CLORAZEPATE DIPOTASSIUM

INDICATIONS AND USAGE Clorazepate dipotassium tablets are indicatedfor the management of anxiety disordersorfortheshort-term relief of the symptoms of anxiety. Anxiety or tensionassociatedwith the stress of everyday life usually does not require treatmentwith an anxiolytic. Clorazepate dipotassium tablets are indicated as adjunctivetherapy in themanagement of partialseizures. Theeffectiveness of Clorazepate dipotassium tablets in long-term management of anxiety, that is,more than 4 months, has not beenassessed by systematicclinicalstudies.Long-term studies in epilepticpatients,however, have showncontinuedtherapeuticactivity.Thephysician should reassessperiodically the usefulnessof the drug for the individualpatient. Clorazepate dipotassium tabletsare indicatedfor the symptomaticrelief of acute alcoholwithdrawal.

DOSAGE AND ADMINISTRATION FortheSymptomatic ReliefofAnxiety: Clorazepate dipotassium tablets are administeredorally in divided doses. The usual daily dose is 30mg.The dose should beadjustedgraduallywithintherange of 15 to 60 mg daily in accordancewith the response of the patient. In elderly or debilitatedpatientsit is advisable to initiate treatment at a daily dose of 7.5 to 15 mg. Clorazepate dipotassium tabletsmay also be administeredin a singledosedaily at bedtime; the recommendedinitialdose is 15 mg.After the initial dose, the response of the patient mayrequireadjustment of subsequent dosage.Lower doses may be indicated in the elderlypatient. Drowsinessmay occur at the initiation of treatment and withdosageincrement. For the Symptomatic Relief of Acute Alcohol Withdrawal: Thefollowing dosage scheduleisrecommended: 1st 24 hours (Day 1) 30 mginitially;followed by 30 to 60 mg in divideddoses 2nd 24 hours (Day 2) 45 to 90 mg in divideddoses 3rd 24 hours (Day 3) 22.5 to 45 mg in divided doses Day 4 15 to 30 mg in divideddoses Thereafter,graduallyreduce the daily dose to 7.5 to 15 mg.Discontinuedrugtherapy as soon as patient’s condition is stable. Themaximum recommendedtotaldailydose is 90 mg. Avoid excessive reductionsin the totalamount of drug administeredonsuccessive days. As an Adjunct to Antiepileptic Drugs: In order to minimizedrowsiness, the recommendedinitialdosages and dosageincrementsshould not be exceeded. Adults: Themaximum recommendedinitialdose in patients over 12 years old is 7.5 mg three times a day. Dosage should be increased by no more than 7.5mg every week and should not exceed 90 mg/day. Children (9-12 years): Themaximum recommendedinitial dose is 7.5 mgtwotimes a day. Dosage should be increased by no more than 7.5mg every week and should not exceed 60 mg/day. Discontinuation or DosageReduction of Clorazepate dipotassium tablets: To reduce the risk of withdrawalreactions,use a gradualtaper to discontinueClorazepate dipotassium tablets or reduce the dosage. If a patient develops withdrawalreactions,consider pausing the taper or increasingthe dosage to the previous tapereddosage level. Subsequentlydecreasethedosagemoreslowly (see WARNINGS and DRUG ABUSE AND DEPENDENCE ).

WARNINGS Risks from Concomitant Use with Opioids: Concomitant use of benzodiazepines, including Clorazepate dipotassium tablets, 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 Clorazepate dipotassium tablets 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 Clorazepate dipotassium tablets than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Clorazepate dipotassium tablets, 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 Clorazepate dipotassium tablets 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 Clorazepate dipotassium tablets, 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 Clorazepate dipotassium tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of Clorazepate dipotassium tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Clorazepate dipotassium tablets 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 Clorazepate dipotassium tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation of Dosage Reduction of Clorazepate dipotassium 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 Clorazepate dipotassium tablets, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Clorazepate dipotassium tablets 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…

CONTRAINDICATIONS Clorazepate dipotassium tabletsare contraindicated in patientswith a knownhypersensitivityto the drug and in those withacutenarrow angle glaucoma.

DRUG INTERACTIONS Theconcomitant use of benzodiazepines and opioidsincreases the riskof respiratorydepressionbecause of actionsatdifferentreceptor sites in the CNS that control respiration.Benzodiazepinesinteract at GABAA sites and opioidsinteractprimarilyatmu receptors. Whenbenzodiazepinesand opioids arecombined, the potentialforbenzodiazepinestosignificantlyworsenopioid-relatedrespiratorydepressionexists.Limitdosageandduration of concomitant use of benzodiazepines and opioids, and monitorpatients closelyforrespiratorydepressionandsedation. If Clorazepate dipotassium tablets is to be combined with other drugs acting on the central nervous system, careful consideration should be given to thepharmacology of the agentsto be employed.Animalexperienceindicates that clorazepatedipotassium prolongs thesleepingtimeafterhexobarbital or afterethylalcohol,increases the inhibitoryeffects of chlorpromazine, but does not exhibitmonoamineoxidaseinhibition.Clinicalstudies have shownincreasedsedationwithconcurrent hypnotic medications.Theactions of the benzodiazepines may be potentiated by barbiturates,narcotics,phenothiazines,monoamine oxidase inhibitors or other antidepressants. If Clorazepate dipotassium tablets are used to treatanxietyassociatedwithsomatic disease states,carefulattentionmust be paid to possible druginteractionwith concomitantmedication. In bioavailabilitystudieswithnormalsubjects,theconcurrentadministration of antacidsattherapeuticlevelsdid not significantlyinfluencethebioavailability of Clorazepate dipotassium tablets.

Pregnancy: Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including Clorazepate dipotassium tablets, during pregnancy. Healthcare providers are encouraged to register patients 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 background risk of major birth defects and 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 Clorazepate dipotassium during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Clorazepate dipotassium 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 In animal reproduction studies, oral administration of clorazepate to pregnant rats and rabbits at doses up to 150 and 15 mg/kg, respectively, did not cause fetal toxicities or malformation. However, the sedative effects of high dose clorazepate interfered with the maternal care of the offspring.

Nursing Mothers: Risk Summary Clorazepate and its active metabolite, nordiazepam, are 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 clorazepate on milk production are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in infants, advise patients that breastfeeding is not recommended during treatment with Clorazepate dipotassium.

ADVERSE REACTIONS The side effectmostfrequentlyreported wasdrowsiness.Lesscommonlyreported (in descending order of occurrence)were:dizziness, various gastrointestinal complaints,nervousness, blurred vision, dry mouth,headache, and mentalconfusion.Other side effects included insomnia,transientskinrashes,fatigue,ataxia,genitourinarycomplaints,irritability,diplopia,depression,tremor, and slurredspeech. There have been reports of abnormalliver and kidneyfunction tests and of decrease in hematocrit. Decrease in systolicbloodpressurehas been observed. 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 .