Oxazepam

• 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 use 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 oxazepam, 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 oxazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction [see WARNINGS ] .
• The continued use of benzodiazepines, including oxazepam, 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 oxazepam 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 oxazepam or reduce the dosage [see DOSAGE AND ADMINISTRATION and WARNINGS ].

History of previous hypersensitivity reaction to oxazepam. Oxazepam is not indicated in psychoses.

• Concomitant use of benzodiazepines, including oxazepam, 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 oxazepam 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 oxazepam than indicated in the absence of an opioid and titrate based on clinical response.
• If an opioid is initiated in a patient already taking oxazepam, 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 oxazepam 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 :
• The use of benzodiazepines, including oxazepam, 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 oxazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool).
• Use of oxazepam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of oxazepam 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.
• To reduce the risk of withdrawal reactions, use a gradual taper to discontinue oxazepam or reduce the dosage (a patient-specific plan should be used to taper the dose) [see DOSAGE AND ADMINISTRATION :
• 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 oxazepam, may lead to clinically significant physical dependence.
• Abrupt discontinuation or rapid dosage reduction of oxazepam 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 ] .
• As with other CNS-acting drugs, patients should be cautioned against driving automobiles or operating dangerous machinery until it is known that they do not become drowsy or dizzy on oxazepam therapy.
• Patients should be warned that the effects of alcohol or other CNS-depressant drugs may be additive to those of Oxazepam, possibly requiring adjustment of dosage or elimination of such agents.
• Neonatal Sedation and Withdrawal Syndrome Use of oxazepam 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 oxazepam during pregnancy or labor for signs of sedation and monitor neonates exposed to oxazepam during pregnancy for signs of withdrawal; manage these neonates accordingly.
• General Although hypotension has occurred only rarely, oxazepam should be administered with caution to patients in whom a drop in blood pressure might lead to cardiac complications.
• This is particularly true in the elderly patient.
• Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide).
• 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.
• Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including oxazepam 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 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 estimated 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 oxazepam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.
• Monitor neonates exposed to oxazepam 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 Oxazepam is present in breast milk.
• There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk [see Clinical Considerations].
• The effects of oxazepam on milk production are unknown.
• The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for oxazepam and any potential adverse effects on the breastfed infant from oxazepam or from the underlying maternal condition.
• Clinical Considerations Infants exposed to oxazepam through breast milk should be monitored for sedation, poor feeding and poor weight gain.
• Pediatric Use Safety and effectiveness in pediatric patients under 6 years of age have not been established.
• Geriatric Use Clinical studies of oxazepam were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects.
• General Although hypotension has occurred only rarely, oxazepam should be administered with caution to patients in whom a drop in blood pressure might lead to cardiac complications. This is particularly true in the elderly patient.

• 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 a poison center (1-800-222-1222), poisoncontrol.org, or a medical toxicologist for additional overdosage management recommendations.

• Controlled Substance Oxazepam is a schedule IV controlled substance.
• Abuse Oxazepam is a benzodiazepine and a CNS depressant with a potential for abuse and addiction.
• Abuse is the intentional, nontherapeutic 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 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 Oxazepam 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 oxazepam or reduce the dosage [see DOSAGE AND ADMINISTRATION :
• Discontinuation or Dosage Reduction of Oxazepam and 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 oxazepam 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 oxazepam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.