Oxazepam


Article Author:
Ravneet Singh


Article Editor:
Sara Abdijadid


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Donald Kushner


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Hajira Basit
Phillip Hynes


Updated:
6/28/2019 10:15:13 AM

Indications

Oxazepam is an FDA-approved benzodiazepine used for the treatment of alcohol withdrawal as well as management of anxiety disorders. Oxazepam has a variety of uses, including several outside of its approved indications such as confusional arousals, sleep terrors, social phobia, PTSD, insomnia, PMDD and catatonia. Currently, oxazepam is not FDA-approved for use in children under the age of six due to the risk of respiratory arrest. Oxazepam can also be a recommended agent in patients who have difficulties remaining asleep in contrast to drugs helping to initiate sleep.[1][2]

Oxazepam classifies, as a short-intermediate acting benzodiazepine; its efficacy in long term use has undergone evaluation in clinical studies. The Convention of Psychotropic Substances classifies oxazepam as a Schedule IV substance, meaning that oxazepam has a lower potential for abuse relative to substances in Schedule III substances (ex. ketamine.)[3]

Mechanism of Action

Benzodiazepines are among the most prescribed medications for the treatment of insomnia and anxiety. Unlike long-acting benzodiazepines ( over 24 hours), short (0 to 6 hours) and intermediate (6 to 24 hours) benzodiazepines do not undergo oxidation by cytochrome P450. Therefore, short-intermediate-acting benzodiazepines like oxazepam are in an active form and undergo direct glucuronidation to produce inactive metabolites.[4]

Benzodiazepines bind to GABA-A receptors, which consist of ligand-gated chloride ion channels that mediate inhibition of the synapses in the CNS. Benzodiazepines bind as allosteric modulators and increase the number of chloride ions crossing the cell membrane. Once benzodiazepines bind to the receptor, the GABA receptor changes conformation and has increased affinity for GABA. This conformational change causes an increased frequency in opening chloride ion channels and, subsequently, hyperpolarization of the neuronal cell membrane occurs, resulting in a decreased rate of firing of the synapse.[3]

Oxazepam is a short-acting benzodiazepine that is metabolized via glucuronidation out the liver into its inactive metabolites, hence it is a preferred drug in patients with hepatic impairment.  It does not have any active metabolites. The drug has a rapid onset of action and an elimination half-life of between 3 to 21 hours. Elimination is via the renal pathway. Oxazepam is not subject to CYP interaction and does not accumulate upon CYP inhibition.[5]

Administration

Oxazepam is administered orally as a capsule of 10 mg, 15 mg or 30 mg or tablet of 15 mg. DOsing is without regard to meals. No dose adjustments are needed for patients with hepatic or renal impairments, though caution advised in renally impaired.[6]

For anxiety:

  • In adults with mild to moderate anxiety; administer 10 to 15 mg orally every 6 to 8 hours, do not exceed 120 mg daily
  • In adults with severe anxiety or agitation; administer 15 to 30 mg orally every 6 to 8 hours
  • In children age 6 to 12; there are no clear guidelines, but may administer 1mg/kg/day by mouth; dose divided to 3 times a day  
  • In the geriatric population: administer 10 to 15 mg orally three or four times daily initially and increase the dose with caution if needed - it is recommended not to exceed 60 mg per day. 

For alcohol withdrawal:  

  • In adults; administer 15 mg orally three times daily

Oxazepam has no indications in children under the age of six. 

It is generally not necessary to titrate oxazepam. It is recommended to use the lowest effective dose possible for the shortest timeframe possible.

Adverse Effects

Common adverse effects associated with benzodiazepines such as oxazepam may include sedation, fatigue, depression, confusion, memory impairment, dizziness, ataxia, slurred speech, hyper-excitability, nervousness, and weakness. Less frequently encountered adverse effects may involve hypotension, hallucinations, mania, dry mouth, hypersalivation, edema, leukopenia, decreased libido, incontinence, rash, menstrual irregularities, jaundice, and diplopia. Severe adverse effects of oxazepam include respiratory depression and neonatal abstinence syndrome. Anterograde amnesia also has correlations with benzodiazepine use.[7]

Several cases of fixed drug eruptions, which clinically present as demarcated ovular macules, have been noted in patients taking oxazepam. In these select cases, however, urticaria and diffuse exanthems have not been observed.[8]

Contraindications

Patients taking oxazepam for insomnia are advised to avoid caffeine-containing products as they may decrease the efficacy of the drug. Coadministering oxazepam with other CNS depressants such as diphenhydramine or hydrocodone may result in enhancement of CNS effects (e.g., severe sedation and respiratory depression). It is also not recommended for those who suffer from sleep apnea.[9]

Concurrent use of opioid agonists such as methadone, morphine, and naltrexone may result in respiratory depression, severe hypotension, and sedation. 

