - Infrequent: abnormal liver function test, increased salivation, nausea, vomiting. METABOLIC AND NUTRITIONAL - Infrequent: acidosis, alkaline phosphatase increased. NERVOUS SYSTEM - Infrequent: agitation, ataxia, brain edema, coma, confusion, convulsion, hallucinations, myoclonus, stupor, thinking abnormal, tremor. RESPIRATORY SYSTEM - Frequent: apnea; Infrequent: hyperventilation, hypoventilation, respiratory disorder. TERMS NOT CLASSIFIABLE - Infrequent: injection site reaction. UROGENITAL SYSTEM - Infrequent: cystitis. Preanesthetic CENTRAL NERVOUS SYSTEM The most frequent adverse drug event reported with injectable lorazepam is central-nervous-system depression.

Infrequent: hyperventilation, hypoventilation, respiratory disorder. TERMS NOT CLASSIFIABLE - Infrequent: injection site reaction. UROGENITAL SYSTEM - Infrequent: cystitis. Preanesthetic CENTRAL NERVOUS SYSTEM The most frequent adverse drug event reported with injectable lorazepam 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. LOCAL EFFECTS 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 ). CARDIOVASCULAR SYSTEM Hypertension (0.1%) and hypotension (0.1%) have occasionally been observed after patients have received injectable lorazepam. RESPIRATORY SYSTEM Five patients (5/446) who underwent regional anesthesia were observed to have airway obstruction.

which may require amputation (see CONTRAINDICATIONS ). CARDIOVASCULAR SYSTEM Hypertension (0.1%) and hypotension (0.1%) have occasionally been observed after patients have received injectable lorazepam. RESPIRATORY SYSTEM Five patients (5/446) who underwent regional anesthesia were observed to have airway obstruction. This was believed due to excessive sleepiness at the time of the procedure and resulted in temporary hypoventilation. In this instance, appropriate airway management may become necessary (see CLINICAL PHARMACOLOGY , WARNINGS, and PRECAUTIONS ). OTHER ADVERSE EXPERIENCES Skin rash, nausea and vomiting have occasionally been noted in patients who have received injectable lorazepam combined with other drugs during anesthesia and surgery. Paradoxical Reactions As with all benzodiazepines, paradoxical reactions such as stimulation, mania, irritability, restlessness, agitation, aggression, psychosis, hostility, rage, or hallucinations may occur in rare instances and in an unpredictable fashion. In these instances, further use of the drug in these patients should be considered with caution (see PRECAUTIONS, General ). Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of Lorazepam Injection that have been received since market introduction and that may have no causal relationship with the use of Lorazepam Injection include the following: acute brain syndrome, aggravation of pheochromocytoma, amnesia, apnea/respiratory arrest, arrhythmia, bradycardia, brain edema, coagulation disorder, coma, convulsion, gastrointestinal hemorrhage, heart arrest/failure, heart block, liver damage, lung edema, lung hemorrhage, nervousness, neuroleptic malignant syndrome, paralysis, pericardial effusion, pneumothorax, pulmonary hypertension, tachycardia, thrombocytopenia, urinary incontinence, ventricular arrhythmia. Fatalities also have been reported, usually in patients on concomitant medications (e.g., respiratory depressants) and/or with other medical conditions (e.g., obstructive sleep apnea).

<table ID="_Reft1" width="100%"><caption>TABLE 1. NUMBER (%) OF STUDY EVENTS IN A DOSE COMPARISON CLINICAL TRIAL </caption><col width="54%"/><col width="44%"/><tfoot><tr><td align="left" colspan="2" valign="top">a: One hundred and thirty (130) patients received Lorazepam Injection. </td></tr><tr><td align="left" colspan="2" valign="top">b: Totals are not necessarily the sum of the individual study events because a patient may report two or more different study events in the same body system.

ign="left" colspan="2" valign="top">a: One hundred and thirty (130) patients received Lorazepam Injection. </td></tr><tr><td align="left" colspan="2" valign="top">b: Totals are not necessarily the sum of the individual study events because a patient may report two or more different study events in the same body system. </td></tr></tfoot><tbody><tr><td align="center" styleCode="Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Body System</content> Event </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Lorazepam Injection</content> (n=130)^a</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Any Study Event</content> (1 or more)^b</paragraph></td><td align="center" valign="middle"><paragraph>16 (12.3%) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Body as a whole</content></paragraph></td><td valign="middle"/></tr><tr><td valign="top"><paragraph> Infection </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Cardiovascular system</content></paragraph></td><td valign="middle"/></tr><tr><td valign="top"><paragraph> Hypotension </paragraph></td><td align="center" valign="middle"><paragraph>2 (1.5%) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Digestive system</content></paragraph></td><td valign="middle"/></tr><tr><td valign="top"><paragraph> Liver function tests abnormal </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph> Nausea </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph> Vomiting </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional</content></paragraph></td><td valign="middle"/></tr><tr><td valign="top"><paragraph> Acidosis </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Nervous system</content></paragraph></td><td valign="middle"/></tr><tr><td valign="top"><paragraph> Brain edema </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph> Coma </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph> Convulsion </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph> Somnolence </paragraph></td><td align="center" valign="middle"><paragraph>2 (1.5%) </paragraph></td></tr><tr><td valign="top"><paragraph> Thinking abnormal </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Respiratory system</content></paragraph></td><td valign="middle"/></tr><tr><td valign="top"><paragraph> Hyperventilation </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph> Hypoventilation </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph> Respiratory failure </paragraph></td><td align="center" valign="middle"><paragraph>2 (1.5%) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Terms not classifiable</content></paragraph></td><td valign="middle"/></tr><tr><td valign="top"><paragraph> Injection site reactio

"top"><paragraph> Respiratory failure </paragraph></td><td align="center" valign="middle"><paragraph>2 (1.5%) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Terms not classifiable</content></paragraph></td><td valign="middle"/></tr><tr><td valign="top"><paragraph> Injection site reactio n </paragraph></td><td align="center" valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Urogenital system</content></paragraph></td><td valign="middle"/></tr><tr><td styleCode="Botrule " valign="top"><paragraph> Cystitis </paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>1 (&lt;1%) </paragraph></td></tr></tbody></table> <table ID="_Reft2" width="100%"><caption>TABLE 2. NUMBER (%) OF STUDY EVENTS IN ACTIVE CONTROLLED CLINICAL TRIAL </caption><col width="52%"/><col width="23%"/><col width="24%"/><tfoot><tr><td align="left" colspan="3" valign="top">a: The number indicates the number of &#x201C;patient-episodes.&#x201D; Patient-episodes were used rather than &#x201C;patients&#x201D; because a total of 7 patients were reenrolled for the treatment of a second episode of status: 5 patients received Lorazepam Injection on two occasions that were far enough apart to establish the diagnosis of status epilepticus for each episode, and, using the same time criterion, 2 patients received diazepam on two occasions. </td></tr><tr><td align="left" colspan="3" valign="top">b: Totals are not necessarily the sum of the individual study events because a patient may report two or more different study events in the same body system.

ticus for each episode, and, using the same time criterion, 2 patients received diazepam on two occasions. </td></tr><tr><td align="left" colspan="3" valign="top">b: Totals are not necessarily the sum of the individual study events because a patient may report two or more different study events in the same body system. </td></tr></tfoot><tbody><tr><td align="center" styleCode="Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Body System</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Lorazepam Injection</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Diazepam</content></paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>Event </paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>(n=85)^a</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>(n=80)^a</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Any Study Event</content> (1 or more)^b</paragraph></td><td align="center" valign="top"><paragraph>14 (16.5%) </paragraph></td><td align="center" valign="top"><paragraph>11 (13.8%) </paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Body as a whole</content></paragraph></td></tr><tr><td valign="top"><paragraph> Headache </paragraph></td><td align="center" valign="top"><paragraph>1 ( 1.2%) </paragraph></td><td align="center" valign="top"><paragraph>1 (1.3%) </paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Cardiovascular system</content></paragraph></td></tr><tr><td valign="top"><paragraph> Hypotension </paragraph></td><td align="center" valign="top"><paragraph>2 (2.4%) </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Hemic and lymphatic system</content></paragraph></td></tr><tr><td valign="top"><paragraph> Hypochromic anemia </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td><td align="center" valign="top"><paragraph>1 (1.3%) </paragraph></td></tr><tr><td valign="top"><paragraph> Leukocytosis </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td><td align="center" valign="top"><paragraph>1 (1.3%) </paragraph></td></tr><tr><td valign="top"><paragraph> Thrombocythemia </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td><td align="center" valign="top"><paragraph>1 (1.3%) </paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Nervous system</content></paragraph></td></tr><tr><td valign="top"><paragraph> Coma </paragraph></td><td align="center" valign="top"><paragraph>1 (1.2 %) </paragraph></td><td align="center" valign="top"><paragraph>1 (1.3%) </paragraph></td></tr><tr><td valign="top"><paragraph> Somnolence </paragraph></td><td align="center" valign="top"><paragraph>3 (3.5%) </paragraph></td><td align="center" valign="top"><paragraph>3 (3.8%) </paragraph></td></tr><tr><td valign="top"><paragraph> Stupor </paragraph></td><td align="center" valign="top"><paragraph>1 (1.2%) </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Respiratory system</content></paragraph></td></tr><tr><td valign="top"><paragraph> Hypoventilation </paragraph></td><td align="center" valign="top"><paragraph>1 (1.2%) </paragraph></td><td align="center" valign="top"><paragraph>2 (2.5%) </paragraph></td></tr><tr><td valign="top"><paragraph> Apnea </paragraph></t

"bold">Respiratory system</content></paragraph></td></tr><tr><td valign="top"><paragraph> Hypoventilation </paragraph></td><td align="center" valign="top"><paragraph>1 (1.2%) </paragraph></td><td align="center" valign="top"><paragraph>2 (2.5%) </paragraph></td></tr><tr><td valign="top"><paragraph> Apnea </paragraph></t d><td align="center" valign="top"><paragraph>1 (1.2%) </paragraph></td><td align="center" valign="top"><paragraph>1 (1.3%) </paragraph></td></tr><tr><td valign="top"><paragraph> Respiratory failure </paragraph></td><td align="center" valign="top"><paragraph>2 (2.4%) </paragraph></td><td align="center" valign="top"><paragraph>1 (1.3%) </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph> Respiratory disorder </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1 (1.2%) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0 </paragraph></td></tr></tbody></table>

ph>1 (1.3%) </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph> Respiratory disorder </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1 (1.2%) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0 </paragraph></td></tr></tbody></table> <table width="100%"><col width="45%"/><col width="53%"/><tbody><tr><td styleCode="Toprule " valign="top"><paragraph><content styleCode="italics">BODY AS A WHOLE -</content></paragraph></td><td styleCode="Toprule " valign="top"><paragraph>Infrequent: asthenia, chills, headache, infection. </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">DIGESTIVE SYSTEM -</content></paragraph></td><td valign="top"><paragraph>Infrequent: abnormal liver function test, increased salivation, nausea, vomiting. </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">METABOLIC AND NUTRITIONAL -</content></paragraph></td><td valign="top"><paragraph>Infrequent: acidosis, alkaline phosphatase increased. </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">NERVOUS SYSTEM -</content></paragraph></td><td valign="top"><paragraph>Infrequent: agitation, ataxia, brain edema, coma, confusion, convulsion, hallucinations, myoclonus, stupor, thinking abnormal, tremor. </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">RESPIRATORY SYSTEM -</content></paragraph></td><td valign="top"><paragraph>Frequent: apnea; Infrequent: hyperventilation, hypoventilation, respiratory disorder. </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">TERMS NOT CLASSIFIABLE -</content></paragraph></td><td valign="top"><paragraph>Infrequent: injection site reaction. </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="italics">UROGENITAL SYSTEM -</content></paragraph></td><td styleCode="Botrule " valign="top"><paragraph>Infrequent: cystitis. </paragraph></td></tr></tbody></table>

DRUG ABUSE AND DEPENDENCE Controlled Substance Lorazepam Injection contains lorazepam, a Schedule IV controlled substance. Abuse Lorazepam 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). Dependence PHYSICAL DEPENDENCE AFTER USE OF LORAZEPAM INJECTION MORE FREQUENTLY THAN RECOMMENDED Lorazepam 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 Lorazepam Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ) , if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction 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 ).

e-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 Lorazepam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Lorazepam 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 Tolerance to Lorazepam 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.

Abuse Lorazepam 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).

Dependence PHYSICAL DEPENDENCE AFTER USE OF LORAZEPAM INJECTION MORE FREQUENTLY THAN RECOMMENDED Lorazepam 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 Lorazepam Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ) , if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction 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 Lorazepam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Lorazepam 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 Tolerance to Lorazepam 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.

OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS, Abuse, Misuse, and Addiction ). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil Injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

DOSAGE AND ADMINISTRATION NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS, Pediatric Use ). Lorazepam Injection must never be used without individualization of dosage particularly when used with other medications capable of producing central-nervous-system depression. EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY SHOULD BE IMMEDIATELY AVAILABLE PRIOR TO INTRAVENOUS ADMINISTRATION OF LORAZEPAM (see WARNINGS ). Status Epilepticus GENERAL ADVICE Status epilepticus is a potentially life-threatening condition associated with a high risk of permanent neurological impairment, if inadequately treated. The treatment of status, however, requires far more than the administration of an anticonvulsant agent. It involves observation and management of all parameters critical to maintaining vital function and the capacity to provide support of those functions as required. Ventilatory support must be readily available. The use of benzodiazepines, like Lorazepam Injection, is ordinarily only an initial step of a complex and sustained intervention which may require additional interventions, (e.g., concomitant intravenous administration of phenytoin). Because status epilepticus may result from a correctable acute cause such as hypoglycemia, hyponatremia, or other metabolic or toxic derangement, such an abnormality must be immediately sought and corrected. Furthermore, patients who are susceptible to further seizure episodes should receive adequate maintenance antiepileptic therapy. Any healthcare professional who intends to treat a patient with status epilepticus should be familiar with this package insert and the pertinent medical literature concerning current concepts for the treatment of status epilepticus. A comprehensive review of the considerations critical to the informed and prudent management of status epilepticus cannot be provided in drug product labeling. The archival medical literature contains many informative references on the management of status epilepticus, among them the report of the working group on status epilepticus of the Epilepsy Foundation of America “Treatment of Convulsive Status Epilepticus” (JAMA 1993; 270:854-859). As noted in the report just cited, it may be useful to consult with a neurologist if a patient fails to respond (e.g., fails to regain consciousness). INTRAVENOUS INJECTION For the treatment of status epilepticus, the usual recommended dose of Lorazepam Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures cease, no additional Lorazepam Injection is required. If seizures continue or recur after a 10- to 15-minute observation period, an additional 4 mg intravenous dose may be slowly administered. Experience with further doses of Lorazepam Injection is very limited. The usual precautions in treating status epilepticus should be employed. An intravenous infusion should be started, vital signs should be monitored, an unobstructed airway should be maintained, and artificial ventilation equipment should be available. INTRAMUSCULAR INJECTION Intramuscular Lorazepam Injection is not preferred in the treatment of status epilepticus because therapeutic lorazepam levels may not be reached as quickly as with intravenous administration. However, when an intravenous port is not available, the intramuscular route may prove useful (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ). PEDIATRIC The safety of Lorazepam Injection in pediatric patients has not been established.

levels may not be reached as quickly as with intravenous administration. However, when an intravenous port is not available, the intramuscular route may prove useful (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ). PEDIATRIC The safety of Lorazepam Injection in pediatric patients has not been established. Preanesthetic INTRAMUSCULAR INJECTION For the designated indications as a premedicant, the usual recommended dose of lorazepam for intramuscular injection is 0.05 mg/kg up to a maximum of 4 mg. As with all premedicant drugs, the dose should be individualized (see CLINICAL PHARMACOLOGY , WARNINGS , PRECAUTIONS, and ADVERSE REACTIONS ). Doses of other central-nervous-system-depressant drugs ordinarily should be reduced (see PRECAUTIONS ). For optimum effect, measured as lack of recall, intramuscular lorazepam should be administered at least 2 hours before the anticipated operative procedure. Narcotic analgesics should be administered at their usual preoperative time. There are insufficient data to support efficacy or make dosage recommendations for intramuscular lorazepam in patients less than 18 years of age; therefore, such use is not recommended. INTRAVENOUS INJECTION For the primary purpose of sedation and relief of anxiety, the usual recommended initial dose of lorazepam for intravenous injection is 2 mg total, or 0.02 mg/lb (0.044 mg/kg), whichever is smaller. This dose will suffice for sedating most adult patients and ordinarily should not be exceeded in patients over 50 years of age. In those patients in whom a greater likelihood of lack of recall for perioperative events would be beneficial, larger doses as high as 0.05 mg/kg up to a total of 4 mg may be administered (see CLINICAL PHARMACOLOGY , WARNINGS , PRECAUTIONS, and ADVERSE REACTIONS ). Doses of other injectable central-nervous-system-depressant drugs ordinarily should be reduced (see PRECAUTIONS ). For optimum effect, measured as lack of recall, intravenous lorazepam should be administered 15 to 20 minutes before the anticipated operative procedure. There are insufficient data to support efficacy or make dosage recommendations for intravenous lorazepam in patients less than 18 years of age; therefore, such use is not recommended. Dose Administration in Special Populations ELDERLY PATIENTS AND PATIENTS WITH HEPATIC DISEASE No dosage adjustments are needed in elderly patients and in patients with hepatic disease. PATIENTS WITH RENAL DISEASE For acute dose administration, adjustment is not needed for patients with renal disease. However, in patients with renal disease, caution should be exercised if frequent doses are given over relatively short periods of time (see CLINICAL PHARMACOLOGY ). DOSE ADJUSTMENT DUE TO DRUG INTERACTIONS The dose of Lorazepam Injection should be reduced by 50% when coadministered with probenecid or valproate (see PRECAUTIONS, Drug Interactions ). It may be necessary to increase the dose of Lorazepam Injection in female patients who are concomitantly taking oral contraceptives. Administration When given intramuscularly, Lorazepam Injection, undiluted, should be injected deep in the muscle mass. Injectable Lorazepam can be used with atropine sulfate, narcotic analgesics, other parenterally used analgesics, commonly used anesthetics, and muscle relaxants. Immediately prior to intravenous use, Lorazepam Injection must be diluted with an equal volume of compatible solution. Contents should be mixed thoroughly by gently inverting the container repeatedly until a homogenous solution results. Do not shake vigorously, as this will result in air entrapment. When properly diluted, the drug may be injected directly into a vein or into the tubing of an existing intravenous infusion. The rate of injection should not exceed 2 mg per minute.

ly inverting the container repeatedly until a homogenous solution results. Do not shake vigorously, as this will result in air entrapment. When properly diluted, the drug may be injected directly into a vein or into the tubing of an existing intravenous infusion. The rate of injection should not exceed 2 mg per minute. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if solution is discolored or contains a precipitate. Discard unused portion. Lorazepam Injection is compatible for dilution purposes with the following solutions: Sterile Water for Injection, USP; Sodium Chloride Injection, USP; 5% Dextrose Injection, USP.

HOW SUPPLIED Lorazepam Injection, USP is available as: Product Code Unit of Sale Strength (Concentration) Each PRX368302 NDC 65219-368-24 Unit of 25 2 mg/mL NDC 65219-368-14 1 mL Single-Dose Vial For Intramuscular or Intravenous injection. Store in a refrigerator. PROTECT FROM LIGHT. Use carton to protect contents from light. The container closure is not made with natural rubber latex.

