rescribe 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 ). 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. 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: clinically significant drug interactions ). use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence. as with all patients on cns-depressant drugs, patients receiving lorazepam should be warned not to operate dangerous machinery or motor vehicles and that their tolerance for alcohol and other cns depressants will be diminished.

before bedtime, but the daily dosage may vary from 1 mg/day to 10 mg/day. for anxiety, most patients require an initial dose of 2 mg/day to 3 mg/day given twice daily or three times daily. for insomnia due to anxiety or transient situational stress, a single daily dose of 2 mg to 4 mg may be given, usually at bedtime. for elderly or debilitated patients, an initial dosage of 1 mg/day 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 ).

ve pulmonary disease; gastrointestinal symptoms including nausea, change in appetite, constipation, jaundice, increase in bilirubin, increase in liver transaminases, increase in alkaline phosphatase; hypersensitivity reactions, anaphylactic/oid reactions; dermatological symptoms, allergic skin reactions, alopecia; 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 akorn operating company llc at 1- 800- 932-5676 or fda at 1-800-fda-1088 or www.fda.gov/medwatch. drug abuse and dependence controlled substance lorazepam oral concentrate 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 ) . 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 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.

the possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. patients should be advised that if they become pregnant, they should communicate with their physician about the desirability of discontinuing the drug. in humans, blood levels obtained from umbilical cord blood indicate placental transfer of lorazepam and lorazepam glucuronide. infants of mothers who ingested benzodiazepines for several weeks or more preceding delivery have been reported to have withdrawal symptoms during the postnatal period. symptoms such as hypoactivity, hypotonia, hypothermia, respiratory depression, apnea, feeding problems, and impaired metabolic response to cold stress have been reported in neonates born of mothers who have received benzodiazepines during the late phase of pregnancy or at delivery.

of lorazepam on administration up to six 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 mg 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.

on; 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 ). 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 results in increased plasma concentrations and reduced clearance of lorazepam. lorazepam dosage should be reduced to approximately 50% when co-administered 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 co-administered 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.