Oxazepam

Indications

• FDA-approved for anxiety, tension, agitation and irritability, including anxiety associated with depression, in adults.
• FDA-approved specifically for anxiety, tension, agitation and irritability in older patients, an unusual labeled geriatric indication.
• FDA-approved for acute alcohol withdrawal, covering tremulousness, anxiety and agitation in patients with acute inebriation.
• Preferred over chlordiazepoxide or diazepam for alcohol withdrawal when cirrhosis or significant hepatic impairment is present.
• Off-label as a substitution agent during benzodiazepine tapers when a low-reinforcement, oxidation-independent option is wanted.
• Not a maintenance treatment for anxiety disorders; SSRIs, SNRIs and psychotherapy remain first line by APA, NICE and CANMAT guidance.

Mechanism of action

• Positive allosteric modulator at the GABA-A benzodiazepine site, increasing chloride channel opening frequency and reducing neuronal excitability.
• Slow absorption and modest lipophilicity give a gradual rise in brain concentration, which blunts the euphoric rush and lowers misuse appeal.
• Non-selective alpha subunit binding still delivers sedation, amnesia and ataxia along with anxiolysis, so impairment is not avoided.
• Cross-tolerance at GABA-A with alcohol provides symptomatic control and seizure protection during acute alcohol withdrawal.
• As the terminal active metabolite of diazepam and temazepam, it represents the endpoint of that oxidative pathway with nothing further to accumulate.

Pharmacokinetics

• Absorption is slower than other benzodiazepines with peak levels at 2-4 hours, so it is a poor choice for rapid symptom relief.
• Elimination half-life is roughly 8 hours, giving three or four times daily dosing and little accumulation between days.
• Conjugated directly by UGT2B15 glucuronidation to an inactive glucuronide excreted in urine, with no active metabolites at all.
• Hepatic oxidation is bypassed entirely, so clearance is largely preserved in cirrhosis and is not altered by CYP inhibitors or inducers.
• With lorazepam and temazepam, this glucuronidation-only pathway defines the three benzodiazepines preferred in liver disease and in older adults.

Dosing

• Mild to moderate anxiety: 10-15 mg PO three or four times daily, titrated to symptom control and tolerability.
• Severe anxiety syndromes and acute alcohol withdrawal: 15-30 mg PO three or four times daily, up to 120 mg/day in divided doses.
• Older adults: begin at 10 mg three times daily and increase cautiously to 15 mg three or four times daily only if clearly needed.
• No dose adjustment is required for hepatic impairment, which is the practical reason to select this agent in cirrhotic patients.
• Available as oral capsules in 10, 15 and 30 mg strengths; there is no parenteral, liquid or extended-release formulation.
• Taper by 10-25 percent every 1-2 weeks after chronic use; abrupt discontinuation can produce withdrawal seizures, delirium and death.

Adverse effects

• Mild transient drowsiness is the most common effect early in therapy, along with dizziness, vertigo and headache.
• Ataxia, slurred speech and impaired coordination at higher doses, with measurable psychomotor and driving impairment.
• Falls, fracture, confusion and delirium in older adults, the same class risk despite the labeled geriatric indication.
• Paradoxical excitement, disinhibition and rage reactions, reported particularly in older adults and patients with brain injury.
• Rare leukopenia, hepatic dysfunction and jaundice have been reported; syncope has occurred rarely at higher doses.
• Additive respiratory depression and overdose death with opioids or alcohol, and full withdrawal syndrome including seizures after chronic use.

Monitoring

• Assess sedation, gait, cognition and falls at each visit, and reconfirm that the indication still justifies continued benzodiazepine exposure.
• Use CIWA-Ar or a similar validated instrument to guide symptom-triggered dosing during acute alcohol withdrawal.
• Screen for substance use disorder and check the prescription drug monitoring program before initiating and periodically thereafter.
• Obtain periodic CBC and liver enzymes during prolonged therapy given rare reports of leukopenia and hepatic dysfunction.
• In alcohol withdrawal give thiamine before glucose and correct magnesium, potassium and phosphate alongside benzodiazepine dosing.

Interactions

• Additive respiratory depression and death with opioids, plus compounding sedation with alcohol, gabapentinoids, antipsychotics and hypnotics.
• Essentially free of CYP-mediated interactions, making it a practical choice for patients on ritonavir, rifampin or carbamazepine.
• Probenecid and valproate inhibit glucuronidation and can raise exposure; consider reducing the dose when either is co-prescribed.
• Contraindicated in known benzodiazepine hypersensitivity and in psychoses where benzodiazepine monotherapy is not appropriate.
• Avoid in untreated obstructive sleep apnea, severe respiratory insufficiency and acute narrow-angle glaucoma.

Special populations

• Pregnancy: benzodiazepine exposure late in pregnancy causes neonatal sedation, hypotonia and withdrawal; avoid or use the lowest effective dose.
• Lactation: transfer into milk is low and there are no active metabolites, but monitor the infant for sedation and poor feeding.
• Pediatrics: dosage is not established below age 6 and no dosing recommendation exists for children aged 6 to 12 years.
• Older adults: the AGS Beers Criteria advise avoiding benzodiazepines, though oxazepam is among the least problematic when one is required.
• Hepatic impairment: the preferred benzodiazepine in cirrhosis along with lorazepam and temazepam because oxidation is not required.

Clinical pearls

• Slow onset makes it less reinforcing than alprazolam but also poor for as-needed panic relief.
• It is the terminal active metabolite of diazepam, so nothing accumulates downstream of it.
• Glucuronidation only, so no CYP interactions and no dose change needed in liver disease.