<table width="100%"><col width="19%"/><col width="26%"/><col width="18%"/><col width="34%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Product Code</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Strength</content> <content styleCode="bold">(Concentration)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Each</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>PRX368302</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC 65219-368-24 Unit of 25 </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2 mg/mL</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC 65219-368-14 1 mL Single-Dose Vial </paragraph></td></tr></tbody></table>

ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY Published studies in animals demonstrate that the use of anesthetic agents 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 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 an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but 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 neonates and young children who require procedures against the potential risks suggested by the nonclinical data (see WARNINGS , Pediatric Neurotoxicity ; PRECAUTIONS , Pregnancy , Pediatric Use ). To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For Product Inquiry call 1-800-551-7176. PREMIERProRx ® is a registered trademark of Premier Healthcare Alliance, L.P., used under license. Manufactured by: Fresenius Kabi Lake Zurich, IL 60047 www.fresenius-kabi.com/us 451865 Issued: December 2025 loraz-img-02.jpg

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS ). The use of benzodiazepines, including lorazepam tablets, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing lorazepam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS ). The continued use of benzodiazepines, including lorazepam tablets may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of lorazepam tablets after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam tablets or reduce the dosage ( DOSAGE AND ADMINISTRATION and WARNINGS ).

DESCRIPTION Lorazepam, USP, an antianxiety agent, has the chemical formula, 7-chloro-5-( o -chlorophenyl)-1,3-dihydro-3-hydroxy-2 H -1,4-benzodiazepin-2-one: It is a nearly white powder almost insoluble in water. Each lorazepam tablet, to be taken orally, contains 0.5 mg, 1 mg, or 2 mg of lorazepam, USP. The inactive ingredients present are lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium.

CLINICAL PHARMACOLOGY Studies in healthy volunteers show that in single high doses lorazepam has a tranquilizing action on the central nervous system with no appreciable effect on the respiratory or cardiovascular systems. Lorazepam is readily absorbed with an absolute bioavailability of 90%. Peak concentrations in plasma occur approximately 2 hours following administration. The peak plasma level of lorazepam from a 2 mg dose is approximately 20 ng/mL. The mean half-life of unconjugated lorazepam in human plasma is about 12 hours and for its major metabolite, lorazepam glucuronide, about 18 hours. At clinically relevant concentrations, lorazepam is approximately 85% bound to plasma proteins. Lorazepam is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepam glucuronide has no demonstrable central nervous system (CNS) activity in animals. The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to 6 months. Studies comparing young and elderly subjects have shown that advancing age does not have a significant effect on the pharmacokinetics of lorazepam. However, in one study involving single intravenous doses of 1.5 to 3 mg of lorazepam injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age.

INDICATIONS AND USAGE Lorazepam tablets are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of lorazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

WARNINGS Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including lorazepam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe lorazepam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of lorazepam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking lorazepam, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when lorazepam is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see PRECAUTIONS: Drug Interactions ). Abuse, Misuse, and Addiction The use of benzodiazepines, including lorazepam, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse ). Before prescribing lorazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of lorazepam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of lorazepam along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Lorazepam Tablets ). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines, including lorazepam, may lead to clinically significant physical dependence.

withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines, including lorazepam, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of lorazepam after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: Dependence ) . Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE: Dependence ). Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam. 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 PRECAUTIONS: Drug Interactions ). 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. Neonatal Sedation and Withdrawal Syndrome Use of lorazepam tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS: Pregnancy ). Monitor neonates exposed to lorazepam during pregnancy or labor for signs of sedation and monitor neonates exposed to lorazepam during pregnancy for signs of withdrawal; manage these neonates accordingly.

PRECAUTIONS In patients with depression, a possibility for suicide should be borne in mind; benzodiazepines should not be used in such patients without adequate antidepressant therapy. Lorazepam should be used with caution in patients with compromised respiratory function (e.g., COPD, sleep apnea syndrome). Elderly or debilitated patients may be more susceptible to the sedative effects of lorazepam. Therefore, these patients should be monitored frequently and have their dosage adjusted carefully according to patient response; the initial dosage should not exceed 2 mg. Paradoxical reactions have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued. The usual precautions for treating patients with impaired renal or hepatic function should be observed. As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy; therefore, lorazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy. Dosage for patients with severe hepatic insufficiency should be adjusted carefully according to patient response; lower doses may be sufficient in such patients. In patients where gastrointestinal or cardiovascular disorders coexist with anxiety, it should be noted that lorazepam has not been shown to be of significant benefit in treating the gastrointestinal or cardiovascular component. Esophageal dilation occurred in rats treated with lorazepam for more than 1 year at 6 mg/kg/day. The no- effect dose was 1.25 mg/kg/day (approximately 6 times the maximum human therapeutic dose of 10 mg/day). The effect was reversible only when the treatment was withdrawn within 2 months of first observation of the phenomenon. The clinical significance of this is unknown. However, use of lorazepam for prolonged periods and in geriatric patients requires caution, and there should be frequent monitoring for symptoms of upper GI disease. Safety and effectiveness of lorazepam in children of less than 12 years have not been established. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when lorazepam is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use of Opioids and PRECAUTIONS: Drug Interactions ). Abuse, Misuse, and Addiction Inform patients that the use of lorazepam even at recommended doses, 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: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ).

sics), 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: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ). Withdrawal Reactions Inform patients that the continued use of lorazepam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of lorazepam 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. Instruct patients that discontinuation or dosage reduction of lorazepam may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ). Pregnancy Advise pregnant females that use of lorazepam tablets late in pregnancy 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 during pregnancy (see PRECAUTIONS: Pregnancy ). Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using lorazepam tablets 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 ). Essential Laboratory Tests Some patients on lorazepam have developed leukopenia, and some have had elevations of LDH. As with other benzodiazepines, periodic blood counts and liver function tests are recommended for patients on long-term therapy. Drug Interactions 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. The benzodiazepines, including lorazepam, produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics. Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest. Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate. Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation.

cid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation. Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam. Carcinogenesis and Mutagenesis No evidence of carcinogenic potential emerged in rats during an 18-month study with lorazepam. No studies regarding mutagenesis have been performed. Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including lorazepam tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/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 Syndrome and Clinical 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 recognized 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 during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to lorazepam during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ). Data 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 and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses. Nursing Mothers Risk Summary 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.

on and increased fetal loss in rabbits which was not seen at lower doses. Nursing Mothers Risk Summary 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 tablets and any potential adverse effects on the breastfed infant from lorazepam or from the underlying maternal condition. Clinical Considerations Infants exposed to lorazepam through breast milk should be monitored for sedation, poor feeding and poor weight gain. Geriatric Use Clinical studies of lorazepam generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age (see ADVERSE REACTIONS ). Age does not appear to have a 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, and lower doses may be sufficient in these patients (see DOSAGE AND ADMINISTRATION ).

Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when lorazepam is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use of Opioids and PRECAUTIONS: Drug Interactions ). Abuse, Misuse, and Addiction Inform patients that the use of lorazepam even at recommended doses, 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: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ). Withdrawal Reactions Inform patients that the continued use of lorazepam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of lorazepam 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. Instruct patients that discontinuation or dosage reduction of lorazepam may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ). Pregnancy Advise pregnant females that use of lorazepam tablets late in pregnancy 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 during pregnancy (see PRECAUTIONS: Pregnancy ). Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using lorazepam tablets 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 ).

Essential Laboratory Tests Some patients on lorazepam have developed leukopenia, and some have had elevations of LDH. As with other benzodiazepines, periodic blood counts and liver function tests are recommended for patients on long-term therapy.

Drug Interactions 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. The benzodiazepines, including lorazepam, produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics. Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest. Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate. Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation. Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including lorazepam tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/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 Syndrome and Clinical 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 recognized 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 during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to lorazepam during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ). Data 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 and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses.

Nursing Mothers Risk Summary 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 tablets and any potential adverse effects on the breastfed infant from lorazepam or from the underlying maternal condition. Clinical Considerations Infants exposed to lorazepam through breast milk should be monitored for sedation, poor feeding and poor weight gain.

Geriatric Use Clinical studies of lorazepam generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age (see ADVERSE REACTIONS ). Age does not appear to have a 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, and lower doses may be sufficient in these patients (see DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS Most adverse reactions to benzodiazepines, including CNS effects and respiratory depression, are dose dependent, with more severe effects occurring with high doses. In a sample of about 3500 patients treated for anxiety, the most frequent adverse reaction to lorazepam was sedation (15.9%), followed by dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). The incidence of sedation and unsteadiness increased with age. Other adverse reactions to benzodiazepines, including lorazepam are fatigue, drowsiness, amnesia, memory impairment, confusion, disorientation, depression, unmasking of depression, disinhibition, euphoria, suicidal ideation/attempt, ataxia, asthenia, extrapyramidal symptoms, convulsions/seizures, tremor, vertigo, eye function/visual disturbance (including diplopia and blurred vision), dysarthria/slurred speech, change in libido, impotence, decreased orgasm; headache, coma; respiratory depression, apnea, worsening of sleep apnea, worsening of obstructive pulmonary disease; gastrointestinal symptoms including nausea, change in appetite, constipation, jaundice, increase in bilirubin, increase in liver transaminases, increase in alkaline phosphatase; hypersensitivity reactions, anaphylactoid reactions; dermatological symptoms, allergic skin reactions, alopecia; syndrome of inappropriate antidiuretic hormone (SIADH), hyponatremia; thrombocytopenia, agranulocytosis, pancytopenia; hypothermia; and autonomic manifestations. Paradoxical reactions, including anxiety, excitation, agitation, hostility, aggression, rage, sleep disturbances/insomnia, sexual arousal, and hallucinations may occur. Small decreases in blood pressure and hypotension may occur but are usually not clinically significant, probably being related to the relief of anxiety produced by lorazepam. To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG ABUSE AND DEPENDENCE Controlled Substance Lorazepam tablets contain lorazepam, a Schedule IV controlled substance. Abuse Lorazepam tablets are 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 healthcare 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). Dependence Physical Dependence Lorazepam tablets may produce physical dependence from continued therapy. 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. Abrupt discontinuation or rapid dosage reduction of benzodiazepines 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 ) . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam tablets or reduce the dosage (see D OSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of lorazepam tablets and WARNINGS ) .

ose who have had longer durations of use (see WARNINGS: Dependence and Withdrawal Reactions ) . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam tablets or reduce the dosage (see D OSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of lorazepam tablets and WARNINGS ) . 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 Tolerance to lorazepam tablets may develop from continued therapy. 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 lorazepam tablets may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DOSAGE AND ADMINISTRATION Lorazepam tablets are administered orally. For optimal results, dose, frequency of administration, and duration of therapy should be individualized according to patient response. To facilitate this, 0.5 mg, 1 mg, and 2 mg tablets are available. The usual range is 2 to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the daily dosage may vary from 1 to 10 mg/day. For anxiety, most patients require an initial dose of 2 to 3 mg/day given two times a day or three times a day. For insomnia due to anxiety or transient situational stress, a single daily dose of 2 to 4 mg may be given, usually at bedtime. For elderly or debilitated patients, an initial dosage of 1 to 2 mg/day in divided doses is recommended, to be adjusted as needed and tolerated. The dosage of lorazepam tablets 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. Discontinuation or Dosage Reduction of Lorazepam Tablets To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam tablets or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence ).

HOW SUPPLIED Lorazepam Tablets, USP are available in the following dosage strengths: 0.5 mg: white to off-white, round flat faced beveled edge tablet, debossed with TV over 0.5 on one side and 5R on the other side, supplied in bottles of 100 (NDC 0093-3425-01), 500 (NDC 0093-3425-05) and 1000 (NDC 0093-3425-10). 1 mg: white to off-white, scored on both sides, round flat faced beveled edge tablet, debossed with TV over 1 on one side and 1 over R on the other side, supplied in bottles of 100 (NDC 0093-3426-01), 500 (NDC 0093-3426-05) and 1000 (NDC 0093-3426-10). 2 mg: white to off-white, scored on both sides, round flat faced beveled edge tablet, debossed with TV over 2 on one side and 2 over R on the other side, supplied in bottles of 100 (NDC 0093-3427-01), 500 (NDC 0093-3427-05) and 1000 (NDC 0093-3427-10). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP. Dispense with Medication Guide available at: www.tevausa.com/medguides Manufactured In Czech Republic By: Teva Czech Industries, s.r.o. Opava-Komarov, Czech Republic Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. D 6/2023

Dispense with Medication Guide available at: www.tevausa.com/medguides MEDICATION GUIDE Lorazepam (lor azʹ e pam) Tablets C-IV What is the most important information I should know about lorazepam tablets? Lorazepam is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens: shallow or slowed breathing breathing stops (which may lead to the heart stopping) excessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking lorazepam tablets with opioids affects you. Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines including lorazepam tablets which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including lorazepam tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take lorazepam tablets exactly as prescribed by your healthcare provider. Take lorazepam tablets exactly as your healthcare provider prescribed. Do not share your lorazepam tablets with other people. Keep lorazepam tablets in a safe place and away from children. Physical dependence and withdrawal reactions. Lorazepam tablets can cause physical dependence and withdrawal reactions. Do not suddenly stop taking lorazepam tablets . Stopping lorazepam tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. Do not take more lorazepam tablets than prescribed or take lorazepam tablets for longer than prescribed. What are lorazepam tablets? Lorazepam tablets are a prescription medicine used: º to treat anxiety disorders º for the short-term relief of the symptoms of anxiety or anxiety that can happen with symptoms of depression Lorazepam tablets are a federal controlled substance (CIV) because they contain lorazepam that can be abused or lead to dependence. Keep lorazepam tablets in a safe place to prevent misuse and abuse.

disorders º for the short-term relief of the symptoms of anxiety or anxiety that can happen with symptoms of depression Lorazepam tablets are a federal controlled substance (CIV) because they contain lorazepam that can be abused or lead to dependence. Keep lorazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away lorazepam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. It is not known if lorazepam tablets are safe and effective for use in children less than 12 years of age. It is not known if lorazepam tablets are safe and effective for use for longer than 4 months. Do not take lorazepam tablets if you: are allergic to lorazepam, other benzodiazepines, or any of the ingredients in lorazepam tablets. See the end of this Medication Guide for a complete list of ingredients in lorazepam tablets. Before you take lorazepam tablets, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems, or suicidal thoughts or behavior have a history of drug or alcohol abuse or addiction have lung disease or breathing problems (such as COPD, sleep apnea syndrome) have liver or kidney problems have or have had seizures are pregnant or plan to become pregnant. Taking lorazepam tablets late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems). Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with lorazepam tablets. There is a pregnancy registry for women who take lorazepam tablets during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with lorazepam tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/. are breastfeeding or plan to breastfeed. Lorazepam passes into your breast milk. Breastfeeding during treatment with lorazepam tablets may cause your baby to have sleepiness, feeding problems, and decreased weight gain. Talk to your healthcare provider about the best way to feed your baby if you take lorazepam tablets. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking lorazepam tablets with certain other medicines can cause side effects or affect how well lorazepam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. How should I take lorazepam tablets? Take lorazepam tablets exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many lorazepam tablets to take and when to take them. If you take too many lorazepam tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of lorazepam tablets? Lorazepam tablets may cause serious side effects, including: See “What is the most important information I should know about lorazepam tablets?” Lorazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how lorazepam tablets affects you.

de effects, including: See “What is the most important information I should know about lorazepam tablets?” Lorazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how lorazepam tablets affects you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking lorazepam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, lorazepam tablets may make your sleepiness or dizziness much worse. Depression. Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam tablets. The most common side effects of lorazepam tablets include: sedation • dizziness weakness • unsteadiness These are not all the possible side effects of lorazepam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store lorazepam tablets? Store lorazepam tablets in a tightly closed container at 68° to 77°F (20° to 25°C). Keep lorazepam tablets and all medicines out of the reach of children. General information about the safe and effective use of lorazepam tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use lorazepam tablets for a condition for which it was not prescribed. Do not give lorazepam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about lorazepam tablets that is written for health professionals. What are the ingredients in lorazepam tablets? Active ingredient: lorazepam Inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium Manufactured In Czech Republic By: Teva Czech Industries, s.r.o., Opava-Komarov, Czech Republic Manufactured For: Teva Pharmaceuticals, Parsippany, NJ 07054 For more information, call Teva at 1-888-838-2872. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. D 6/2023

<table width="778.2px"><col/><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="bottom"><paragraph><content styleCode="bold">MEDICATION GUIDE </content><content styleCode="bold">Lorazepam (lor az&#x2B9; e pam) </content><content styleCode="bold">Tablets C-IV</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph><content styleCode="bold">What is the most important information I should know about lorazepam tablets?</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Lorazepam is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. </content>Get emergency help right away if any of the following happens: </item><item>shallow or slowed breathing</item><item>breathing stops (which may lead to the heart stopping)</item><item>excessive sleepiness (sedation)</item></list><paragraph>Do not drive or operate heavy machinery until you know how taking lorazepam tablets with opioids affects you.</paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Risk of abuse, misuse, and addiction.</content>There is a risk of abuse, misuse, and addiction with benzodiazepines including lorazepam tablets which can lead to overdose and serious side effects including coma and death. <list listType="unordered" styleCode="Circle"><item><content styleCode="bold">Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including</content>lorazepam tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.</content></item><item><content styleCode="bold">You can develop an addiction even if you take</content><content styleCode="bold">lorazepam tablets exactly as prescribed by your healthcare provider.</content></item><item><content styleCode="bold">Take</content><content styleCode="bold">lorazepam tablets exactly as your healthcare provider prescribed.</content></item><item>Do not share your lorazepam tablets with other people.</item><item>Keep lorazepam tablets in a safe place and away from children.</item></list></item><item><content styleCode="bold">Physical dependence and withdrawal reactions.</content>Lorazepam tablets can cause physical dependence and withdrawal reactions. </item></list><list listType="unordered" styleCode="Circle"><item><content styleCode="bold">Do not suddenly stop taking</content>lorazepam tablets <content styleCode="bold">.</content>Stopping lorazepam tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions.

fe-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms.</content></item><item><content styleCode="bold">Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months,</content>including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. </item><item><content styleCode="bold">Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.</content></item></list><list listType="unordered"><item><content styleCode="bold">Do not take more lorazepam tablets than prescribed or take lorazepam tablets for longer than prescribed.</content></item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are lorazepam tablets?</content></paragraph><list listType="unordered"><item>Lorazepam tablets are a prescription medicine used: &#xBA; to treat anxiety disorders &#xBA; for the short-term relief of the symptoms of anxiety or anxiety that can happen with symptoms of depression </item><item><content styleCode="bold">Lorazepam tablets are a federal controlled substance (CIV) because they <content styleCode="bold">contain lorazepam that </content>can be abused or lead to dependence. </content>Keep lorazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away lorazepam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. </item><item>It is not known if lorazepam tablets are safe and effective for use in children less than 12 years of age.</item><item>It is not known if lorazepam tablets are safe and effective for use for longer than 4 months.</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Do not take lorazepam tablets if you:</content></paragraph><list listType="unordered"><item>are allergic to lorazepam, other benzodiazepines, or any of the ingredients in lorazepam tablets. See the end of this Medication Guide for a complete list of ingredients in lorazepam tablets.</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Before you take lorazepam tablets, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered" styleCode="Disc"><item>have or have had depression, mood problems, or suicidal thoughts or behavior</item><item>have a history of drug or alcohol abuse or addiction</item><item>have lung disease or breathing problems (such as COPD, sleep apnea syndrome)</item><item>have liver or kidney problems</item><item>have or have had seizures</item><item>are pregnant or plan to become pregnant.