Oxazepam may also cross the placenta and may be excreted into breastmilk; thus, it is not recommended in pregnant or nursing women. According to the FDA categorization of the safety of medications during pregnancy, there is evidence of risk to the fetus when using benzodiazepines during pregnancy. In some instances, potential benefits may still justify use. In mothers receiving benzodiazepines during pregnancy, neonatal flaccidity, as well as withdrawal symptoms, may be present.[10]

Oxazepam use is not recommended for geriatric patients due to increased risk of dependence and cognitive impairment as well as falls. Several studies have indicated that long term use of benzodiazepines such as oxazepam may potentiate the development of dementia in the elderly; clinicians should exercise caution when prescribing oxazepam in the geriatric population.[11]

Patients who have demonstrated hypersensitivity to previous oxazepam use or other benzodiazepines are not recommended to take oxazepam. Also, patients with substance misuse disorders should not be prescribed oxazepam. 

Monitoring

For patients using oxazepam, it is critical to monitor cardiovascular and respiratory status. Hemodynamic stability and vital signs also require frequent monitoring. Benzodiazepine adverse effects, overdose, toxicity can present as other conditions—especially in long term oxazepam use—so it is crucial to collect appropriate labs such as CBC, BUN/creatinine, and other serum values when deemed necessary. 

Toxicity

A patient with oxazepam overdose typically presents with normal vital signs with severe CNS depression. Clinical symptoms may include ataxia, slurred speech, confusion, drowsiness, and lethargy. Comatose patients are also commonly seen with severe toxicity. Respiratory compromise most commonly occurs when patients intentionally ingest benzodiazepine with another sedative agent such as an opioid. Oxazepam is least sedating among all benzodiazepines due to slower absorption.[12][13][14]

If toxicity is suspected, maintenance of airway, breathing, and circulation must be rapid and immediate. Intubation may be necessary if there is a severe compromise.

If the clinician suspects an isolated oxazepam overdose with a patient having stable hemodynamics and relatively normal physical examination, monitoring of vital signs and clinical observation are appropriate. 

In patients who are in respiratory compromise due to oxazepam toxicity, they may have also taken another drug such as an opioid. Therefore, it may be appropriate to administer naloxone. Flumazenil, a competitive benzodiazepine receptor antagonist, can be administered to reverse an overdose. However, the administration may precipitate withdrawal seizures in patients who chronically use benzodiazepines and have developed tolerance.[15][16]

Enhancing Healthcare Team Outcomes

Oxazepam is a commonly prescribed benzodiazepine and can potentially be subject to misuse. Managing patients on oxazepam requires an interdisciplinary team of healthcare professionals, including nurses, laboratory technicians, pharmacists, and different specialty physicians. The healthcare team must vigilantly monitor patients on oxazepam by observing for changes in hemodynamic stability (respiratory compromise) or of patient demeanor (stupor, altered mental status). Careful consideration of adverse effects and signs of toxicity by the interprofessional team is necessary to ensure effective treatment and care for patients who exhibit signs of oxazepam use toxicity. Additionally, prescribers and pharmacists collaborate in improving patient safety outcomes through CURES report and could help decrease the likelihood of drug-drug interaction by prescribing oxazepam to a patient receiving an opioid therapy through another provider.

In summary, oxazepam therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


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Oxazepam - Questions

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A 79-year-old male comes to the clinic complaining of fatigue and tiredness. He is sleep-deprived and usually gets only 3-4 hours of sleep. He is not stressed, shows no signs of depression, and no trauma has occurred. His appetite and diet are normal, and his weight is appropriate for his age. He further states that he can initiate sleep but is not able to remain asleep. Physical examination, vital signs, laboratory tests, and imaging are all within normal limits. He has a past medical history of hypertension, which is managed with lisinopril and denies other symptoms. What is the most appropriate next step in the management?



