Lorazepam

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Benzodiazepine, Anxiolytic, Schedule IV controlled substance

Lorazepam

Ativan (oral, injectable), Loreev XR

Experience

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Problems

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Titration strategies

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Effects

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Monitoring

Boxed warning: in September 2020 the FDA required an updated boxed warning across the benzodiazepine class for the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions.^[2] Physical dependence can develop with continued use even at prescribed doses, and abrupt discontinuation or rapid dose reduction can precipitate acute, sometimes life-threatening withdrawal (including seizures), so prolonged use requires a gradual, individualized taper. This is in addition to the earlier boxed warning for fatal respiratory depression, coma, and death when benzodiazepines are combined with opioids or other CNS depressants.^[3] The intravenous formulation of lorazepam is solubilized in propylene glycol; high-dose or prolonged continuous infusion (for example in refractory status epilepticus or prolonged intensive-care sedation) can cause propylene glycol to accumulate, producing a high-anion-gap metabolic (lactic) acidosis, hyperosmolarity, and acute kidney injury. The osmolar gap and serum lactate should be monitored when large cumulative intravenous doses are given.^[4]

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Pharmacy

Starting dose

Anxiety: 0.5-1 mg PO BID-TID. Insomnia: 1-2 mg PO at bedtime. Status epilepticus: 4 mg IV (adult), repeat after 5-10 minutes if needed. Acute agitation: 1-2 mg IM

Preparations

Tablets 0.5, 1, 2 mg; oral concentrate 2 mg/mL; injection 2 mg/mL and 4 mg/mL; Loreev XR capsules 1, 2, 3 mg

US FDA Max

10 mg/day (anxiety, oral)

Common uses

Classification(s)

Classes

Benzodiazepine, Anxiolytic, Schedule IV controlled substance

Pharmacology

Routes

Oral, intramuscular, intravenous

Onset

30-60 minutes (oral); 5 minutes (IV); 15-30 minutes (IM)

Duration

6-8 hours

Half-life

12-15 hours (intermediate); no active metabolites (key clinical feature)^[1]

Bioavailability

~90% (oral)^[1]

Pregnancy

Some signal for cleft lip/palate with first-trimester exposure (debated); neonatal sedation and withdrawal with third-trimester exposure.^{[citation needed]}

Legal status

Schedule IV controlled substance in US. Carries the benzodiazepine class Boxed Warning for risk of fatal respiratory depression, coma, and death when combined with opioids^[1]

Purported mechanism

Positive allosteric modulator of the GABA-A receptor at the benzodiazepine binding site (α-γ subunit interface), enhancing chloride ion conductance and consequent neuronal inhibition. The intermediate half-life sits between short-acting alprazolam and long-acting diazepam/clonazepam, making lorazepam a clinically versatile choice.0 Metabolized by glucuronidation rather than CYP, so unlike alprazolam and diazepam, lorazepam has minimal CYP-mediated interactions, and the lack of active metabolites makes it the preferred benzodiazepine in elderly patients and in hepatic impairment. Tolerance, dependence, and significant withdrawal syndrome on abrupt discontinuation; slow taper essential after extended use^[1].

Pharmacopedia is intended for reference. Nothing here is advice. In an emergency call 911; US Poison Control 1-800-222-1222. See the full disclaimer.

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 FDA Prescribing Information, Ativan (lorazepam), Bausch/Pfizer, current revision. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017794s044lbl.pdf
↑ U.S. Food and Drug Administration. Drug Safety Communication: FDA requiring Boxed Warning updated to improve safe use of benzodiazepine drug class. September 23, 2020.
↑ U.S. Food and Drug Administration. Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines. August 31, 2016.
↑ Wilson KC, Reardon C, Theodore AC, Farber HW. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving intravenous benzodiazepines. Chest. 2005;128(3):1674-1681.

[ativan-label-1] 1.0 ^1.1 ^1.2 ^1.3 FDA Prescribing Information, Ativan (lorazepam), Bausch/Pfizer, current revision. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017794s044lbl.pdf

[2] U.S. Food and Drug Administration. Drug Safety Communication: FDA requiring Boxed Warning updated to improve safe use of benzodiazepine drug class. September 23, 2020.

[3] U.S. Food and Drug Administration. Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines. August 31, 2016.

[4] Wilson KC, Reardon C, Theodore AC, Farber HW. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving intravenous benzodiazepines. Chest. 2005;128(3):1674-1681.

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