or suicidal thoughts or behavior</item><item>have a history of drug or alcohol abuse or addiction</item><item>have lung disease or breathing problems (such as COPD, sleep apnea syndrome)</item><item>have liver or kidney problems</item><item>have or have had seizures</item><item>are pregnant or plan to become pregnant. <list listType="unordered" styleCode="Disc"><item>Taking lorazepam tablets late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).</item><item>Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with lorazepam tablets.</item><item>There is a pregnancy registry for women who take lorazepam tablets during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with lorazepam tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/. </item></list></item><item>are breastfeeding or plan to breastfeed. Lorazepam passes into your breast milk. <list listType="unordered" styleCode="Disc"><item>Breastfeeding during treatment with lorazepam tablets may cause your baby to have sleepiness, feeding problems, and decreased weight gain.</item><item>Talk to your healthcare provider about the best way to feed your baby if you take lorazepam tablets.</item></list></item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. </paragraph><paragraph>Taking lorazepam tablets with certain other medicines can cause side effects or affect how well lorazepam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How should I take lorazepam tablets? </content></paragraph><list listType="unordered"><item>Take lorazepam tablets exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many lorazepam tablets to take and when to take them.</item><item>If you take too many lorazepam tablets, call your healthcare provider or go to the nearest hospital emergency room right away.</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the possible side effects of lorazepam tablets?</content></paragraph><paragraph><content styleCode="bold">Lorazepam tablets may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">See &#x201C;What is the most important information I should know about lorazepam tablets?&#x201D;</content></item><item><content styleCode="bold"><content styleCode="bold">Lorazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills.

rdered" styleCode="Disc"><item><content styleCode="bold">See &#x201C;What is the most important information I should know about lorazepam tablets?&#x201D;</content></item><item><content styleCode="bold"><content styleCode="bold">Lorazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. </content></content></item></list><list listType="unordered" styleCode="Circle"><item>Do not drive, operate heavy machinery, or do other dangerous activities until you know how lorazepam tablets affects you.</item><item><content styleCode="bold"><content styleCode="bold"><content styleCode="bold">Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking</content><content styleCode="bold">lorazepam tablets without first talking to your healthcare provider.</content></content></content>When taken with alcohol or drugs that cause sleepiness or dizziness, lorazepam tablets may make your sleepiness or dizziness much worse. </item></list><list listType="unordered"><item><content styleCode="bold">Depression.</content>Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam tablets. </item></list><paragraph><content styleCode="bold">The most common side effects of lorazepam tablets include:</content></paragraph><list listType="unordered"><item>sedation &#x2022; dizziness</item></list><list listType="unordered" styleCode="Disc"><item>weakness &#x2022; unsteadiness</item></list><paragraph>These are not all the possible side effects of lorazepam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">How should I store lorazepam tablets?</content><list listType="unordered" styleCode="Disc"><item>Store lorazepam tablets in a tightly closed container at 68&#xB0; to 77&#xB0;F (20&#xB0; to 25&#xB0;C).</item><item><content styleCode="bold">Keep lorazepam tablets and all medicines out of the reach of children.</content></item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">General information about the safe and effective use of lorazepam tablets </content>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use lorazepam tablets for a condition for which it was not prescribed. Do not give lorazepam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about lorazepam tablets that is written for health professionals. </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">What are the ingredients in lorazepam tablets?</content><paragraph><content styleCode="bold">Active ingredient:</content>lorazepam </paragraph><content styleCode="bold">Inactive ingredients:</content>lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Manufactured In Czech Republic By: <content styleCode="bold">Teva Czech Industries, s.r.o., </content>Opava-Komarov, Czech Republic Manufactured For: <content styleCode="bold">Teva Pharmaceuticals, </content>Parsippany, NJ 07054 For more information, call Teva at 1-888-838-2872. </paragraph></td></tr></tbody></table>

DESCRIPTION Lorazepam, USP, an antianxiety agent, has the chemical formula, 7-chloro-5-( o -chlorophenyl)-1,3-dihydro-3-hydroxy-2 H -1,4-benzodiazepin-2-one: It is a nearly white powder almost insoluble in water. Each lorazepam tablet, to be taken orally, contains 0.5 mg, 1 mg, or 2 mg of lorazepam, USP. The inactive ingredients present are lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium. 1

sics), 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: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ). Withdrawal Reactions Inform patients that the continued use of lorazepam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of lorazepam 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. Instruct patients that discontinuation or dosage reduction of lorazepam may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ). Pregnancy Advise pregnant females that use of lorazepam tablets late in pregnancy 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 during pregnancy (see PRECAUTIONS: Pregnancy ). Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using lorazepam tablets 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 ). Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 Essential Laboratory Tests Some patients on lorazepam have developed leukopenia, and some have had elevations of LDH. As with other benzodiazepines, periodic blood counts and liver function tests are recommended for patients on long-term therapy. Drug Interactions 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. The benzodiazepines, including lorazepam, produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics. Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest. Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate. Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid.

mately 50% when coadministered with valproate. Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation. Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam. Carcinogenesis and Mutagenesis No evidence of carcinogenic potential emerged in rats during an 18-month study with lorazepam. No studies regarding mutagenesis have been performed. Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including lorazepam tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/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 Syndrome and Clinical 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 recognized 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 during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to lorazepam during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ). Data 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 and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses. Nursing Mothers Risk Summary 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.

40 mg/kg and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses. Nursing Mothers Risk Summary 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 tablets and any potential adverse effects on the breastfed infant from lorazepam or from the underlying maternal condition. Clinical Considerations Infants exposed to lorazepam through breast milk should be monitored for sedation, poor feeding and poor weight gain. Geriatric Use Clinical studies of lorazepam generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age (see ADVERSE REACTIONS ). Age does not appear to have a 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, and lower doses may be sufficient in these patients (see DOSAGE AND ADMINISTRATION ).

Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when lorazepam is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use of Opioids and PRECAUTIONS: Drug Interactions ). Abuse, Misuse, and Addiction Inform patients that the use of lorazepam even at recommended doses, 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: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ). Withdrawal Reactions Inform patients that the continued use of lorazepam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of lorazepam 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. Instruct patients that discontinuation or dosage reduction of lorazepam may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ). Pregnancy Advise pregnant females that use of lorazepam tablets late in pregnancy 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 during pregnancy (see PRECAUTIONS: Pregnancy ). Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using lorazepam tablets 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 ). Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

HOW SUPPLIED Lorazepam Tablets, USP are available in the following dosage strengths: 1 mg: white to off-white, scored on both sides, round flat faced beveled edge tablet, debossed with TV over 1 on one side and 1 over R on the other side, supplied in NDC: 70518-3423-00 NDC: 70518-3423-01 NDC: 70518-3423-02 NDC: 70518-3423-03 NDC: 70518-3423-04 NDC: 70518-3423-05 PACKAGING: 30 in 1 BLISTER PACK PACKAGING: 30 In 1 BLISTER PACK PACKAGING: 100 in 1 BOX PACKAGING: 1 in 1 POUCH PACKAGING: 100 in 1 BOX PACKAGING: 1 in 1 POUCH Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

MEDICATION GUIDE Lorazepam (lor azʹ e pam) Tablets C-IV What is the most important information I should know about lorazepam tablets? Lorazepam is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens: shallow or slowed breathing breathing stops (which may lead to the heart stopping) excessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking lorazepam tablets with opioids affects you. Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines including lorazepam tablets which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including lorazepam tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take lorazepam tablets exactly as prescribed by your healthcare provider. Take lorazepam tablets exactly as your healthcare provider prescribed. Do not share your lorazepam tablets with other people. Keep lorazepam tablets in a safe place and away from children. Physical dependence and withdrawal reactions. Lorazepam tablets can cause physical dependence and withdrawal reactions. Do not suddenly stop taking lorazepam tablets . Stopping lorazepam tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. Do not take more lorazepam tablets than prescribed or take lorazepam tablets for longer than prescribed. What are lorazepam tablets? Lorazepam tablets are a prescription medicine used: º to treat anxiety disorders º for the short-term relief of the symptoms of anxiety or anxiety that can happen with symptoms of depression Lorazepam tablets are a federal controlled substance (CIV) because they contain lorazepam that can be abused or lead to dependence. Keep lorazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away lorazepam tablets may harm others, and is against the law.

can happen with symptoms of depression Lorazepam tablets are a federal controlled substance (CIV) because they contain lorazepam that can be abused or lead to dependence. Keep lorazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away lorazepam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. It is not known if lorazepam tablets are safe and effective for use in children less than 12 years of age. It is not known if lorazepam tablets are safe and effective for use for longer than 4 months. Do not take lorazepam tablets if you: are allergic to lorazepam, other benzodiazepines, or any of the ingredients in lorazepam tablets. See the end of this Medication Guide for a complete list of ingredients in lorazepam tablets. Before you take lorazepam tablets, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems, or suicidal thoughts or behavior have a history of drug or alcohol abuse or addiction have lung disease or breathing problems (such as COPD, sleep apnea syndrome) have liver or kidney problems have or have had seizures are pregnant or plan to become pregnant. Taking lorazepam tablets late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems). Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with lorazepam tablets. There is a pregnancy registry for women who take lorazepam tablets during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with lorazepam tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/. are breastfeeding or plan to breastfeed. Lorazepam passes into your breast milk. Breastfeeding during treatment with lorazepam tablets may cause your baby to have sleepiness, feeding problems, and decreased weight gain. Talk to your healthcare provider about the best way to feed your baby if you take lorazepam tablets. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking lorazepam tablets with certain other medicines can cause side effects or affect how well lorazepam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. How should I take lorazepam tablets? Take lorazepam tablets exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many lorazepam tablets to take and when to take them. If you take too many lorazepam tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of lorazepam tablets? Lorazepam tablets may cause serious side effects, including: See “What is the most important information I should know about lorazepam tablets?” Lorazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how lorazepam tablets affects you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking lorazepam tablets without first talking to your healthcare provider.

can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how lorazepam tablets affects you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking lorazepam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, lorazepam tablets may make your sleepiness or dizziness much worse. Depression. Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam tablets. The most common side effects of lorazepam tablets include: sedation • dizziness weakness • unsteadiness These are not all the possible side effects of lorazepam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store lorazepam tablets? Store lorazepam tablets in a tightly closed container at 68° to 77°F (20° to 25°C). Keep lorazepam tablets and all medicines out of the reach of children. General information about the safe and effective use of lorazepam tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use lorazepam tablets for a condition for which it was not prescribed. Do not give lorazepam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about lorazepam tablets that is written for health professionals. What are the ingredients in lorazepam tablets? Active ingredient: lorazepam Inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. D 6/2023 Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

<table width="778.2px"><colgroup><col/></colgroup><tbody><tr><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph><content styleCode="bold">MEDICATION GUIDE </content> <content styleCode="bold">Lorazepam (lor az&#x2B9; e pam) </content> <content styleCode="bold">Tablets C-IV</content></paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What is the most important information I should know about lorazepam tablets?</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Lorazepam is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. </content>Get emergency help right away if any of the following happens: </item><item>shallow or slowed breathing</item><item>breathing stops (which may lead to the heart stopping)</item><item>excessive sleepiness (sedation)</item></list><paragraph>Do not drive or operate heavy machinery until you know how taking lorazepam tablets with opioids affects you.</paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Risk of abuse, misuse, and addiction.</content>There is a risk of abuse, misuse, and addiction with benzodiazepines including lorazepam tablets which can lead to overdose and serious side effects including coma and death. <list listType="unordered" styleCode="Circle"><item><content styleCode="bold">Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including</content>lorazepam tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.</content></item><item><content styleCode="bold">You can develop an addiction even if you take</content><content styleCode="bold">lorazepam tablets exactly as prescribed by your healthcare provider.</content></item><item><content styleCode="bold">Take</content><content styleCode="bold">lorazepam tablets exactly as your healthcare provider prescribed.</content></item><item>Do not share your lorazepam tablets with other people.</item><item>Keep lorazepam tablets in a safe place and away from children.</item></list></item><item><content styleCode="bold">Physical dependence and withdrawal reactions.</content>Lorazepam tablets can cause physical dependence and withdrawal reactions. </item></list><list listType="unordered" styleCode="Circle"><item><content styleCode="bold">Do not suddenly stop taking</content>lorazepam tablets <content styleCode="bold">.</content>Stopping lorazepam tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions.

fe-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms.</content></item><item><content styleCode="bold">Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months,</content>including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. </item><item><content styleCode="bold">Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.</content></item></list><list listType="unordered"><item><content styleCode="bold">Do not take more lorazepam tablets than prescribed or take lorazepam tablets for longer than prescribed.</content></item></list></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are lorazepam tablets?</content></paragraph><list listType="unordered"><item>Lorazepam tablets are a prescription medicine used: &#xBA; to treat anxiety disorders &#xBA; for the short-term relief of the symptoms of anxiety or anxiety that can happen with symptoms of depression </item><item><content styleCode="bold">Lorazepam tablets are a federal controlled substance (CIV) because they <content styleCode="bold">contain lorazepam that </content>can be abused or lead to dependence. </content>Keep lorazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away lorazepam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. </item><item>It is not known if lorazepam tablets are safe and effective for use in children less than 12 years of age.</item><item>It is not known if lorazepam tablets are safe and effective for use for longer than 4 months.</item></list></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Do not take lorazepam tablets if you:</content></paragraph><list listType="unordered"><item>are allergic to lorazepam, other benzodiazepines, or any of the ingredients in lorazepam tablets. See the end of this Medication Guide for a complete list of ingredients in lorazepam tablets.</item></list></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Before you take lorazepam tablets, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered" styleCode="Disc"><item>have or have had depression, mood problems, or suicidal thoughts or behavior</item><item>have a history of drug or alcohol abuse or addiction</item><item>have lung disease or breathing problems (such as COPD, sleep apnea syndrome)</item><item>have liver or kidney problems</item><item>have or have had seizures</item><item>are pregnant or plan to become pregnant.

or suicidal thoughts or behavior</item><item>have a history of drug or alcohol abuse or addiction</item><item>have lung disease or breathing problems (such as COPD, sleep apnea syndrome)</item><item>have liver or kidney problems</item><item>have or have had seizures</item><item>are pregnant or plan to become pregnant. <list listType="unordered" styleCode="Disc"><item>Taking lorazepam tablets late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).</item><item>Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with lorazepam tablets.</item><item>There is a pregnancy registry for women who take lorazepam tablets during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with lorazepam tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/.</item></list></item><item>are breastfeeding or plan to breastfeed. Lorazepam passes into your breast milk. <list listType="unordered" styleCode="Disc"><item>Breastfeeding during treatment with lorazepam tablets may cause your baby to have sleepiness, feeding problems, and decreased weight gain.</item><item>Talk to your healthcare provider about the best way to feed your baby if you take lorazepam tablets.</item></list></item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. </paragraph><paragraph>Taking lorazepam tablets with certain other medicines can cause side effects or affect how well lorazepam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How should I take lorazepam tablets? </content></paragraph><list listType="unordered"><item>Take lorazepam tablets exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many lorazepam tablets to take and when to take them.</item><item>If you take too many lorazepam tablets, call your healthcare provider or go to the nearest hospital emergency room right away.</item></list></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the possible side effects of lorazepam tablets?</content></paragraph><paragraph><content styleCode="bold">Lorazepam tablets may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">See &#x201C;What is the most important information I should know about lorazepam tablets?&#x201D;</content></item><item><content styleCode="bold"><content styleCode="bold">Lorazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills.

rdered" styleCode="Disc"><item><content styleCode="bold">See &#x201C;What is the most important information I should know about lorazepam tablets?&#x201D;</content></item><item><content styleCode="bold"><content styleCode="bold">Lorazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. </content></content></item></list><list listType="unordered" styleCode="Circle"><item>Do not drive, operate heavy machinery, or do other dangerous activities until you know how lorazepam tablets affects you.</item><item><content styleCode="bold"><content styleCode="bold"><content styleCode="bold">Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking</content><content styleCode="bold">lorazepam tablets without first talking to your healthcare provider.</content></content></content>When taken with alcohol or drugs that cause sleepiness or dizziness, lorazepam tablets may make your sleepiness or dizziness much worse. </item></list><list listType="unordered"><item><content styleCode="bold">Depression.</content>Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam tablets. </item></list><paragraph><content styleCode="bold">The most common side effects of lorazepam tablets include:</content></paragraph><list listType="unordered"><item>sedation &#x2022; dizziness</item></list><list listType="unordered" styleCode="Disc"><item>weakness &#x2022; unsteadiness</item></list><paragraph>These are not all the possible side effects of lorazepam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule"><content styleCode="bold">How should I store lorazepam tablets?</content><list listType="unordered" styleCode="Disc"><item>Store lorazepam tablets in a tightly closed container at 68&#xB0; to 77&#xB0;F (20&#xB0; to 25&#xB0;C).</item><item><content styleCode="bold">Keep lorazepam tablets and all medicines out of the reach of children.</content></item></list></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule"><content styleCode="bold">General information about the safe and effective use of lorazepam tablets </content> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use lorazepam tablets for a condition for which it was not prescribed. Do not give lorazepam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about lorazepam tablets that is written for health professionals. </td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule"><content styleCode="bold">What are the ingredients in lorazepam tablets?</content><paragraph><content styleCode="bold">Active ingredient:</content>lorazepam </paragraph><content styleCode="bold">Inactive ingredients:</content>lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium </td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule"><paragraph/></td></tr></tbody></table>

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS ). The use of benzodiazepines, including lorazepam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing lorazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS ). The continued use of benzodiazepines, including lorazepam may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of lorazepam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam or reduce the dosage ( DOSAGE AND ADMINISTRATION and WARNINGS ).

DESCRIPTION Lorazepam, an antianxiety agent, has the chemical formula, 7-chloro-5-( o -chlorophenyl)-1,3-dihydro-3-hydroxy-2 H -1,4-benzodiazepin-2-one: It is a nearly white powder almost insoluble in water. Each Lorazepam tablet, to be taken orally, contains 0.5 mg, 1 mg, or 2 mg of lorazepam. The inactive ingredients present are lactose anhydrous, magnesium stearate, microcrystalline cellulose, and polacrilin potassium.

CLINICAL PHARMACOLOGY Studies in healthy volunteers show that in single high doses lorazepam has a tranquilizing action on the central nervous system with no appreciable effect on the respiratory or cardiovascular systems. Lorazepam is readily absorbed with an absolute bioavailability of 90%. Peak concentrations in plasma occur approximately 2 hours following administration. The peak plasma level of lorazepam from a 2 mg dose is approximately 20 ng/mL. The mean half-life of unconjugated lorazepam in human plasma is about 12 hours and for its major metabolite, lorazepam glucuronide, about 18 hours. At clinically relevant concentrations, lorazepam is approximately 85% bound to plasma proteins. Lorazepam is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepam glucuronide has no demonstrable central nervous system (CNS) activity in animals. The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to 6 months. Studies comparing young and elderly subjects have shown that advancing age does not have a significant effect on the pharmacokinetics of lorazepam. However, in one study involving single intravenous doses of 1.5 to 3 mg of lorazepam injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects 19 to 38 years of age.

INDICATIONS AND USAGE Lorazepam is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of lorazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

WARNINGS Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including Lorazepam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe Lorazepam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of Lorazepam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Lorazepam, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when Lorazepam is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see PRECAUTIONS : Drug Interactions ). Abuse, Misuse, and Addiction The use of benzodiazepines, including Lorazepam, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE : Abuse ). Before prescribing Lorazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of Lorazepam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Lorazepam along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Lorazepam or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINSTRATION : Discontinuation or Dosage Reduction of Lorazepam ). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines, including Lorazepam, may lead to clinically significant physical dependence.

withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines, including Lorazepam, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Lorazepam after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: Dependence ). Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE: Dependence ). Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam. 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 PRECAUTIONS : Drug Interactions ). 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. Neonatal Sedation and Withdrawal Syndrome Use of lorazepam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS: Pregnancy ). Monitor neonates exposed to lorazepam during pregnancy or labor for signs of sedation and monitor neonates exposed to lorazepam during pregnancy for signs of withdrawal; manage these neonates accordingly.