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A 50-year-old female presents to the clinic complaining of fatigue and inability to concentrate on her work for the past two months. When asked about her day-to-day life, the patient states she constantly worries about failing at her job as an accountant and about her son's health. When asked about her sleep and appetite, the patient reports feeling restless at night and is tired throughout the day. She has tried relaxation techniques and adjusted her sleep routine as suggested at previous visits. She has a major presentation at work next week. What is the next step in management for this patient?



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A 40-year-old male with a history of alcohol use disorder is admitted to the hospital for skin lacerations following a motor vehicle accident. Urgent care is given with intravenous fluids and sutures where required. On physical examination, the blood pressure is 130/82 mmHg. The pulse is 86/min, respiratory rate is 18/min, and temperature is 98.7 F. After 5 hours, the nurse goes to draw blood, and the patient refuses, citing restlessness and agitation. The patient yells and states that his heart is pounding and he would not let anyone come close to him. He has a previous history of hepatitis C that has been treated. What is the next step in management?



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A 65-year-old male patient presents to the clinic complaining of severe daytime drowsiness for the past two days. Upon detailed inquiry, the patient reports he is currently on oxazepam for insomnia and taking diphenhydramine for allergic rhinitis. His vital signs are BP 137/89 mmHg, pulse 85 per minute, respiratory rate 18 per minute, and temperature 98.6F. physical examination is unremarkable. What is the next step in management?



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A 54-year-old war veteran presents to the clinic complaining of anxiety and agitation. His past medical history consists of liver failure due to hepatitis C and post-traumatic stress disorder (PTSD). Vital signs and physical examination show no abnormalities. Lab studies are significant for AST of 54 IU/L and ALT of 65 IU/L. The patient denies any other symptoms or pain. He is currently taking an SSRI and vitamins. Which of the following is the next best step in the management of this patient?



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Oxazepam - References

References

Metabolic profile of oxazepam and related benzodiazepines: clinical and forensic aspects., Dinis-Oliveira RJ,, Drug metabolism reviews, 2017 Sep 14     [PubMed]
Singh I,Oosthuizen F, A retrospective review on benzodiazepine use: A case study from a chronic dispensary unit. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde. 2019 Jan 31;     [PubMed]
Krischer J,Prins C,Ruffieux P,Kondo-Oestreicher M,Saurat JH, Extensive fixed drug eruption induced by oxazepam. Archives of dermatology. 1996 Jun;     [PubMed]
Hok L,BoŽičević L,Sremec H,Šakić D,Vrček V, Racemization of oxazepam and chiral 1,4-benzodiazepines. DFT study of the reaction mechanism in aqueous solution. Organic     [PubMed]
Howland RH, Safety and Abuse Liability of Oxazepam: Is This Benzodiazepine Drug Underutilized? Journal of psychosocial nursing and mental health services. 2016 Apr;     [PubMed]
de Leon J, Glucuronidation enzymes, genes and psychiatry. The international journal of neuropsychopharmacology. 2003 Mar;     [PubMed]
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Martinez L,Vorspan F,Declèves X,Azuar J,Fortias M,Questel F,Dereux A,Grichy L,Barreteau H,Bellivier F,Lépine JP,Bloch V, An observational study of benzodiazepine prescription during inpatient alcohol detoxification for patients with vs. without chronic pretreatment with high-dosage baclofen. Fundamental     [PubMed]
Flint AJ, Generalised anxiety disorder in elderly patients : epidemiology, diagnosis and treatment options. Drugs     [PubMed]
Iqbal MM,Sobhan T,Ryals T, Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatric services (Washington, D.C.). 2002 Jan;     [PubMed]
Höjer J, [Flumazenil--a valuable diagnostic agent in coma but only with clear indications]. Lakartidningen. 1992 Feb 19;     [PubMed]
Höjer J,Baehrendtz S,Gustafsson L, Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. Journal of internal medicine. 1989 Aug;     [PubMed]
Sake FT,Wong K,Bartlett DJ,Saini B, Benzodiazepine usage and patient preference for alternative therapies: A descriptive study. Health science reports. 2019 May;     [PubMed]
Buckley NA,Dawson AH,Whyte IM,O'Connell DL, Relative toxicity of benzodiazepines in overdose. BMJ (Clinical research ed.). 1995 Jan 28;     [PubMed]
Marriott S,Tyrer P, Benzodiazepine dependence. Avoidance and withdrawal. Drug safety. 1993 Aug;     [PubMed]
Jones CM,McAninch JK, Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines. American journal of preventive medicine. 2015 Oct;     [PubMed]

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