LORAZEPAM

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 ).

WARNINGS Risks from Concomitant Use with Opioids Concomitantuse of benzodiazepines, including lorazepam,andopioidsmayresult in profoundsedation,respiratorydepression,coma,anddeath.Because of theserisks,reserveconcomitantprescribing of these drugs in patients for whomalternativetreatmentoptionsareinadequate. Observationalstudieshavedemonstratedthatconcomitantuse of opioid analgesicsandbenzodiazepinesincreases the risk of drug-relatedmortalitycompared to use of opioidsalone. If a decision is made to prescribelorazepam concomitantlywithopioids,prescribe the lowesteffectivedosagesandminimumdurations of concomitantuse,andfollowpatientsclosely for signsandsymptoms of respiratorydepression andsedation. In patientsalreadyreceivinganopioidanalgesic,prescribe a lowerinitialdose of lorazepam thanindicated in theabsence of anopioidandtitratebased on clinicalresponse. If an opioid is initiated in a patientalreadytakinglorazepam,prescribe a lowerinitialdose of the opioidandtitratebased upon clinicalresponse. Advise both patientsandcaregiversabout the risks of respiratorydepressionandsedationwhenlorazepam is usedwithopioids.Advisepatients not to drive or operateheavymachineryuntil the effects of concomitantusewith the opioidhavebeendetermined(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 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.

ADVERSE REACTIONS Mostadversereactions to benzodiazepines,includingCNSeffectsandrespiratorydepression,aredose dependent,withmoresevereeffectsoccurringwithhighdoses. In a sample of about3500patientstreated for anxiety, the mostfrequentadversereaction to lorazepam wassedation(15.9%),followedbydizziness(6.9%),weakness(4.2%),andunsteadiness(3.4%). The incidence of sedationandunsteadinessincreasedwithage. Otheradversereactions to benzodiazepines,includinglorazepam arefatigue,drowsiness,amnesia,memoryimpairment,confusion,disorientation,depression,unmasking of depression,disinhibition,euphoria,suicidalideation/attempt,ataxia,asthenia,extrapyramidalsymptoms,convulsions/seizures,tremor,vertigo,eyefunction/visualdisturbance(includingdiplopiaandblurredvision),dysarthria/slurred speech,change in libido,impotence,decreasedorgasm;headache,coma;respiratorydepression,apnea,worsening of sleepapnea,worsening of obstructivepulmonarydisease;gastrointestinalsymptoms includingnausea,change in appetite,constipation,jaundice,increase in bilirubin,increase in liver transaminases,increase in alkalinephosphatase;hypersensitivityreactions,anaphylactoidreactions;dermatologicalsymptoms,allergicskinreactions,alopecia;syndrome of inappropriateantidiuretic hormone(SIADH),hyponatremia;thrombocytopenia,agranulocytosis,pancytopenia;hypothermia;andautonomicmanifestations. Paradoxicalreactions,includinganxiety,excitation,agitation,hostility,aggression,rage,sleepdisturbances/insomnia,sexualarousal,andhallucinationsmayoccur.Small decreases in blood pressure andhypotensionmayoccur but areusually not clinicallysignificant,probablybeingrelated to therelief of anxietyproducedbylorazepam. To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.