PRECAUTIONS In patients with depression, a possibility for suicide should be borne in mind; benzodiazepines should not be used in such patients without adequate antidepressant therapy. Lorazepam should be used with caution in patients with compromised respiratory function (e.g. COPD, sleep apnea syndrome). Elderly or debilitated patients may be more susceptible to the sedative effects of lorazepam. Therefore, these patients should be monitored frequently and have their dosage adjusted carefully according to patient response; the initial dosage should not exceed 2 mg. Paradoxical reactions have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued. The usual precautions for treating patients with impaired renal or hepatic function should be observed. As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy; therefore, lorazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy. Dosage for patients with severe hepatic insufficiency should be adjusted carefully according to patient response; lower doses may be sufficient in such patients. In patients where gastrointestinal or cardiovascular disorders coexist with anxiety, it should be noted that lorazepam has not been shown to be of significant benefit in treating the gastrointestinal or cardiovascular component. Esophageal dilation occurred in rats treated with lorazepam for more than 1 year at 6 mg/kg/day. The no-effect dose was 1.25 mg/kg/day (approximately 6 times the maximum human therapeutic dose of 10 mg/day). The effect was reversible only when the treatment was withdrawn within 2 months of first observation of the phenomenon. The clinical significance of this is unknown. However, use of lorazepam for prolonged periods and in geriatric patients requires caution, and there should be frequent monitoring for symptoms of upper GI disease. Safety and effectiveness of lorazepam in children of less than 12 years have not been established. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when lorazepam is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use of Opioids and PRECAUTIONS: Drug Interactions ). Abuse, Misuse, and Addiction Inform patients that the use of lorazepam even at recommended doses, 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: Abuse Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ).

esics), 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: Abuse Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ). Withdrawal Reactions Inform patients that the continued use of lorazepam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of lorazepam 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. Instruct patients that discontinuation or dosage reduction of lorazepam may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ). Pregnancy Advise pregnant females that use of lorazepam late in pregnancy 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 during pregnancy (see PRECAUTIONS: Pregnancy ). Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using lorazepam 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 ). Essential Laboratory Tests Some patients on lorazepam have developed leukopenia, and some have had elevations of LDH. As with other benzodiazepines, periodic blood counts and liver function tests are recommended for patients on long-term therapy. Drug Interactions 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 A 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. The benzodiazepines, including lorazepam, produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics. Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium and respiratory arrest. Concurrent administration of lorazepam with valproate may result in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate. Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation.

cid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation. Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam. Carcinogenesis and Mutagenesis No evidence of carcinogenic potential emerged in rats during an 18-month study with lorazepam. No studies regarding mutagenesis have been performed. Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including lorazepam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications 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 Syndrome and Clinical 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 recognized 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 during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to lorazepam during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ). Data 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 and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses. Nursing Mothers Risk Summary 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.

on and increased fetal loss in rabbits which was not seen at lower doses. Nursing Mothers Risk Summary 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 and any potential adverse effects on the breastfed infant from lorazepam or from the underlying maternal condition. Clinical Considerations Infants exposed to lorazepam through breast milk should be monitored for sedation, poor feeding and poor weight gain. Geriatric Use Clinical studies of lorazepam generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age (see ADVERSE REACTIONS ). Age does not appear to have a 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, and lower doses may be sufficient in these patients (see DOSAGE AND ADMINISTRATION ).

Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when lorazepam is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use of Opioids and PRECAUTIONS: Drug Interactions ). Abuse, Misuse, and Addiction Inform patients that the use of lorazepam even at recommended doses, 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: Abuse Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ). Withdrawal Reactions Inform patients that the continued use of lorazepam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of lorazepam 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. Instruct patients that discontinuation or dosage reduction of lorazepam may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ). Pregnancy Advise pregnant females that use of lorazepam late in pregnancy 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 during pregnancy (see PRECAUTIONS: Pregnancy ). Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using lorazepam 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 ). Essential Laboratory Tests Some patients on lorazepam have developed leukopenia, and some have had elevations of LDH. As with other benzodiazepines, periodic blood counts and liver function tests are recommended for patients on long-term therapy.

Drug Interactions 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 A 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. The benzodiazepines, including lorazepam, produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics. Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium and respiratory arrest. Concurrent administration of lorazepam with valproate may result in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate. Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation. Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including lorazepam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications 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 Syndrome and Clinical 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 recognized 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 during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to lorazepam during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ). Data 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 and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses.

Nursing Mothers Risk Summary 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 and any potential adverse effects on the breastfed infant from lorazepam or from the underlying maternal condition. Clinical Considerations Infants exposed to lorazepam through breast milk should be monitored for sedation, poor feeding and poor weight gain.

Geriatric Use Clinical studies of lorazepam generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age (see ADVERSE REACTIONS ). Age does not appear to have a 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, and lower doses may be sufficient in these patients (see DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS Most adverse reactions to benzodiazepines, including CNS effects and respiratory depression, are dose dependent, with more severe effects occurring with high doses. In a sample of about 3500 patients treated for anxiety, the most frequent adverse reaction to lorazepam was sedation (15.9%), followed by dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). The incidence of sedation and unsteadiness increased with age. Other adverse reactions to benzodiazepines, including lorazepam are fatigue, drowsiness, amnesia, memory impairment, confusion, disorientation, depression, unmasking of depression, disinhibition, euphoria, suicidal ideation/attempt, ataxia, asthenia, extrapyramidal symptoms, convulsions/seizures, tremor, vertigo, eye-function/visual disturbance (including diplopia and blurred vision), dysarthria, slurred speech, change in libido, impotence, decreased orgasm; headache, coma; respiratory depression, apnea, worsening of sleep apnea, worsening of obstructive pulmonary disease; gastrointestinal symptoms including nausea, change in appetite, constipation, jaundice, increase in bilirubin, increase in liver transaminases, increase in alkaline phosphatase; hypersensitivity reactions, anaphylacticoid reactions; dermatological symptoms, allergic skin reactions, alopecia; syndrome of inappropriate antidiuretic hormone (SIADH), hyponatremia, thrombocytopenia, agranulocytosis, pancytopenia; hypothermia; and autonomic manifestations. Paradoxical reactions, including anxiety, excitation, agitation, hostility, aggression, rage, sleep disturbances/insomnia, sexual arousal, and hallucinations may occur. Small decreases in blood pressure and hypotension may occur but are usually not clinically significant, probably being related to the relief of anxiety produced by lorazepam. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA at 1-800-FDA-1088 or www.fda.gov/medwatch OR LEADING PHARMA, LLC AT 1-844-740-7500.

DRUG ABUSE AND DEPENDENCE Controlled Substance Lorazepam contains lorazepam, a Schedule IV controlled substance. Abuse Lorazepam 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). Dependence Physical Dependence Lorazepam may produce physical dependence from continued therapy. 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. Abrupt discontinuation or rapid dosage reduction of benzodiazepines 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 ). To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam or reduce the dosage (see DOSAGE and ADMINISTRATION : Discontinuation or Dosage Reduction of Lorazepam and WARNINGS ).

ent doses) and those who have had longer durations of use (see WARNINGS : Dependence and Withdrawal Reactions ). To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam or reduce the dosage (see DOSAGE and ADMINISTRATION : Discontinuation or Dosage Reduction of Lorazepam and WARNINGS ). Acute Withdrawal Signs and Symptom 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 reemergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to lorazepam may develop from continued therapy. 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 lorazepam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Abuse Lorazepam 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).

Dependence Physical Dependence Lorazepam may produce physical dependence from continued therapy. 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. Abrupt discontinuation or rapid dosage reduction of benzodiazepines 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 ). To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam or reduce the dosage (see DOSAGE and ADMINISTRATION : Discontinuation or Dosage Reduction of Lorazepam and WARNINGS ). Acute Withdrawal Signs and Symptom 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 reemergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to lorazepam may develop from continued therapy. 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 lorazepam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DOSAGE AND ADMINISTRATION Lorazepam is administered orally. For optimal results, dose, frequency of administration, and duration of therapy should be individualized according to patient response. To facilitate this, 0.5 mg, 1 mg, and 2 mg tablets are available. The usual range is 2 to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the daily dosage may vary from 1 to 10 mg/day. For anxiety, most patients require an initial dose of 2 to 3 mg/day given two times a day or three times a day. For insomnia due to anxiety or transient situational stress, a single daily dose of 2 to 4 mg may be given, usually at bedtime. For elderly or debilitated patients, an initial dosage of 1 to 2 mg/day in divided doses is recommended, to be adjusted as needed and tolerated. The dosage of lorazepam 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. Discontinuation or Dosage Reduction of Lorazepam To reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence ).

HOW SUPPLIED Lorazepam ® (lorazepam) Tablets are available in the following dosage strengths: 0.5 mg White color, round, flat face beveled edge compressed tablets, debossed "EP" and "904" on one side, and plain on the other side. NDC# 69315-904-01 Bottles of 100 Tablets. NDC# 69315-904-05 Bottles of 500 Tablets. NDC# 69315-904-10 Bottles of 1000 Tablets. 1 mg White color, round, bisected flat face beveled edge compressed tablets, debossed "EP" above bisect and "905" below bisect on one side, and "1" on the other side. NDC# 69315-905-01 Bottles of 100 Tablets. NDC# 69315-905-05 Bottles of 500 Tablets. NDC# 69315-905-10 Bottles of 1000 Tablets. 2 mg White color, round, bisected flat face beveled edge compressed tablets, debossed "EP" above bisect and "906" below bisect on one side, and "2" on the other side. NDC# 69315-906-01 Bottles of 100 Tablets. NDC# 69315-906-05 Bottles of 500 Tablets. NDC# 69315-906-10 Bottles of 1000 Tablets. Dispense in a tight container. light-resistant container as defined in the USP, using a child-resistant closure. Keep this and all Medications out of the reach of children. Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Excursions permitted to 59° to 86°F (15° to 30°C).

MEDICATION GUIDE Lorazepam Tablets, CIV (lor az' e pam) What is the most important information I should know about lorazepam tablets? Lorazepam tablets are a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens: shallow or slowed breathing breathing stops (which may lead to the heart stopping) excessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking lorazepam tablets with opioids affects you. Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines including lorazepam tablets which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including lorazepam tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take lorazepam tablets exactly as prescribed by your healthcare provider. Take lorazepam tablets exactly as your healthcare provider prescribed. Do not share your lorazepam tablets with other people. Keep lorazepam tabletsin a safe place and away from children. Physical dependence and withdrawal reactions. Lorazepam tablets can cause physical dependence and withdrawal reactions. Do not suddenly stop taking lorazepam tablets. Stopping Lorazepam suddenly can cause serious and life-threatening side effects, including, unusual movements, responses or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. Do not take more lorazepam tablets than prescribed or take lorazepam tablets for longer than prescribed. What is lorazepam tablets? Lorazepam tablets are a prescription medicine used: to treat anxiety disorders for the short-term relief of the symptoms of anxiety or anxiety that can happen with symptoms of depression Lorazepam tablets is a federal controlled substance (CIV) because it contains lorazepam that can be abused or lead to dependence. Keep lorazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away lorazepam tablets may harm others and is against the law.

at can happen with symptoms of depression Lorazepam tablets is a federal controlled substance (CIV) because it contains lorazepam that can be abused or lead to dependence. Keep lorazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away lorazepam tablets may harm others and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. It is not known if lorazepam tablets are safe and effective for use in children less than 12 years of age. It is not known if lorazepam tablets are safe and effective for use for longer than 4 months. Do not take lorazepam if you: are allergic to lorazepam, other benzodiazepines, or any of the ingredients in lorazepam tablets. See the end of this Medication Guide for a complete list of ingredients inlorazepam tablets. Before you take lorazepam , tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems, or suicidal thoughts or behavior have a history of drug or alcohol abuse or addiction have lung disease or breathing problems (such as COPD, sleep apnea syndrome) have liver or kidney problems have or have had seizures are pregnant or plan to become pregnant. Taking lorazepam tablets late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems). Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with lorazepam tablets. There is a pregnancy registry for women who take lorazepam tablets during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with lorazepam tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/ . are breastfeeding or plan to breastfeed. Lorazepam passes into your breast milk. Breastfeeding during treatment with Lorazepam may cause your baby to have sleepiness, feeding problems, and decreased weight gain. Talk to your healthcare provider about the best way to feed your baby if you take lorazepam tablets. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking lorazepam tablets with certain other medicines can cause side effects or affect how well lorazepam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. How should I take lorazepam tablets? Take lorazepam tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much lorazepam tablets to take and when to take it. If you take too much lorazepam tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of lorazepam tablets? Lorazepam tablets may cause serious side effects, including: See “What is the most important information I should know about lorazepam tablets?” Lorazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how lorazepam tablets affects you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking lorazepam tablets without first talking to your healthcare provider.

can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how lorazepam tablets affects you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking lorazepam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, lorazepam tablets may make your sleepiness or dizziness much worse. Depression. Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam. The most common side effects of lorazepam include: sedation dizziness weakness unsteadiness These are not all the possible side effects of lorazepam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or LEADING PHARMA, LLC AT 1-844-740-7500. How should I store lorazepam tablets? Store lorazepam tablets in a tightly closed container at 77°F (25°C); excursions permitted to 59° to 86°F (15° to 30°C). Keep lorazepam tablets and all medicines out of the reach of children. General information about the safe and effective use of lorazepam tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use lorazepam tablets for a condition for which it was not prescribed. Do not give lorazepam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about lorazepam tablets that is written for health professionals What are the ingredients in lorazepam tablets? A ctive ingredient: lorazepam Inactive ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose, and polacrilin potassium. Manufactured and Distributed by Leading Pharma, LLC Fairfield, NJ 07004 USA Rev. 05 03/23

CIV For intravenous and intramuscular use NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY Published studies in animals demonstrate that the use of anesthetic agents 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 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 an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but 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 neonates and young children who require procedures against the potential risks suggested by the nonclinical data (see WARNINGS , Pediatric Neurotoxicity ; PRECAUTIONS , Pregnancy , Pediatric Use ). To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689. The Ativan trademark is used under license. Manufactured by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 Revised January 2023 462-162-10

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS ; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS ). The use of benzodiazepines, including ATIVAN Injection, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing ATIVAN Injection and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS ) . The continued use of benzodiazepines for several days to weeks may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although ATIVAN Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of ATIVAN Injection may precipitate acute withdrawal reactions, which can be life-threatening. 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 ).

DESCRIPTION Lorazepam, a benzodiazepine with antianxiety, sedative, and anticonvulsant effects, is intended for the intramuscular or intravenous routes of administration. It has the chemical formula: 7-chloro-5(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2 H -1, 4-benzodiazepin-2-one. The molecular weight is 321.16, and the C.A.S. No. is [846-49-1]. The structural formula is: Lorazepam is a nearly white powder almost insoluble in water. Each mL of sterile injection contains either 2.0 or 4.0 mg of lorazepam, 0.18 mL polyethylene glycol 400 in propylene glycol with 2.0% benzyl alcohol as preservative. Ativan structural formula

CLINICAL PHARMACOLOGY Lorazepam interacts with the γ-aminobutyric acid (GABA)-benzodiazepine receptor complex, which is widespread in the brain of humans as well as other species. This interaction is presumed to be responsible for lorazepam’s mechanism of action. Lorazepam exhibits relatively high and specific affinity for its recognition site but does not displace GABA. Attachment to the specific binding site enhances the affinity of GABA for its receptor site on the same receptor complex. The pharmacodynamic consequences of benzodiazepine agonist actions include antianxiety effects, sedation, and reduction of seizure activity. The intensity of action is directly related to the degree of benzodiazepine receptor occupancy. Effects in Pre-Operative Patients Intravenous or intramuscular administration of the recommended dose of 2 mg to 4 mg of 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.

who received lorazepam injection and no other drugs revealed that visual tracking (the ability to keep a moving line centered) was impaired for a mean of 8 hours following administration of 4 mg of intramuscular lorazepam and 4 hours following administration of 2 mg intramuscularly with considerable subject variation. Similar findings were noted with pentobarbital, 150 and 75 mg. Although this study showed that both lorazepam and pentobarbital interfered with eye-hand coordination, the data are insufficient to predict when it would be safe to operate a motor vehicle or engage in a hazardous occupation or sport. Pharmacokinetics and Metabolism ABSORPTION Intravenous A 4-mg dose provides an initial concentration of approximately 70 ng/mL. Intramuscular Following intramuscular administration, lorazepam is completely and rapidly absorbed reaching peak concentrations within 3 hours. A 4-mg dose provides a C max of approximately 48 ng/mL. Following administration of 1.5 to 5.0 mg of lorazepam IM, the amount of lorazepam delivered to the circulation is proportional to the dose administered. DISTRIBUTION/METABOLISM/ELIMINATION At clinically relevant concentrations, lorazepam is 91±2% bound to plasma proteins; its volume of distribution is approximately 1.3 L/kg. Unbound lorazepam penetrates the blood/brain barrier freely by passive diffusion, a fact confirmed by CSF sampling. Following parenteral administration, the terminal half-life and total clearance averaged 14±5 hours and 1.1±0.4 mL/min/kg, respectively. Lorazepam is extensively conjugated to the 3-O-phenolic glucuronide in the liver and is known to undergo enterohepatic recirculation. Lorazepam glucuronide is an inactive metabolite and is eliminated mainly by the kidneys. Following a single 2-mg oral dose of 14 C-lorazepam to 8 healthy subjects, 88±4% of the administered dose was recovered in urine and 7±2% was recovered in feces. The percent of administered dose recovered in urine as lorazepam glucuronide was 74±4%. Only 0.3% of the dose was recovered as unchanged lorazepam, and the remainder of the radioactivity represented minor metabolites. Special Populations EFFECT OF AGE Pediatrics NEONATES (BIRTH TO 1 MONTH) Following a single 0.05 mg/kg (n=4) or 0.1 mg/kg (n=6) intravenous dose of lorazepam, mean total clearance normalized to body weight was reduced by 80% compared to normal adults, terminal half-life was prolonged 3-fold, and volume of distribution was decreased by 40% in neonates with asphyxia neonatorum compared to normal adults. All neonates were of ≥37 weeks of gestational age. INFANTS (1 MONTH UP TO 2 YEARS) There is no information on the pharmacokinetic profile of lorazepam in infants in the age range of 1 month to 2 years. CHILDREN (2 YEARS TO 12 YEARS) Total (bound and unbound) lorazepam had a 50% higher mean volume of distribution (normalized to body-weight) and a 30% longer mean half-life in children with acute lymphocytic leukemia in complete remission (2 to 12 years, n=37) compared to normal adults (n=10). Unbound lorazepam clearance normalized to body-weight was comparable in children and adults. ADOLESCENTS (12 YEARS TO 18 YEARS) Total (bound and unbound) lorazepam had a 50% higher mean volume of distribution (normalized to body-weight) and a mean half-life that was two fold greater in adolescents with acute lymphocytic leukemia in complete remission (12 to 18 years, n=13) compared to normal adults (n=10). Unbound lorazepam clearance normalized to body-weight was comparable in adolescents and adults. Elderly Following single intravenous doses of 1.5 to 3 mg of 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.

nce 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. EFFECT OF GENDER Gender has no effect on the pharmacokinetics of lorazepam. EFFECT OF RACE Young Americans (n=15) and Japanese subjects (n=7) had very comparable mean total clearance value of 1.0 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. PATIENTS WITH RENAL INSUFFICIENCY Because the kidney is the primary route of elimination of lorazepam glucuronide, renal impairment would be expected to compromise its clearance. This should have no direct effect on the glucuronidation (and inactivation) of lorazepam. There is a possibility that the enterohepatic circulation of lorazepam glucuronide leads to a reduced efficiency of the net clearance of lorazepam in this population. Six normal subjects, six patients with renal impairment (Cl cr of 22±9 mL/min), and four patients on chronic maintenance 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. HEPATIC DISEASE 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. EFFECT OF SMOKING 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.

h 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.

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.

INDICATIONS AND USAGE Status Epilepticus ATIVAN Injection is indicated for the treatment of status epilepticus. Preanesthetic ATIVAN Injection is indicated in adult patients for preanesthetic medication, producing sedation (sleepiness or drowsiness), relief of anxiety, and a decreased ability to recall events related to the day of surgery. It is most useful in those patients who are anxious about their surgical procedure and who would prefer to have diminished recall of the events of the day of surgery (see PRECAUTIONS, Information for Patients ).

CONTRAINDICATIONS ATIVAN Injection is contraindicated in patients with a known sensitivity to benzodiazepines or its vehicle (polyethylene glycol, propylene glycol, and benzyl alcohol), in patients with acute narrow-angle glaucoma, or in patients with sleep apnea syndrome. It is also contraindicated in patients with severe respiratory insufficiency, except in those patients requiring relief of anxiety and/or diminished recall of events while being mechanically ventilated. The use of ATIVAN Injection intra-arterially is contraindicated because, as with other injectable benzodiazepines, inadvertent intra-arterial injection may produce arteriospasm resulting in gangrene which may require amputation (see WARNINGS ). ATIVAN Injection is contraindicated for use in premature infants because the formulation contains benzyl alcohol (see WARNINGS and PRECAUTIONS, Pediatric Use ).

WARNINGS Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including ATIVAN Injection, and opioids may result in profound sedation, respiratory depression, coma, and death. If a decision is made to use ATIVAN Injection concomitantly with opioids, monitor patients closely for respiratory depression and sedation (see PRECAUTIONS, Drug Interactions ). Abuse, Misuse, and Addiction The use of benzodiazepines, including ATIVAN Injection, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE, Abuse ). Before prescribing ATIVAN Injection and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. Use of ATIVAN Injection, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of ATIVAN Injection along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions After Use of ATIVAN Injection More Frequently Than Recommended For patients using ATIVAN Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue ATIVAN Injection (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. ACUTE WITHDRAWAL REACTIONS The continued use of benzodiazepines may lead to clinically significant physical dependence. Although ATIVAN Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of ATIVAN Injection, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE, Dependence ) . PROTRACTED WITHDRAWAL SYNDROME In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE, Dependence ). Use in Status Epilepticus MANAGEMENT OF STATUS EPILEPTICUS Status epilepticus is a potentially life-threatening condition associated with a high risk of permanent neurological impairment, if inadequately treated. The treatment of status, however, requires far more than the administration of an anticonvulsant agent. It involves observation and management of all parameters critical to maintaining vital function and the capacity to provide support of those functions as required.

nt 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 one step of a complex and sustained intervention which may require additional interventions (e.g., concomitant intravenous administration of phenytoin). Because status epilepticus may result from a correctable acute cause such as hypoglycemia, hyponatremia, or other metabolic or toxic derangement, such an abnormality must be immediately sought and corrected. Furthermore, patients who are susceptible to further seizure episodes should receive adequate maintenance antiepileptic therapy. Any healthcare professional who intends to treat a patient with status epilepticus should be familiar with this package insert and the pertinent medical literature concerning current concepts for the treatment of status epilepticus. A comprehensive review of the considerations critical to the informed and prudent management of status epilepticus cannot be provided in drug product labeling. The archival medical literature contains many informative references on the management of status epilepticus, among them the report of the working group on status epilepticus of the Epilepsy Foundation of America “Treatment of Convulsive Status Epilepticus” (JAMA 1993; 270:854-859). As noted in the report just cited, it may be useful to consult with a neurologist if a patient fails to respond (e.g., fails to regain consciousness). For the treatment of status epilepticus, the usual recommended dose of 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. RESPIRATORY DEPRESSION The most important risk associated with the use of ATIVAN Injection in status epilepticus is respiratory depression. Accordingly, airway patency must be assured and respiration monitored closely. Ventilatory support should be given as required. EXCESSIVE SEDATION Because of its prolonged duration of action, the prescriber should be alert to the possibility, especially when multiple doses have been given, that the sedative effects of lorazepam may add to the impairment of consciousness seen in the post-ictal state. Preanesthetic Use AIRWAY OBSTRUCTION MAY OCCUR IN HEAVILY SEDATED PATIENTS. INTRAVENOUS LORAZEPAM AT ANY DOSE, WHEN GIVEN EITHER ALONE OR IN COMBINATION WITH OTHER DRUGS ADMINISTERED DURING ANESTHESIA, MAY PRODUCE HEAVY SEDATION; THEREFORE, EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY AND TO SUPPORT RESPIRATION/VENTILATION SHOULD BE AVAILABLE. As is true of similar CNS-acting drugs, the decision as to when patients who have received injectable lorazepam, particularly on an outpatient basis, may again operate machinery, drive a motor vehicle, or engage in hazardous or other activities requiring attention and coordination must be individualized. It is recommended that no patient engage in such activities for a period of 24 to 48 hours or until the effects of the drug, such as drowsiness, have subsided, whichever is longer.

e machinery, drive a motor vehicle, or engage in hazardous or other activities requiring attention and coordination must be individualized. It is recommended that no patient engage in such activities for a period of 24 to 48 hours or until the effects of the drug, such as drowsiness, have subsided, whichever is longer. Impairment of performance may persist for greater intervals because of extremes of age, concomitant use of other drugs, stress of surgery, or the general condition of the patient. Clinical trials have shown that patients over the age of 50 years may have a more profound and prolonged sedation with intravenous lorazepam (see DOSAGE AND ADMINISTRATION, Preanesthetic ). As with all central-nervous-system-depressant drugs, care should be exercised in patients given injectable lorazepam as premature ambulation may result in injury from falling. There is no added beneficial effect from the addition of scopolamine to injectable lorazepam, and their combined effect may result in an increased incidence of sedation, hallucination and irrational behavior. General (All Uses) PRIOR TO INTRAVENOUS USE, ATIVAN INJECTION MUST BE DILUTED WITH AN EQUAL AMOUNT OF COMPATIBLE DILUENT (see DOSAGE AND ADMINISTRATION ). INTRAVENOUS INJECTION SHOULD BE MADE SLOWLY AND WITH REPEATED ASPIRATION. CARE SHOULD BE TAKEN TO DETERMINE THAT ANY INJECTION WILL NOT BE INTRA-ARTERIAL AND THAT PERIVASCULAR EXTRAVASATION WILL NOT TAKE PLACE. IN THE EVENT THAT A PATIENT COMPLAINS OF PAIN DURING INTENDED INTRAVENOUS INJECTION OF ATIVAN INJECTION, THE INJECTION SHOULD BE STOPPED IMMEDIATELY TO DETERMINE IF INTRA-ARTERIAL INJECTION OR PERIVASCULAR EXTRAVASATION HAS TAKEN PLACE. Since the liver is the most likely site of conjugation of lorazepam and since excretion of conjugated lorazepam (glucuronide) is a renal function, this drug is not recommended for use in patients with hepatic and/or renal failure . ATIVAN should be used with caution in patients with mild-to-moderate hepatic or renal disease (see DOSAGE AND ADMINISTRATION ). Neonatal Sedation and Withdrawal Syndrome Use of ATIVAN Injection late in pregnancy can result in sedation (respiratory depression. lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS , Pregnancy ). Monitor neonates exposed to Ativan Injection during pregnancy or labor for signs of sedation and monitor neonates exposed to Ativan Injection during pregnancy for signs of withdrawal; manage these neonates accordingly. Usage in Preterm Infants and Neonates ATIVAN Injection contains benzyl alcohol. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including ATIVAN) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of ATIVAN for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known.

ining this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of ATIVAN for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see WARNINGS and PRECAUTIONS, Pediatric Use ). Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, 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 three years of age in humans (see PRECAUTIONS, Pregnancy , Pediatric Use ; ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks. Endoscopic Procedures There are insufficient data to support the use of ATIVAN Injection for outpatient endoscopic procedures. Inpatient endoscopic procedures require adequate recovery room observation time. When ATIVAN Injection is used for peroral endoscopic procedures, adequate topical or regional anesthesia is recommended to minimize reflex activity associated with such procedures.

PRECAUTIONS General 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 ATIVAN Injection (see CLINICAL PHARMACOLOGY and WARNINGS ). Extreme caution must be used when administering ATIVAN 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 IV 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 ATIVAN Injection at higher than recommended doses. Symptoms may be more likely to develop in patients with renal impairment. Information for Patients RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines, including ATIVAN Injection, and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS and PRECAUTIONS, Drug Interactions ) . ABUSE, MISUSE, AND ADDICTION Inform patients that the use of ATIVAN 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 ) . WITHDRAWAL REACTIONS Inform patients that use of ATIVAN Injection more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of ATIVAN 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 ) . EXCESSIVE SEDATION 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.

12 months (see WARNINGS and DRUG ABUSE AND DEPENDENCE ) . EXCESSIVE SEDATION 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 ATIVAN 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 ATIVAN. 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 ATIVAN 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 ATIVAN Injection may make them very sleepy for a period longer than 6 to 8 hours following surgery. EFFECT OF ANESTHETIC AND SEDATION DRUGS ON EARLY BRAIN DEVELOPMENT 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 ). PREGNANCY Advise pregnant females who are administered ATIVAN Injection late in pregnancy that ATIVAN 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 Ativan Injection during pregnancy (see PRECAUTIONS, Pregnancy ). NURSING Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who are administered ATIVAN 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 ). Laboratory Tests In clinical trials, no laboratory test abnormalities were identified with either single or multiple doses of ATIVAN Injection. These tests included: CBC, urinalysis, SGOT, SGPT, bilirubin, alkaline phosphatase, LDH, cholesterol, uric acid, BUN, glucose, calcium, phosphorus, and total proteins. Drug Interactions 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 A sites and opioids interact primarily at mu receptors.

TION 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 A 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 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 ATIVAN dosage is necessary when concomitantly given with any of these drugs. LORAZEPAM-VALPROATE INTERACTION 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 ). LORAZEPAM-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 ). LORAZEPAM-PROBENECID INTERACTION 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 ).

rs) 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/Laboratory Test Interactions 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. Carcinogenesis, Mutagenesis, Impairment of Fertility 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 There is a pregnancy registry that monitors pregnancy outcomes in woman exposed to psychiatric medications including ATIVAN 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 Syndrome and PRECAUTIONS , Clinical 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 Ativan Injection during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Ativan Injection during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS , Neonatal Sedation and Withdrawal Syndrome ). Labor or Delivery There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in cesarean section. Such use, therefore, is not recommended. Data 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.

ed 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 al lower doses. Nursing Risk Summary 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 ATIVAN Injection and any potential adverse effects on the breastfed infant from ATIVAN Injection or from the underlying maternal condition. Clinical Considerations Infants exposed to ATIVAN 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 , and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). Pediatric Use STATUS EPILEPTICUS The safety and effectiveness of ATIVAN for status epilepticus have not been established in pediatric patients. A randomized, double-blind, superiority-design clinical trial of ATIVAN versus intravenous diazepam in 273 pediatric patients ages 3 months to 17 years failed to establish the efficacy of ATIVAN for the treatment of status epilepticus. In that trial, assisted ventilation was required in 18% of patients treated with ATIVAN versus 16% of patients treated with diazepam. Patients treated with ATIVAN were also more likely to be reported as sedated (67% for ATIVAN vs. 50% for diazepam), and the time for return to baseline mental status was, on average, 2 hours longer for ATIVAN 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.

tients 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 ATIVAN 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). ATIVAN 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. PREANESTHETIC There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age. GENERAL Seizure activity and myoclonus have been reported to occur following administration of ATIVAN Injection, especially in very low birth weight neonates. Pediatric patients may exhibit a sensitivity to benzyl alcohol, polyethylene glycol and propylene glycol, components of ATIVAN 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 ATIVAN 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.

pnea, tachycardia, and diaphoresis have been associated with propylene glycol toxicity. Although normal therapeutic doses of ATIVAN 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 ATIVAN 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 ). Geriatric Use Clinical studies of ATIVAN 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 ).

Information for Patients RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines, including ATIVAN Injection, and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS and PRECAUTIONS, Drug Interactions ) . ABUSE, MISUSE, AND ADDICTION Inform patients that the use of ATIVAN 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 ) . WITHDRAWAL REACTIONS Inform patients that use of ATIVAN Injection more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of ATIVAN 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 ) . EXCESSIVE SEDATION 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 ATIVAN 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 ATIVAN. 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 ATIVAN 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 ATIVAN Injection may make them very sleepy for a period longer than 6 to 8 hours following surgery. EFFECT OF ANESTHETIC AND SEDATION DRUGS ON EARLY BRAIN DEVELOPMENT 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 ).

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 ). PREGNANCY Advise pregnant females who are administered ATIVAN Injection late in pregnancy that ATIVAN 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 Ativan Injection during pregnancy (see PRECAUTIONS, Pregnancy ). NURSING Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who are administered ATIVAN 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 ).

Laboratory Tests In clinical trials, no laboratory test abnormalities were identified with either single or multiple doses of ATIVAN Injection. These tests included: CBC, urinalysis, SGOT, SGPT, bilirubin, alkaline phosphatase, LDH, cholesterol, uric acid, BUN, glucose, calcium, phosphorus, and total proteins.

Drug Interactions 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 A 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 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 ATIVAN dosage is necessary when concomitantly given with any of these drugs. LORAZEPAM-VALPROATE INTERACTION 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 ). LORAZEPAM-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 ).

ncrease 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 ). LORAZEPAM-PROBENECID INTERACTION 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 ).

Pediatric Use STATUS EPILEPTICUS The safety and effectiveness of ATIVAN for status epilepticus have not been established in pediatric patients. A randomized, double-blind, superiority-design clinical trial of ATIVAN versus intravenous diazepam in 273 pediatric patients ages 3 months to 17 years failed to establish the efficacy of ATIVAN for the treatment of status epilepticus. In that trial, assisted ventilation was required in 18% of patients treated with ATIVAN versus 16% of patients treated with diazepam. Patients treated with ATIVAN were also more likely to be reported as sedated (67% for ATIVAN vs. 50% for diazepam), and the time for return to baseline mental status was, on average, 2 hours longer for ATIVAN 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 ATIVAN 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). ATIVAN 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. PREANESTHETIC There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age. GENERAL Seizure activity and myoclonus have been reported to occur following administration of ATIVAN Injection, especially in very low birth weight neonates.

ources. PREANESTHETIC There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age. GENERAL Seizure activity and myoclonus have been reported to occur following administration of ATIVAN Injection, especially in very low birth weight neonates. Pediatric patients may exhibit a sensitivity to benzyl alcohol, polyethylene glycol and propylene glycol, components of ATIVAN 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 ATIVAN 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 ATIVAN 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 ).

Geriatric Use Clinical studies of ATIVAN 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 ).

ADVERSE REACTIONS 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. 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 Body System Event ATIVAN Injection (n=130) One hundred and thirty (130) patients received ATIVAN Injection. Any Study Event (1 or more) 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. 16 (12.3%) Body as a whole Infection 1 ( <1%) Cardiovascular system Hypotension 2 (1.5%) Digestive system Liver function tests abnormal 1 ( <1%) Nausea 1 ( <1%) Vomiting 1 ( <1%) Metabolic and Nutritional Acidosis 1 ( <1%) Nervous system Brain edema 1 ( <1%) Coma 1 ( <1%) Convulsion 1 ( <1%) Somnolence 2 (1.5%) Thinking abnormal 1 ( <1%) Respiratory system Hyperventilation 1 ( <1%) Hypoventilation 1 ( <1%) Respiratory failure 2 (1.5%) Terms not classifiable Injection site reaction 1 ( <1%) Urogenital system Cystitis 1 ( <1%) 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.

ent 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 (n=85) 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. Diazepam (n=80) Any Study Event (1 or more) 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. 14 (16.5%) 11 (13.8%) Body as a whole Headache 1 ( 1.2%) 1 (1.3%) Cardiovascular system Hypotension 2 (2.4%) 0 Hemic and lymphatic system Hypochromic anemia 0 1 (1.3%) Leukocytosis 0 1 (1.3%) Thrombocythemia 0 1 (1.3%) Nervous system Coma 1 (1.2 %) 1 (1.3%) Somnolence 3 (3.5%) 3 (3.8%) Stupor 1 (1.2%) 0 Respiratory system 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 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 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 BODY AS A WHOLE - Infrequent: asthenia, chills, headache, infection. DIGESTIVE SYSTEM - Infrequent: abnormal liver function test, increased salivation, nausea, vomiting. METABOLIC AND NUTRITIONAL - Infrequent: acidosis, alkaline phosphatase increased. NERVOUS SYSTEM - Infrequent: agitation, ataxia, brain edema, coma, confusion, convulsion, hallucinations, myoclonus, stupor, thinking abnormal, tremor. RESPIRATORY SYSTEM - Frequent: apnea; Infrequent: hyperventilation, hypoventilation, respiratory disorder. TERMS NOT CLASSIFIABLE - Infrequent: injection site reaction. UROGENITAL SYSTEM - Infrequent: cystitis. Preanesthetic CENTRAL NERVOUS SYSTEM The most frequent adverse drug event reported with injectable lorazepam is central-nervous-system depression.

Infrequent: hyperventilation, hypoventilation, respiratory disorder. TERMS NOT CLASSIFIABLE - Infrequent: injection site reaction. UROGENITAL SYSTEM - Infrequent: cystitis. Preanesthetic CENTRAL NERVOUS SYSTEM The most frequent adverse drug event reported with injectable lorazepam 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. LOCAL EFFECTS 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 ). CARDIOVASCULAR SYSTEM Hypertension (0.1%) and hypotension (0.1%) have occasionally been observed after patients have received injectable lorazepam. RESPIRATORY SYSTEM Five patients (5/446) who underwent regional anesthesia were observed to have airway obstruction.

which may require amputation (see CONTRAINDICATIONS ). CARDIOVASCULAR SYSTEM Hypertension (0.1%) and hypotension (0.1%) have occasionally been observed after patients have received injectable lorazepam. RESPIRATORY SYSTEM Five patients (5/446) who underwent regional anesthesia were observed to have airway obstruction. This was believed due to excessive sleepiness at the time of the procedure and resulted in temporary hypoventilation. In this instance, appropriate airway management may become necessary (see CLINICAL PHARMACOLOGY , WARNINGS , and PRECAUTIONS ). OTHER ADVERSE EXPERIENCES Skin rash, nausea and vomiting have occasionally been noted in patients who have received injectable lorazepam combined with other drugs during anesthesia and surgery. Paradoxical Reactions As with all benzodiazepines, paradoxical reactions such as stimulation, mania, irritability, restlessness, agitation, aggression, psychosis, hostility, rage, or hallucinations may occur in rare instances and in an unpredictable fashion. In these instances, further use of the drug in these patients should be considered with caution (see PRECAUTIONS, General ). Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of 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).

<table><caption>TABLE 1. NUMBER (%) OF STUDY EVENTS IN A DOSE COMPARISON CLINICAL TRIAL</caption><col/><col/><col/><thead><tr><td valign="bottom" styleCode=" Botrule"><paragraph><content styleCode="bold">Body System </content>Event</paragraph></td><td align="center" valign="bottom" styleCode=" Botrule"> </td><td valign="bottom" styleCode=" Botrule"><paragraph><content styleCode="bold">ATIVAN Injection </content>(n=130)<footnote ID="FOOT_2800">One hundred and thirty (130) patients received ATIVAN Injection.</footnote></paragraph></td></tr></thead><tbody><tr><td><content styleCode="bold">Any Study Event</content> (1 or more)<footnote ID="FOOT_2801">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.</footnote></td><td> </td><td valign="top">16 (12.3%)</td></tr><tr><td><content styleCode="bold">Body as a whole</content></td><td> </td><td valign="top"> </td></tr><tr><td>Infection</td><td/><td>1 ( &lt;1%)</td></tr><tr><td><content styleCode="bold">Cardiovascular system</content></td><td> </td><td valign="top"> </td></tr><tr><td>Hypotension</td><td> </td><td valign="top">2 (1.5%)</td></tr><tr><td><content styleCode="bold">Digestive system</content></td><td> </td><td valign="top"> </td></tr><tr><td>Liver function tests abnormal</td><td/><td>1 ( &lt;1%)</td></tr><tr><td>Nausea</td><td> </td><td valign="top">1 ( &lt;1%)</td></tr><tr><td>Vomiting</td><td> </td><td valign="top">1 ( &lt;1%)</td></tr><tr><td><content styleCode="bold">Metabolic and Nutritional</content></td><td> </td><td valign="top"> </td></tr><tr><td>Acidosis</td><td> </td><td valign="top">1 ( &lt;1%)</td></tr><tr><td><content styleCode="bold">Nervous system</content></td><td> </td><td valign="top"> </td></tr><tr><td>Brain edema</td><td/><td>1 ( &lt;1%)</td></tr><tr><td>Coma</td><td> </td><td valign="top">1 ( &lt;1%)</td></tr><tr><td>Convulsion</td><td/><td>1 ( &lt;1%)</td></tr><tr><td>Somnolence</td><td/><td>2 (1.5%)</td></tr><tr><td>Thinking abnormal</td><td> </td><td valign="top">1 ( &lt;1%)</td></tr><tr><td><content styleCode="bold">Respiratory system</content></td><td> </td><td valign="top"> </td></tr><tr><td>Hyperventilation</td><td> </td><td valign="top">1 ( &lt;1%)</td></tr><tr><td>Hypoventilation</td><td/><td>1 ( &lt;1%)</td></tr><tr><td>Respiratory failure</td><td> </td><td valign="top">2 (1.5%)</td></tr><tr><td><content styleCode="bold">Terms not classifiable</content></td><td> </td><td valign="top"> </td></tr><tr><td>Injection site reaction</td><td> </td><td valign="top">1 ( &lt;1%)</td></tr><tr><td><content styleCode="bold">Urogenital system</content></td><td> </td><td valign="top"> </td></tr><tr><td>Cystitis</td><td/><td>1 ( &lt;1%)</td></tr></tbody></table>

classifiable</content></td><td> </td><td valign="top"> </td></tr><tr><td>Injection site reaction</td><td> </td><td valign="top">1 ( &lt;1%)</td></tr><tr><td><content styleCode="bold">Urogenital system</content></td><td> </td><td valign="top"> </td></tr><tr><td>Cystitis</td><td/><td>1 ( &lt;1%)</td></tr></tbody></table> <table><caption>TABLE 2. NUMBER (%) OF STUDY EVENTS IN ACTIVE CONTROLLED CLINICAL TRIAL</caption><col/><col/><col/><col/><thead><tr><td valign="bottom" styleCode=" Botrule"><paragraph><content styleCode="bold">Body System </content>Event</paragraph></td><td valign="bottom" styleCode=" Botrule"> </td><td><paragraph><content styleCode="bold">ATIVAN Injection </content>(n=85)<footnote ID="FOOT_2802">The number indicates the number of &#x201C;patient-episodes.&#x201D; Patient-episodes were used rather than &#x201C;patients&#x201D; 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.</footnote></paragraph></td><td valign="bottom" styleCode=" Botrule"><paragraph><content styleCode="bold">Diazepam </content>(n=80)<footnoteRef IDREF="FOOT_2802"/></paragraph></td></tr></thead><tbody><tr><td><content styleCode="bold">Any Study Event</content> (1 or more)<footnote ID="FOOT_2803">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.</footnote></td><td valign="bottom"> </td><td valign="top">14 (16.5%)</td><td valign="top">11 (13.8%)</td></tr><tr><td><content styleCode="bold">Body as a whole</content></td><td valign="bottom"> </td><td valign="top"> </td><td valign="top"> </td></tr><tr><td>Headache</td><td valign="bottom"/><td>1 ( 1.2%)</td><td valign="top">1 (1.3%)</td></tr><tr><td><content styleCode="bold">Cardiovascular system</content></td><td valign="bottom"> </td><td valign="top"> </td><td valign="top"> </td></tr><tr><td>Hypotension</td><td valign="bottom"> </td><td valign="top">2 (2.4%)</td><td valign="top"> 0</td></tr><tr><td><content styleCode="bold">Hemic and lymphatic system</content></td><td valign="bottom"> </td><td valign="top"> </td><td valign="top"> </td></tr><tr><td>Hypochromic anemia</td><td valign="bottom"> </td><td valign="top"> 0</td><td valign="top">1 (1.3%)</td></tr><tr><td>Leukocytosis</td><td valign="bottom"> </td><td valign="top"> 0</td><td valign="top">1 (1.3%)</td></tr><tr><td>Thrombocythemia</td><td valign="bottom"> </td><td valign="top"> 0</td><td valign="top">1 (1.3%)</td></tr><tr><td><content styleCode="bold">Nervous system</content></td><td valign="bottom"> </td><td valign="top"> </td><td valign="top"> </td></tr><tr><td>Coma</td><td valign="bottom"> </td><td valign="top">1 (1.2 %)</td><td valign="top">1 (1.3%)</td></tr><tr><td>Somnolence</td><td valign="bottom"/><td>3 (3.5%)</td><td valign="top">3 (3.8%)</td></tr><tr><td>Stupor</td><td valign="bottom"/><td>1 (1.2%)</td><td valign="top"> 0</td></tr><tr><td><content styleCode="bold">Respiratory system</content></td><td valign="bottom"> </td><td valign="top"> </td><td valign="top"> </td></tr><tr><td>Hypoventilation</td><td valign="bottom"/><td>1 (1.2%)</td><td valign="top">2 (2.5%)</td></tr><tr><td>Apnea</td><td valign="bottom"/><td>1 (1.2%)</td><td valign="top">1 (1.3%)</td></tr><tr><td>Respiratory failure</td><td valign="bottom"> </td><td valign="top">2 (2.4%)</td><td valign="top">1 (1.3%)</td></tr><tr><td>Respiratory disorder</td><td valign="bottom"/><td>1 (1.2%)</td><td valign="top"> 0</td></tr></tbody></table>

nea</td><td valign="bottom"/><td>1 (1.2%)</td><td valign="top">1 (1.3%)</td></tr><tr><td>Respiratory failure</td><td valign="bottom"> </td><td valign="top">2 (2.4%)</td><td valign="top">1 (1.3%)</td></tr><tr><td>Respiratory disorder</td><td valign="bottom"/><td>1 (1.2%)</td><td valign="top"> 0</td></tr></tbody></table> <table><col/><col/><tbody><tr><td valign="top"><content styleCode="italics">BODY AS A WHOLE -</content></td><td>Infrequent: asthenia, chills, headache, infection.</td></tr><tr><td valign="top"><content styleCode="italics">DIGESTIVE SYSTEM </content>-</td><td>Infrequent: abnormal liver function test, increased salivation, nausea, vomiting.</td></tr><tr><td valign="top"><content styleCode="italics">METABOLIC AND NUTRITIONAL </content>-</td><td>Infrequent: acidosis, alkaline phosphatase increased.</td></tr><tr><td valign="top"><content styleCode="italics">NERVOUS SYSTEM </content>-</td><td>Infrequent: agitation, ataxia, brain edema, coma, confusion, convulsion, hallucinations, myoclonus, stupor, thinking abnormal, tremor.</td></tr><tr><td valign="top"><content styleCode="italics">RESPIRATORY SYSTEM </content>-</td><td>Frequent: apnea; Infrequent: hyperventilation, hypoventilation, respiratory disorder.</td></tr><tr><td valign="top"><content styleCode="italics">TERMS NOT CLASSIFIABLE </content>-</td><td>Infrequent: injection site reaction.</td></tr><tr><td valign="top"><content styleCode="italics">UROGENITAL SYSTEM</content>-</td><td>Infrequent: cystitis.</td></tr></tbody></table>

DRUG ABUSE AND DEPENDENCE Controlled Substance ATIVAN Injection contains lorazepam, a Schedule IV controlled substance. Abuse 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). Dependence 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 I NDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ) , if used 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 ) .

-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 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.

Abuse 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).

Dependence 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 I NDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ) , if used 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 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.

OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS , Abuse, Misuse, and Addiction ). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil Injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

DOSAGE AND ADMINISTRATION 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 GENERAL ADVICE Status epilepticus is a potentially life-threatening condition associated with a high risk of permanent neurological impairment, if inadequately treated. The treatment of status, however, requires far more than the administration of an anticonvulsant agent. It involves observation and management of all parameters critical to maintaining vital function and the capacity to provide support of those functions as required. Ventilatory support must be readily available. The use of benzodiazepines, like 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 healthcare professional who intends to treat a patient with status epilepticus should be familiar with this package insert and the pertinent medical literature concerning current concepts for the treatment of status epilepticus. A comprehensive review of the considerations critical to the informed and prudent management of status epilepticus cannot be provided in drug product labeling. The archival medical literature contains many informative references on the management of status epilepticus, among them the report of the working group on status epilepticus of the Epilepsy Foundation of America “Treatment of Convulsive Status Epilepticus” (JAMA 1993; 270:854-859). As noted in the report just cited, it may be useful to consult with a neurologist if a patient fails to respond (e.g., fails to regain consciousness). INTRAVENOUS INJECTION For the treatment of status epilepticus, the usual recommended dose of 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. INTRAMUSCULAR INJECTION 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 ). PEDIATRIC The safety of ATIVAN in pediatric patients has not been established.

us 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 ). PEDIATRIC The safety of ATIVAN in pediatric patients has not been established. Preanesthetic INTRAMUSCULAR INJECTION For the designated indications as a premedicant, the usual recommended dose of lorazepam for intramuscular injection is 0.05 mg/kg up to a maximum of 4 mg. As with all premedicant drugs, the dose should be individualized (see CLINICAL PHARMACOLOGY , WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS ). Doses of other central-nervous-system-depressant drugs ordinarily should be reduced (see PRECAUTIONS ). For optimum effect, measured as lack of recall, intramuscular lorazepam should be administered at least 2 hours before the anticipated operative procedure. Narcotic analgesics should be administered at their usual preoperative time. There are insufficient data to support efficacy or make dosage recommendations for intramuscular lorazepam in patients less than 18 years of age; therefore, such use is not recommended. INTRAVENOUS INJECTION For the primary purpose of sedation and relief of anxiety, the usual recommended initial dose of lorazepam for intravenous injection is 2 mg total, or 0.02 mg/lb (0.044 mg/kg), whichever is smaller. This dose will suffice for sedating most adult patients and ordinarily should not be exceeded in patients over 50 years of age. In those patients in whom a greater likelihood of lack of recall for perioperative events would be beneficial, larger doses as high as 0.05 mg/kg up to a total of 4 mg may be administered (see CLINICAL PHARMACOLOGY , WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS ). Doses of other injectable central-nervous-system-depressant drugs ordinarily should be reduced (see PRECAUTIONS ). For optimum effect, measured as lack of recall, intravenous lorazepam should be administered 15 to 20 minutes before the anticipated operative procedure. There are insufficient data to support efficacy or make dosage recommendations for intravenous lorazepam in patients less than 18 years of age; therefore, such use is not recommended. Dose Administration in Special Populations ELDERLY PATIENTS AND PATIENTS WITH HEPATIC DISEASE No dosage adjustments are needed in elderly patients and in patients with hepatic disease. PATIENTS WITH RENAL DISEASE For acute dose administration, adjustment is not needed for patients with renal disease. However, in patients with renal disease, caution should be exercised if frequent doses are given over relatively short periods of time (see CLINICAL PHARMACOLOGY ). DOSE ADJUSTMENT DUE TO DRUG INTERACTIONS The dose of 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.

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.

HOW SUPPLIED ATIVAN Injection (lorazepam injection, USP) is available in the following dosage strengths in single-dose and multiple-dose vials: 2 mg per mL, NDC 0641-6001-25, 25 x 1 mL vial NDC 0641-6000-10, 10 x 10 mL vial 4 mg per mL, NDC 0641-6003-25, 25 x 1 mL vial NDC 0641-6002-10, 10 x 10 mL vial For IM or IV injection. Store in a refrigerator. PROTECT FROM LIGHT. Use carton to protect contents from light.

CIV For intravenous and intramuscular use NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY Published studies in animals demonstrate that the use of anesthetic agents 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 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 an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but 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 neonates and young children who require procedures against the potential risks suggested by the nonclinical data (see WARNINGS , Pediatric Neurotoxicity ; PRECAUTIONS , Pregnancy , Pediatric Use ). To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689. Manufactured by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 Novaplus is a registered trademark of Vizient, Inc. Revised March 2021 462-380-06 logo

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS ). The use of benzodiazepines, including Lorazepam Injection, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing Lorazepam Injection and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS ). The continued use of benzodiazepines for several days to weeks may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although Lorazepam Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of Lorazepam Injection may precipitate acute withdrawal reactions, which can be life-threatening. For patients using Lorazepam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Lorazepam Injection (see WARNINGS ).

DESCRIPTION Lorazepam, a benzodiazepine with antianxiety, sedative, and anticonvulsant effects, is intended for the intramuscular or intravenous routes of administration. It has the chemical formula: 7-chloro-5(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2 H -1,4-benzodiazepin-2-one. The molecular weight is 321.16, and the C.A.S. No. is [846-49-1]. The structural formula is: Lorazepam is a nearly white powder almost insoluble in water. Each mL of sterile injection contains either 2.0 or 4.0 mg of lorazepam, 0.18 mL polyethylene glycol 400 in propylene glycol with 2.0% benzyl alcohol as preservative. structural formula

CLINICAL PHARMACOLOGY Lorazepam interacts with the γ-aminobutyric acid (GABA)-benzodiazepine receptor complex, which is widespread in the brain of humans as well as other species. This interaction is presumed to be responsible for lorazepam’s mechanism of action. Lorazepam exhibits relatively high and specific affinity for its recognition site but does not displace GABA. Attachment to the specific binding site enhances the affinity of GABA for its receptor site on the same receptor complex. The pharmacodynamic consequences of benzodiazepine agonist actions include antianxiety effects, sedation, and reduction of seizure activity. The intensity of action is directly related to the degree of benzodiazepine receptor occupancy. Effects in Pre-Operative Patients Intravenous or intramuscular administration of the recommended dose of 2 mg to 4 mg of Lorazepam Injection to adult patients is followed by dose-related effects of sedation (sleepiness or drowsiness), relief of preoperative anxiety, and lack of recall of events related to the day of surgery in the majority of patients. The clinical sedation (sleepiness or drowsiness) thus noted is such that the majority of patients are able to respond to simple instructions whether they give the appearance of being awake or asleep. The lack of recall is relative rather than absolute, as determined under conditions of careful patient questioning and testing, using props designed to enhance recall. The majority of patients under these reinforced conditions had difficulty recalling perioperative events or recognizing props from before surgery. The lack of recall and recognition was optimum within 2 hours following intramuscular administration and 15 to 20 minutes after intravenous injection. The intended effects of the recommended adult dose of Lorazepam Injection usually last 6 to 8 hours. In rare instances, and where patients received greater than the recommended dose, excessive sleepiness and prolonged lack of recall were noted. As with other benzodiazepines, unsteadiness, enhanced sensitivity to CNS-depressant effects of ethyl alcohol and other drugs were noted in isolated and rare cases for greater than 24 hours. Physiologic Effects in Healthy Adults Studies in healthy adult volunteers reveal that intravenous lorazepam in doses up to 3.5 mg/70 kg does not alter sensitivity to the respiratory stimulating effect of carbon dioxide and does not enhance the respiratory-depressant effects of doses of meperidine up to 100 mg/70 kg (also determined by carbon dioxide challenge) as long as patients remain sufficiently awake to undergo testing. Upper airway obstruction has been observed in rare instances where the patient received greater than the recommended dose and was excessively sleepy and difficult to arouse (see WARNINGS and ADVERSE REACTIONS ). Clinically employed doses of Lorazepam Injection do not greatly affect the circulatory system in the supine position or employing a 70-degree tilt test. Doses of 8 mg to 10 mg of intravenous lorazepam (2 to 2-1/2 times the maximum recommended dosage) will produce loss of lid reflexes within 15 minutes. Studies in 6 healthy young adults who received Lorazepam Injection and no other drugs revealed that visual tracking (the ability to keep a moving line centered) was impaired for a mean of 8 hours following administration of 4 mg of intramuscular lorazepam and 4 hours following administration of 2 mg intramuscularly with considerable subject variation.

who received Lorazepam Injection and no other drugs revealed that visual tracking (the ability to keep a moving line centered) was impaired for a mean of 8 hours following administration of 4 mg of intramuscular lorazepam and 4 hours following administration of 2 mg intramuscularly with considerable subject variation. Similar findings were noted with pentobarbital, 150 and 75 mg. Although this study showed that both lorazepam and pentobarbital interfered with eye-hand coordination, the data are insufficient to predict when it would be safe to operate a motor vehicle or engage in a hazardous occupation or sport. Pharmacokinetics and Metabolism ABSORPTION Intravenous A 4-mg dose provides an initial concentration of approximately 70 ng/mL. Intramuscular Following intramuscular administration, lorazepam is completely and rapidly absorbed reaching peak concentrations within 3 hours. A 4-mg dose provides a C max of approximately 48 ng/mL. Following administration of 1.5 to 5.0 mg of lorazepam IM, the amount of lorazepam delivered to the circulation is proportional to the dose administered. DISTRIBUTION/METABOLISM/ELIMINATION At clinically relevant concentrations, lorazepam is 91±2% bound to plasma proteins; its volume of distribution is approximately 1.3 L/kg. Unbound lorazepam penetrates the blood/brain barrier freely by passive diffusion, a fact confirmed by CSF sampling. Following parenteral administration, the terminal half-life and total clearance averaged 14±5 hours and 1.1±0.4 mL/min/kg, respectively. Lorazepam is extensively conjugated to the 3-O-phenolic glucuronide in the liver and is known to undergo enterohepatic recirculation. Lorazepam glucuronide is an inactive metabolite and is eliminated mainly by the kidneys. Following a single 2-mg oral dose of 14 C-lorazepam to 8 healthy subjects, 88±4% of the administered dose was recovered in urine and 7±2% was recovered in feces. The percent of administered dose recovered in urine as lorazepam glucuronide was 74±4%. Only 0.3% of the dose was recovered as unchanged lorazepam, and the remainder of the radioactivity represented minor metabolites. Special Populations EFFECT OF AGE Pediatrics NEONATES (BIRTH TO 1 MONTH) Following a single 0.05 mg/kg (n=4) or 0.1 mg/kg (n=6) intravenous dose of lorazepam, mean total clearance normalized to body weight was reduced by 80% compared to normal adults, terminal half-life was prolonged 3-fold, and volume of distribution was decreased by 40% in neonates with asphyxia neonatorum compared to normal adults. All neonates were of ≥37 weeks of gestational age. INFANTS (1 MONTH UP TO 2 YEARS) There is no information on the pharmacokinetic profile of lorazepam in infants in the age range of 1 month to 2 years. CHILDREN (2 YEARS TO 12 YEARS) Total (bound and unbound) lorazepam had a 50% higher mean volume of distribution (normalized to body-weight) and a 30% longer mean half-life in children with acute lymphocytic leukemia in complete remission (2 to 12 years, n=37) compared to normal adults (n=10). Unbound lorazepam clearance normalized to body-weight was comparable in children and adults. ADOLESCENTS (12 YEARS TO 18 YEARS) Total (bound and unbound) lorazepam had a 50% higher mean volume of distribution (normalized to body-weight) and a mean half-life that was two fold greater in adolescents with acute lymphocytic leukemia in complete remission (12 to 18 years, n=13) compared to normal adults (n=10). Unbound lorazepam clearance normalized to body-weight was comparable in adolescents and adults. Elderly Following single intravenous doses of 1.5 to 3 mg of Lorazepam Injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age.

normalized to body-weight was comparable in adolescents and adults. Elderly Following single intravenous doses of 1.5 to 3 mg of Lorazepam Injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age. Consequently, no dosage adjustment appears to be necessary in elderly subjects based solely on their age. EFFECT OF GENDER Gender has no effect on the pharmacokinetics of lorazepam. EFFECT OF RACE Young Americans (n=15) and Japanese subjects (n=7) had very comparable mean total clearance value of 1.0 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. PATIENTS WITH RENAL INSUFFICIENCY Because the kidney is the primary route of elimination of lorazepam glucuronide, renal impairment would be expected to compromise its clearance. This should have no direct effect on the glucuronidation (and inactivation) of lorazepam. There is a possibility that the enterohepatic circulation of lorazepam glucuronide leads to a reduced efficiency of the net clearance of lorazepam in this population. Six normal subjects, six patients with renal impairment (Cl cr of 22±9 mL/min), and four patients on chronic maintenance 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. HEPATIC DISEASE 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. EFFECT OF SMOKING 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 Lorazepam 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 Lorazepam Injection and diazepam.

tudy 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 Lorazepam Injection and diazepam. Patients were randomized to receive lorazepam 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 lorazepam and 16/28 (57%) patients were deemed responders to diazepam (p=0.04). Of the 24 lorazepam responders, 23 received both 2 mg infusions. Non-responders to lorazepam 4 mg were given an additional 2 to 4 mg lorazepam; 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 lorazepam 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 lorazepam as the treatment for status epilepticus, it cannot speak reliably or meaningfully to the comparative performance of either diazepam (Valium) or lorazepam (Lorazepam Injection) under the conditions of actual use. A second study (n=119) was a double-blind dose-comparison trial with 3 doses of Lorazepam Injection: 1 mg, 2 mg, and 4 mg. Patients were randomized to receive one of the three doses of lorazepam. The primary outcome and definition of responder were as in the first study. Twenty-five of 41 patients (61%) responded to 1 mg lorazepam; 21/37 patients (57%) responded to 2 mg lorazepam; and 31/41 (76%) responded to 4 mg lorazepam. The p-value for a statistical test of the difference between the lorazepam 4 mg dose group and the lorazepam 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 lorazepam in status epilepticus, the numbers of patients evaluated were too few to allow a definitive conclusion about the role these factors may play.

Pharmacokinetics and Metabolism ABSORPTION Intravenous A 4-mg dose provides an initial concentration of approximately 70 ng/mL. Intramuscular Following intramuscular administration, lorazepam is completely and rapidly absorbed reaching peak concentrations within 3 hours. A 4-mg dose provides a C max of approximately 48 ng/mL. Following administration of 1.5 to 5.0 mg of lorazepam IM, the amount of lorazepam delivered to the circulation is proportional to the dose administered. DISTRIBUTION/METABOLISM/ELIMINATION At clinically relevant concentrations, lorazepam is 91±2% bound to plasma proteins; its volume of distribution is approximately 1.3 L/kg. Unbound lorazepam penetrates the blood/brain barrier freely by passive diffusion, a fact confirmed by CSF sampling. Following parenteral administration, the terminal half-life and total clearance averaged 14±5 hours and 1.1±0.4 mL/min/kg, respectively. Lorazepam is extensively conjugated to the 3-O-phenolic glucuronide in the liver and is known to undergo enterohepatic recirculation. Lorazepam glucuronide is an inactive metabolite and is eliminated mainly by the kidneys. Following a single 2-mg oral dose of 14 C-lorazepam to 8 healthy subjects, 88±4% of the administered dose was recovered in urine and 7±2% was recovered in feces. The percent of administered dose recovered in urine as lorazepam glucuronide was 74±4%. Only 0.3% of the dose was recovered as unchanged lorazepam, and the remainder of the radioactivity represented minor metabolites.

Clinical Studies The effectiveness of Lorazepam 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 Lorazepam Injection and diazepam. Patients were randomized to receive lorazepam 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 lorazepam and 16/28 (57%) patients were deemed responders to diazepam (p=0.04). Of the 24 lorazepam responders, 23 received both 2 mg infusions. Non-responders to lorazepam 4 mg were given an additional 2 to 4 mg lorazepam; 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 lorazepam 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 lorazepam as the treatment for status epilepticus, it cannot speak reliably or meaningfully to the comparative performance of either diazepam (Valium) or lorazepam (Lorazepam Injection) under the conditions of actual use. A second study (n=119) was a double-blind dose-comparison trial with 3 doses of Lorazepam Injection: 1 mg, 2 mg, and 4 mg. Patients were randomized to receive one of the three doses of lorazepam. The primary outcome and definition of responder were as in the first study. Twenty-five of 41 patients (61%) responded to 1 mg lorazepam; 21/37 patients (57%) responded to 2 mg lorazepam; and 31/41 (76%) responded to 4 mg lorazepam. The p-value for a statistical test of the difference between the lorazepam 4 mg dose group and the lorazepam 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 lorazepam in status epilepticus, the numbers of patients evaluated were too few to allow a definitive conclusion about the role these factors may play.

WARNINGS Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including Lorazepam Injection, and opioids may result in profound sedation, respiratory depression, coma, and death. If a decision is made to use Lorazepam Injection concomitantly with opioids, monitor patients closely for respiratory depression and sedation (see PRECAUTIONS, Drug Interactions ). Abuse, Misuse, and Addiction The use of benzodiazepines, including Lorazepam Injection, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE, Abuse ). Before prescribing Lorazepam Injection and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. Use of Lorazepam Injection, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Lorazepam Injection along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions After Use of Lorazepam Injection More Frequently Than Recommended For patients using Lorazepam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Lorazepam Injection (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. ACUTE WITHDRAWAL REACTIONS The continued use of benzodiazepines may lead to clinically significant physical dependence. Although Lorazepam Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of Lorazepam Injection, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE, Dependence ). PROTRACTED WITHDRAWAL SYNDROME In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE, Dependence ). Use in Status Epilepticus MANAGEMENT OF STATUS EPILEPTICUS Status epilepticus is a potentially life-threatening condition associated with a high risk of permanent neurological impairment, if inadequately treated. The treatment of status, however, requires far more than the administration of an anticonvulsant agent.

). Use in Status Epilepticus MANAGEMENT OF STATUS EPILEPTICUS Status epilepticus is a potentially life-threatening condition associated with a high risk of permanent neurological impairment, if inadequately treated. The treatment of status, however, requires far more than the administration of an anticonvulsant agent. It involves observation and management of all parameters critical to maintaining vital function and the capacity to provide support of those functions as required. Ventilatory support must be readily available. The use of benzodiazepines, like Lorazepam Injection, is ordinarily only one step of a complex and sustained intervention which may require additional interventions (e.g., concomitant intravenous administration of phenytoin). Because status epilepticus may result from a correctable acute cause such as hypoglycemia, hyponatremia, or other metabolic or toxic derangement, such an abnormality must be immediately sought and corrected. Furthermore, patients who are susceptible to further seizure episodes should receive adequate maintenance antiepileptic therapy. Any healthcare professional who intends to treat a patient with status epilepticus should be familiar with this package insert and the pertinent medical literature concerning current concepts for the treatment of status epilepticus. A comprehensive review of the considerations critical to the informed and prudent management of status epilepticus cannot be provided in drug product labeling. The archival medical literature contains many informative references on the management of status epilepticus, among them the report of the working group on status epilepticus of the Epilepsy Foundation of America “Treatment of Convulsive Status Epilepticus” (JAMA 1993; 270:854-859). As noted in the report just cited, it may be useful to consult with a neurologist if a patient fails to respond (e.g., fails to regain consciousness). For the treatment of status epilepticus, the usual recommended dose of Lorazepam Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures cease, no additional Lorazepam Injection is required. If seizures continue or recur after a 10- to 15-minute observation period, an additional 4 mg intravenous dose may be slowly administered. Experience with further doses of lorazepam is very limited. The usual precautions in treating status epilepticus should be employed. An intravenous infusion should be started, vital signs should be monitored, an unobstructed airway should be maintained, and artificial ventilation equipment should be available. RESPIRATORY DEPRESSION The most important risk associated with the use of Lorazepam Injection in status epilepticus is respiratory depression. Accordingly, airway patency must be assured and respiration monitored closely. Ventilatory support should be given as required. EXCESSIVE SEDATION Because of its prolonged duration of action, the prescriber should be alert to the possibility, especially when multiple doses have been given, that the sedative effects of lorazepam may add to the impairment of consciousness seen in the post-ictal state. Preanesthetic Use AIRWAY OBSTRUCTION MAY OCCUR IN HEAVILY SEDATED PATIENTS. INTRAVENOUS LORAZEPAM AT ANY DOSE, WHEN GIVEN EITHER ALONE OR IN COMBINATION WITH OTHER DRUGS ADMINISTERED DURING ANESTHESIA, MAY PRODUCE HEAVY SEDATION; THEREFORE, EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY AND TO SUPPORT RESPIRATION/VENTILATION SHOULD BE AVAILABLE. As is true of similar CNS-acting drugs, the decision as to when patients who have received injectable lorazepam, particularly on an outpatient basis, may again operate machinery, drive a motor vehicle, or engage in hazardous or other activities requiring attention and coordination must be individualized.

BE AVAILABLE. As is true of similar CNS-acting drugs, the decision as to when patients who have received injectable lorazepam, particularly on an outpatient basis, may again operate machinery, drive a motor vehicle, or engage in hazardous or other activities requiring attention and coordination must be individualized. It is recommended that no patient engage in such activities for a period of 24 to 48 hours or until the effects of the drug, such as drowsiness, have subsided, whichever is longer. Impairment of performance may persist for greater intervals because of extremes of age, concomitant use of other drugs, stress of surgery, or the general condition of the patient. Clinical trials have shown that patients over the age of 50 years may have a more profound and prolonged sedation with intravenous lorazepam (see DOSAGE AND ADMINISTRATION, Preanesthetic ). As with all central-nervous-system-depressant drugs, care should be exercised in patients given injectable lorazepam as premature ambulation may result in injury from falling. There is no added beneficial effect from the addition of scopolamine to injectable lorazepam, and their combined effect may result in an increased incidence of sedation, hallucination and irrational behavior. General (All Uses) PRIOR TO INTRAVENOUS USE, LORAZEPAM INJECTION MUST BE DILUTED WITH AN EQUAL AMOUNT OF COMPATIBLE DILUENT (see DOSAGE AND ADMINISTRATION ). INTRAVENOUS INJECTION SHOULD BE MADE SLOWLY AND WITH REPEATED ASPIRATION. CARE SHOULD BE TAKEN TO DETERMINE THAT ANY INJECTION WILL NOT BE INTRA-ARTERIAL AND THAT PERIVASCULAR EXTRAVASATION WILL NOT TAKE PLACE. IN THE EVENT THAT A PATIENT COMPLAINS OF PAIN DURING INTENDED INTRAVENOUS INJECTION OF LORAZEPAM INJECTION, THE INJECTION SHOULD BE STOPPED IMMEDIATELY TO DETERMINE IF INTRA-ARTERIAL INJECTION OR PERIVASCULAR EXTRAVASATION HAS TAKEN PLACE. Since the liver is the most likely site of conjugation of lorazepam and since excretion of conjugated lorazepam (glucuronide) is a renal function, this drug is not recommended for use in patients with hepatic and/or renal failure . Lorazepam should be used with caution in patients with mild-to-moderate hepatic or renal disease (see DOSAGE AND ADMINISTRATION ). Pregnancy LORAZEPAM MAY CAUSE FETAL DAMAGE WHEN ADMINISTERED TO PREGNANT WOMEN. Ordinarily, Lorazepam Injection should not be used during pregnancy except in serious or life-threatening conditions where safer drugs cannot be used or are ineffective. Status epilepticus may represent such a serious and life-threatening condition. An increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam and meprobamate) during the first trimester of pregnancy has been suggested in several studies. In humans, blood levels obtained from umbilical cord blood indicate placental transfer of lorazepam and lorazepam glucuronide. Reproductive studies in animals were performed in mice, rats, and two strains of rabbits. Occasional anomalies (reduction of tarsals, tibia, metatarsals, malrotated limbs, gastroschisis, malformed skull, and microphthalmia) were seen in drug-treated rabbits without relationship to dosage. Although all of these anomalies were not present in the concurrent control group, they have been reported to occur randomly in historical controls. At doses of 40 mg/kg orally or 4 mg/kg intravenously and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses. The possibility that a woman of childbearing potential may be pregnant at the time of therapy should be considered. There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in cesarean section. Such use, therefore, is not recommended.

in rabbits which was not seen at lower doses. The possibility that a woman of childbearing potential may be pregnant at the time of therapy should be considered. There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in cesarean section. Such use, therefore, is not recommended. Usage in Preterm Infants and Neonates Lorazepam Injection contains benzyl alcohol. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including lorazepam) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of lorazepam for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see WARNINGS and PRECAUTIONS, Pediatric Use ). Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, 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 three years of age in humans (see PRECAUTIONS , Pregnancy , Pediatric Use ; ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks. Endoscopic Procedures There are insufficient data to support the use of Lorazepam Injection for outpatient endoscopic procedures. Inpatient endoscopic procedures require adequate recovery room observation time. When Lorazepam Injection is used for peroral endoscopic procedures, adequate topical or regional anesthesia is recommended to minimize reflex activity associated with such procedures.

PRECAUTIONS General 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 IV 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. Information for Patients RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines, including Lorazepam Injection, and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS and PRECAUTIONS, Drug Interactions ). ABUSE, MISUSE, AND ADDICTION 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 ). WITHDRAWAL REACTIONS 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 ). EXCESSIVE SEDATION 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.

n 12 months (see WARNINGS and DRUG ABUSE AND DEPENDENCE ). EXCESSIVE SEDATION 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. EFFECT OF ANESTHETIC AND SEDATION DRUGS ON EARLY BRAIN DEVELOPMENT 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 ). Laboratory Tests 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. Drug Interactions 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 A 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.

rational 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. LORAZEPAM-VALPROATE INTERACTION 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 ). LORAZEPAM-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 lorazepam in female patients who are concomitantly taking oral contraceptives (see DOSAGE AND ADMINISTRATION ). LORAZEPAM-PROBENECID INTERACTION 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 ). Drug/Laboratory Test Interactions 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. Carcinogenesis, Mutagenesis, Impairment of Fertility 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 Teratogenic Effects (see WARNINGS ). 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.

GS ). 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 , and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). Labor and Delivery There are insufficient data to support the use of Lorazepam Injection during labor and delivery, including cesarean section; therefore, its use in this clinical circumstance is not recommended. Nursing Mothers Lorazepam has been detected in human breast milk. Therefore, lorazepam should not be administered to nursing mothers because, like other benzodiazepines, the possibility exists that lorazepam may sedate or otherwise adversely affect the infant. Pediatric Use STATUS EPILEPTICUS 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.

ported (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. PREANESTHETIC There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age. GENERAL 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.

he 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 ). Geriatric Use 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 ).

General 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 IV 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.

Information for Patients RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines, including Lorazepam Injection, and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS and PRECAUTIONS, Drug Interactions ). ABUSE, MISUSE, AND ADDICTION 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 ). WITHDRAWAL REACTIONS 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 ). EXCESSIVE SEDATION 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. EFFECT OF ANESTHETIC AND SEDATION DRUGS ON EARLY BRAIN DEVELOPMENT 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.

longer than 6 to 8 hours following surgery. EFFECT OF ANESTHETIC AND SEDATION DRUGS ON EARLY BRAIN DEVELOPMENT 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 ).

Drug Interactions 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 A 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. LORAZEPAM-VALPROATE INTERACTION 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 ). LORAZEPAM-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 lorazepam in female patients who are concomitantly taking oral contraceptives (see DOSAGE AND ADMINISTRATION ).

ease 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 ). LORAZEPAM-PROBENECID INTERACTION 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 ).

Pregnancy Teratogenic Effects (see WARNINGS ). 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 , and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ).

Labor and Delivery There are insufficient data to support the use of Lorazepam Injection during labor and delivery, including cesarean section; therefore, its use in this clinical circumstance is not recommended.

Nursing Mothers Lorazepam has been detected in human breast milk. Therefore, lorazepam should not be administered to nursing mothers because, like other benzodiazepines, the possibility exists that lorazepam may sedate or otherwise adversely affect the infant.

Pediatric Use STATUS EPILEPTICUS 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. PREANESTHETIC There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age. GENERAL Seizure activity and myoclonus have been reported to occur following administration of Lorazepam Injection, especially in very low birth weight neonates.

ces. PREANESTHETIC There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age. GENERAL 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 ).

Geriatric Use 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 ).

ADVERSE REACTIONS Status Epilepticus The most important adverse clinical event caused by the use of Lorazepam Injection is respiratory depression (see WARNINGS ). The adverse clinical events most commonly observed with the use of Lorazepam Injection in clinical trials evaluating its use in status epilepticus were hypotension, somnolence, and respiratory failure. INCIDENCE IN CONTROLLED CLINICAL TRIALS All adverse events were recorded during the trials by the clinical investigators using terminology of their own choosing. Similar types of events were grouped into standardized categories using modified COSTART dictionary terminology. These categories are used in the table and listings below with the frequencies representing the proportion of individuals exposed to Lorazepam Injection or to comparative therapy. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigators involving different treatment, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. COMMONLY OBSERVED ADVERSE EVENTS IN A CONTROLLED DOSE-COMPARISON CLINICAL TRIAL Table 1 lists the treatment-emergent adverse events that occurred in the patients treated with Lorazepam Injection in a dose-comparison trial of lorazepam 1 mg, 2 mg, and 4 mg. TABLE 1. NUMBER (%) OF STUDY EVENTS IN A DOSE COMPARISON CLINICAL TRIAL Body System Event Lorazepam Injection (n=130) One hundred and thirty (130) patients received Lorazepam Injection. Any Study Event (1 or more) 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. 16 (12.3%) Body as a whole Infection 1 ( <1%) Cardiovascular system Hypotension 2 (1.5%) Digestive system Liver function tests abnormal 1 ( <1%) Nausea 1 ( <1%) Vomiting 1 ( <1%) Metabolic and Nutritional Acidosis 1 ( <1%) Nervous system Brain edema 1 ( <1%) Coma 1 ( <1%) Convulsion 1 ( <1%) Somnolence 2 (1.5%) Thinking abnormal 1 ( <1%) Respiratory system Hyperventilation 1 ( <1%) Hypoventilation 1 ( <1%) Respiratory failure 2 (1.5%) Terms not classifiable Injection site reaction 1 ( <1%) Urogenital system Cystitis 1 ( <1%) COMMONLY OBSERVED ADVERSE EVENTS IN ACTIVE-CONTROLLED CLINICAL TRIALS In two studies, patients who completed the course of treatment for status epilepticus were permitted to be reenrolled and to receive treatment for a second status episode, given that there was a sufficient interval between the two episodes. Safety was determined from all treatment episodes for all intent-to-treat patients, i.e., from all “patient-episodes.” Table 2 lists the treatment-emergent adverse events that occurred in at least 1% of the patient-episodes in which Lorazepam Injection or diazepam was given. The table represents the pooling of results from the two controlled trials. TABLE 2.

episodes for all intent-to-treat patients, i.e., from all “patient-episodes.” Table 2 lists the treatment-emergent adverse events that occurred in at least 1% of the patient-episodes in which Lorazepam Injection or diazepam was given. The table represents the pooling of results from the two controlled trials. TABLE 2. NUMBER (%) OF STUDY EVENTS IN ACTIVE CONTROLLED CLINICAL TRIAL Body System Event Lorazepam Injection (n=85) The number indicates the number of “patient-episodes.” Patient-episodes were used rather than “patients” because a total of 7 patients were reenrolled for the treatment of a second episode of status: 5 patients received Lorazepam Injection on two occasions that were far enough apart to establish the diagnosis of status epilepticus for each episode, and, using the same time criterion, 2 patients received diazepam on two occasions. Diazepam (n=80) Any Study Event (1 or more) 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. 14 (16.5%) 11 (13.8%) Body as a whole Headache 1 ( 1.2%) 1 (1.3%) Cardiovascular system Hypotension 2 (2.4%) 0 Hemic and lymphatic system Hypochromic anemia 0 1 (1.3%) Leukocytosis 0 1 (1.3%) Thrombocythemia 0 1 (1.3%) Nervous system Coma 1 (1.2 %) 1 (1.3%) Somnolence 3 (3.5%) 3 (3.8%) Stupor 1 (1.2%) 0 Respiratory system 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 These trials were not designed or intended to demonstrate the comparative safety of the two treatments. The overall adverse experience profile for lorazepam was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse events by race. Generally, age greater than 65 years may be associated with a greater incidence of central-nervous-system depression and more respiratory depression. OTHER EVENTS OBSERVED DURING THE PRE-MARKETING EVALUATION OF LORAZEPAM INJECTION FOR THE TREATMENT OF STATUS EPILEPTICUS Lorazepam Injection, active comparators, and Lorazepam Injection in combination with a comparator were administered to 488 individuals during controlled and open-label clinical trials. Because of reenrollments, these 488 patients participated in a total of 521 patient-episodes. Lorazepam Injection alone was given in 69% of these patient-episodes (n=360). The safety information below is based on data available from 326 of these patient-episodes in which Lorazepam Injection was given alone. All adverse events that were seen once are listed, except those already included in previous listings (Table 1 and Table 2). Study events were classified by body system in descending frequency by using the following definitions: frequent adverse events were those that occurred in at least 1/100 individuals; infrequent study events were those that occurred in 1/100 to 1/1000 individuals. Frequent and Infrequent Study Events BODY AS A WHOLE - Infrequent: asthenia, chills, headache, infection. DIGESTIVE SYSTEM - Infrequent: abnormal liver function test, increased salivation, nausea, vomiting. METABOLIC AND NUTRITIONAL - Infrequent: acidosis, alkaline phosphatase increased. NERVOUS SYSTEM - Infrequent: agitation, ataxia, brain edema, coma, confusion, convulsion, hallucinations, myoclonus, stupor, thinking abnormal, tremor. RESPIRATORY SYSTEM - Frequent: apnea; Infrequent: hyperventilation, hypoventilation, respiratory disorder. TERMS NOT CLASSIFIABLE - Infrequent: injection site reaction. UROGENITAL SYSTEM- Infrequent: cystitis. Preanesthetic CENTRAL NERVOUS SYSTEM The most frequent adverse drug event reported with injectable lorazepam is central-nervous-system depression.

; Infrequent: hyperventilation, hypoventilation, respiratory disorder. TERMS NOT CLASSIFIABLE - Infrequent: injection site reaction. UROGENITAL SYSTEM- Infrequent: cystitis. Preanesthetic CENTRAL NERVOUS SYSTEM The most frequent adverse drug event reported with injectable lorazepam 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. LOCAL EFFECTS 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 ). CARDIOVASCULAR SYSTEM Hypertension (0.1%) and hypotension (0.1%) have occasionally been observed after patients have received injectable lorazepam. RESPIRATORY SYSTEM Five patients (5/446) who underwent regional anesthesia were observed to have airway obstruction.

which may require amputation (see CONTRAINDICATIONS ). CARDIOVASCULAR SYSTEM Hypertension (0.1%) and hypotension (0.1%) have occasionally been observed after patients have received injectable lorazepam. RESPIRATORY SYSTEM Five patients (5/446) who underwent regional anesthesia were observed to have airway obstruction. This was believed due to excessive sleepiness at the time of the procedure and resulted in temporary hypoventilation. In this instance, appropriate airway management may become necessary (see CLINICAL PHARMACOLOGY , WARNINGS , and PRECAUTIONS ). OTHER ADVERSE EXPERIENCES Skin rash, nausea and vomiting have occasionally been noted in patients who have received injectable lorazepam combined with other drugs during anesthesia and surgery. Paradoxical Reactions As with all benzodiazepines, paradoxical reactions such as stimulation, mania, irritability, restlessness, agitation, aggression, psychosis, hostility, rage, or hallucinations may occur in rare instances and in an unpredictable fashion. In these instances, further use of the drug in these patients should be considered with caution (see PRECAUTIONS, General ). Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of Lorazepam Injection that have been received since market introduction and that may have no causal relationship with the use of Lorazepam Injection include the following: acute brain syndrome, aggravation of pheochromocytoma, amnesia, apnea/respiratory arrest, arrhythmia, bradycardia, brain edema, coagulation disorder, coma, convulsion, gastrointestinal hemorrhage, heart arrest/failure, heart block, liver damage, lung edema, lung hemorrhage, nervousness, neuroleptic malignant syndrome, paralysis, pericardial effusion, pneumothorax, pulmonary hypertension, tachycardia, thrombocytopenia, urinary incontinence, ventricular arrhythmia. Fatalities also have been reported, usually in patients on concomitant medications (e.g., respiratory depressants) and/or with other medical conditions (e.g., obstructive sleep apnea).

<table><caption>TABLE 1. NUMBER (%) OF STUDY EVENTS IN A DOSE COMPARISON CLINICAL TRIAL</caption><col/><col/><thead><tr><th align="center" valign="bottom" styleCode=" Botrule"> <content styleCode="bold">Body System</content> Event</th><th align="center" valign="bottom" styleCode=" Botrule"> <content styleCode="bold">Lorazepam Injection</content> (n=130)<footnote ID="FOOT_3215">One hundred and thirty (130) patients received Lorazepam Injection.</footnote></th></tr></thead><tbody><tr><td> <content styleCode="bold">Any Study Event</content> (1 or more)<footnote ID="FOOT_3216">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.</footnote></td><td align="center" valign="top"> 16 (12.3%)</td></tr><tr><td> <content styleCode="bold">Body as a whole</content></td><td align="center" valign="top"> </td></tr><tr><td> Infection</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> <content styleCode="bold">Cardiovascular system</content></td><td align="center" valign="top"> </td></tr><tr><td> Hypotension</td><td align="center" valign="top"> 2 (1.5%)</td></tr><tr><td> <content styleCode="bold">Digestive system</content></td><td align="center" valign="top"> </td></tr><tr><td> Liver function tests abnormal</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> Nausea</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> Vomiting</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> <content styleCode="bold">Metabolic and Nutritional</content></td><td align="center" valign="top"> </td></tr><tr><td> Acidosis</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> <content styleCode="bold">Nervous system</content></td><td align="center" valign="top"> </td></tr><tr><td> Brain edema</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> Coma</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> Convulsion</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> Somnolence</td><td align="center" valign="top"> 2 (1.5%)</td></tr><tr><td> Thinking abnormal</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> <content styleCode="bold">Respiratory system</content></td><td align="center" valign="top"> </td></tr><tr><td> Hyperventilation</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> Hypoventilation</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> Respiratory failure</td><td align="center" valign="top"> 2 (1.5%)</td></tr><tr><td> <content styleCode="bold">Terms not classifiable</content></td><td align="center" valign="top"> </td></tr><tr><td> Injection site reaction</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> <content styleCode="bold">Urogenital system</content></td><td align="center" valign="top"> </td></tr><tr><td> Cystitis</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr></tbody></table>

r" valign="top"> </td></tr><tr><td> Injection site reaction</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> <content styleCode="bold">Urogenital system</content></td><td align="center" valign="top"> </td></tr><tr><td> Cystitis</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr></tbody></table> <table><caption>TABLE 2.

r" valign="top"> </td></tr><tr><td> Injection site reaction</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr><tr><td> <content styleCode="bold">Urogenital system</content></td><td align="center" valign="top"> </td></tr><tr><td> Cystitis</td><td align="center" valign="top"> 1 ( &lt;1%)</td></tr></tbody></table> <table><caption>TABLE 2. NUMBER (%) OF STUDY EVENTS IN ACTIVE CONTROLLED CLINICAL TRIAL</caption><col/><col/><col/><tbody><tr><td align="center" valign="top" styleCode=" Botrule"> <content styleCode="bold">Body System</content> Event</td><td align="center" valign="top" styleCode=" Botrule"> <content styleCode="bold">Lorazepam Injection</content> (n=85)<footnote ID="FOOT_3217">The number indicates the number of &#x201C;patient-episodes.&#x201D; Patient-episodes were used rather than &#x201C;patients&#x201D; because a total of 7 patients were reenrolled for the treatment of a second episode of status: 5 patients received Lorazepam Injection on two occasions that were far enough apart to establish the diagnosis of status epilepticus for each episode, and, using the same time criterion, 2 patients received diazepam on two occasions.</footnote></td><td align="center" valign="top" styleCode=" Botrule"> <content styleCode="bold">Diazepam</content> (n=80)<footnoteRef IDREF="FOOT_3217"/></td></tr><tr><td valign="top"> <content styleCode="bold">Any Study Event</content> (1 or more)<footnote ID="FOOT_3218">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.</footnote></td><td align="center" valign="top"> 14 (16.5%)</td><td align="center" valign="top"> 11 (13.8%)</td></tr><tr><td valign="top"> <content styleCode="bold">Body as a whole</content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td valign="top"> Headache</td><td align="center" valign="top"> 1 ( 1.2%)</td><td align="center" valign="top"> 1 (1.3%)</td></tr><tr><td valign="top"> <content styleCode="bold">Cardiovascular system</content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td valign="top"> Hypotension</td><td align="center" valign="top"> 2 (2.4%)</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top"> <content styleCode="bold">Hemic and lymphatic system</content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td valign="top"> Hypochromic anemia</td><td align="center" valign="top"> 0</td><td align="center" valign="top"> 1 (1.3%)</td></tr><tr><td valign="top"> Leukocytosis</td><td align="center" valign="top"> 0</td><td align="center" valign="top"> 1 (1.3%)</td></tr><tr><td valign="top"> Thrombocythemia</td><td align="center" valign="top"> 0</td><td align="center" valign="top"> 1 (1.3%)</td></tr><tr><td valign="top"> <content styleCode="bold">Nervous system</content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td valign="top"> Coma</td><td align="center" valign="top"> 1 (1.2 %)</td><td align="center" valign="top"> 1 (1.3%)</td></tr><tr><td valign="top"> Somnolence</td><td align="center" valign="top"> 3 (3.5%)</td><td align="center" valign="top"> 3 (3.8%)</td></tr><tr><td valign="top"> Stupor</td><td align="center" valign="top"> 1 (1.2%)</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top"> <content styleCode="bold">Respiratory system</content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td valign="top"> Hypoventilation</td><td align="center" valign="top"> 1 (1.2%)</td><td align="center" valign="top"> 2 (2.5%)</td></tr><tr><td valign="top"> Apnea</td><td align="center" valign="top"> 1 (1.2%)</td><td align="center" valign="top"> 1 (1.3%)</td></tr><tr><td valign="

gn="center" valign="top"> </td></tr><tr><td valign="top"> Hypoventilation</td><td align="center" valign="top"> 1 (1.2%)</td><td align="center" valign="top"> 2 (2.5%)</td></tr><tr><td valign="top"> Apnea</td><td align="center" valign="top"> 1 (1.2%)</td><td align="center" valign="top"> 1 (1.3%)</td></tr><tr><td valign=" top"> Respiratory failure</td><td align="center" valign="top"> 2 (2.4%)</td><td align="center" valign="top"> 1 (1.3%)</td></tr><tr><td valign="top"> Respiratory disorder</td><td align="center" valign="top"> 1 (1.2%)</td><td align="center" valign="top"> 0</td></tr></tbody></table> <table><col/><col/><tbody><tr><td valign="top"><content styleCode="italics">BODY AS A WHOLE -</content></td><td valign="top"> Infrequent: asthenia, chills, headache, infection.</td></tr><tr><td valign="top"><content styleCode="italics">DIGESTIVE SYSTEM -</content></td><td valign="top"> Infrequent: abnormal liver function test, increased salivation, nausea, vomiting.</td></tr><tr><td valign="top"><content styleCode="italics">METABOLIC AND NUTRITIONAL -</content></td><td valign="top"> Infrequent: acidosis, alkaline phosphatase increased.</td></tr><tr><td valign="top"><content styleCode="italics">NERVOUS SYSTEM -</content></td><td valign="top"> Infrequent: agitation, ataxia, brain edema, coma, confusion, convulsion, hallucinations, myoclonus, stupor, thinking abnormal, tremor.</td></tr><tr><td valign="top">RESPIRATORY SYSTEM -</td><td valign="top"> Frequent: apnea; Infrequent: hyperventilation, hypoventilation, respiratory disorder.</td></tr><tr><td valign="top"><content styleCode="italics">TERMS NOT CLASSIFIABLE -</content></td><td valign="top"> Infrequent: injection site reaction.</td></tr><tr><td valign="top"><content styleCode="italics">UROGENITAL SYSTEM-</content></td><td valign="top"> Infrequent: cystitis.</td></tr></tbody></table>

DRUG ABUSE AND DEPENDENCE Controlled Substance Lorazepam Injection is a Schedule IV controlled substance. Abuse Lorazepam 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). Dependence PHYSICAL DEPENDENCE AFTER USE OF LORAZEPAM INJECTION MORE FREQUENTLY THAN RECOMMENDED Lorazepam 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 Lorazepam Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction 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 ).

e-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 Lorazepam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Lorazepam 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 Tolerance to Lorazepam 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.

OVERDOSAGE Symptoms Overdosage of benzodiazepines is usually manifested by varying degrees of central-nervous-system depression, ranging from drowsiness to coma. In mild cases symptoms include drowsiness, mental confusion and lethargy. In more serious examples, symptoms may include ataxia, hypotonia, hypotension, hypnosis, stages one (1) to three (3) coma, and, very rarely, death. Treatment Treatment of overdosage is mainly supportive until the drug is eliminated from the body. Vital signs and fluid balance should be carefully monitored in conjunction with close observation of the patient. An adequate airway should be maintained and assisted respiration used as needed. With normally functioning kidneys, forced diuresis with intravenous fluids and electrolytes may accelerate elimination of benzodiazepines from the body. In addition, osmotic diuretics, such as mannitol, may be effective as adjunctive measures. In more critical situations, renal dialysis and exchange blood transfusions may be indicated. Lorazepam does not appear to be removed in significant quantities by dialysis, although lorazepam glucuronide may be highly dialyzable. The value of dialysis has not been adequately determined for lorazepam. The benzodiazepine antagonist flumazenil may be used in hospitalized patients as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS , WARNINGS and PRECAUTIONS should be consulted prior to use.

DOSAGE AND ADMINISTRATION NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS, Pediatric Use ). Lorazepam must never be used without individualization of dosage particularly when used with other medications capable of producing central-nervous-system depression. EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY SHOULD BE IMMEDIATELY AVAILABLE PRIOR TO INTRAVENOUS ADMINISTRATION OF LORAZEPAM (see WARNINGS ). Status Epilepticus GENERAL ADVICE Status epilepticus is a potentially life-threatening condition associated with a high risk of permanent neurological impairment, if inadequately treated. The treatment of status, however, requires far more than the administration of an anticonvulsant agent. It involves observation and management of all parameters critical to maintaining vital function and the capacity to provide support of those functions as required. Ventilatory support must be readily available. The use of benzodiazepines, like Lorazepam Injection, is ordinarily only an initial step of a complex and sustained intervention which may require additional interventions, (e.g., concomitant intravenous administration of phenytoin). Because status epilepticus may result from a correctable acute cause such as hypoglycemia, hyponatremia, or other metabolic or toxic derangement, such an abnormality must be immediately sought and corrected. Furthermore, patients who are susceptible to further seizure episodes should receive adequate maintenance antiepileptic therapy. Any healthcare professional who intends to treat a patient with status epilepticus should be familiar with this package insert and the pertinent medical literature concerning current concepts for the treatment of status epilepticus. A comprehensive review of the considerations critical to the informed and prudent management of status epilepticus cannot be provided in drug product labeling. The archival medical literature contains many informative references on the management of status epilepticus, among them the report of the working group on status epilepticus of the Epilepsy Foundation of America “Treatment of Convulsive Status Epilepticus” (JAMA 1993; 270:854-859). As noted in the report just cited, it may be useful to consult with a neurologist if a patient fails to respond (e.g., fails to regain consciousness). INTRAVENOUS INJECTION For the treatment of status epilepticus, the usual recommended dose of Lorazepam Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures cease, no additional Lorazepam Injection is required. If seizures continue or recur after a 10- to 15-minute observation period, an additional 4 mg intravenous dose may be slowly administered. Experience with further doses of lorazepam is very limited. The usual precautions in treating status epilepticus should be employed. An intravenous infusion should be started, vital signs should be monitored, an unobstructed airway should be maintained, and artificial ventilation equipment should be available. INTRAMUSCULAR INJECTION IM lorazepam 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 ). PEDIATRIC The safety of lorazepam in pediatric patients has not been established.

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 ). PEDIATRIC The safety of lorazepam in pediatric patients has not been established. Preanesthetic INTRAMUSCULAR INJECTION For the designated indications as a premedicant, the usual recommended dose of lorazepam for intramuscular injection is 0.05 mg/kg up to a maximum of 4 mg. As with all premedicant drugs, the dose should be individualized (see CLINICAL PHARMACOLOGY , WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS ). Doses of other central-nervous-system-depressant drugs ordinarily should be reduced (see PRECAUTIONS ). For optimum effect, measured as lack of recall, intramuscular lorazepam should be administered at least 2 hours before the anticipated operative procedure. Narcotic analgesics should be administered at their usual preoperative time. There are insufficient data to support efficacy or make dosage recommendations for intramuscular lorazepam in patients less than 18 years of age; therefore, such use is not recommended. INTRAVENOUS INJECTION For the primary purpose of sedation and relief of anxiety, the usual recommended initial dose of lorazepam for intravenous injection is 2 mg total, or 0.02 mg/lb (0.044 mg/kg), whichever is smaller. This dose will suffice for sedating most adult patients and ordinarily should not be exceeded in patients over 50 years of age. In those patients in whom a greater likelihood of lack of recall for perioperative events would be beneficial, larger doses as high as 0.05 mg/kg up to a total of 4 mg may be administered (see CLINICAL PHARMACOLOGY , WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS ). Doses of other injectable central-nervous-system-depressant drugs ordinarily should be reduced (see PRECAUTIONS ). For optimum effect, measured as lack of recall, intravenous lorazepam should be administered 15 to 20 minutes before the anticipated operative procedure. There are insufficient data to support efficacy or make dosage recommendations for intravenous lorazepam in patients less than 18 years of age; therefore, such use is not recommended. Dose Administration in Special Populations ELDERLY PATIENTS AND PATIENTS WITH HEPATIC DISEASE No dosage adjustments are needed in elderly patients and in patients with hepatic disease. PATIENTS WITH RENAL DISEASE For acute dose administration, adjustment is not needed for patients with renal disease. However, in patients with renal disease, caution should be exercised if frequent doses are given over relatively short periods of time (see CLINICAL PHARMACOLOGY ). DOSE ADJUSTMENT DUE TO DRUG INTERACTIONS The dose of lorazepam should be reduced by 50% when coadministered with probenecid or valproate (see PRECAUTIONS, Drug Interactions ). It may be necessary to increase the dose of lorazepam in female patients who are concomitantly taking oral contraceptives. Administration When given intramuscularly, Lorazepam Injection, undiluted, should be injected deep in the muscle mass. Injectable lorazepam can be used with atropine sulfate, narcotic analgesics, other parenterally used analgesics, commonly used anesthetics, and muscle relaxants. Immediately prior to intravenous use, Lorazepam Injection must be diluted with an equal volume of compatible solution. Contents should be mixed thoroughly by gently inverting the container repeatedly until a homogenous solution results. Do not shake vigorously, as this will result in air entrapment. When properly diluted, the drug may be injected directly into a vein or into the tubing of an existing intravenous infusion. The rate of injection should not exceed 2.0 mg per minute.

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

HOW SUPPLIED Lorazepam Injection, USP is available in the following dosage strengths in single-dose and multiple-dose vials: 2 mg per mL, NDC 0641-6048-25, 25 x 1 mL vial NDC 0641-6050-10, 10 x 10 mL vial 4 mg per mL, NDC 0641-6049-25, 25 x 1 mL vial NDC 0641-6051-10, 10 x 10 mL vial For IM or IV injection. Store in a refrigerator. PROTECT FROM LIGHT. Use carton to protect contents from light.